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Psychotomimetic effects of PCP, LSD, and Ecstasy: Pharmacological models of schizophrenia?

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Facts box Phencyclidine (PCP), ketamine, D-lysergic acid diethylamide (LSD) and 3, 4-methylenedioxy-methamphetamine (MDMA) have been variously referred to as schizophrenomimetics, psychotogens, or psychotomimetics. There have been many reports that these drugs can induce psychotic symptoms (hallucinations, delusions, formal thought disorder, or catatonia-like abnormalities) in the absence of delirium. here is abundant evidence that PCP induces psychotic disorder beyond the acute symptoms of intoxication. There is no clear evidence that either LSD or MDMA induces psychotic disorder, let alone schizophrenia, in individuals who did not have vulnerability to schizophrenia premorbidly. PCP and ketamine are noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) glutamatergic receptor that bind at the intrachannel site of the receptor to prevent calcium ion flux into the cell. LSD is a serotonin-like hallucinogenic indoleamine that acts as an agonist at the serotonin-subtype-2A (5HT2A) receptor, and MDMA is an indirect serotonin agonist. Rodent and primate models induced by PCP and analogues have been presented as models of human schizophrenia, with construct validity, showing homologous behavior, cognitive deficits, alterations in regional brain activation, and underlying neuronal dysfunction, to PCP-induced psychotomimetic effects in healthy volunteers and patients with schizophrenia. Ketamine is considered to be a safe and valid model of PCP psychosis and applicable to preclinical human studies. More translational science is needed to relate animal findings to humans and vice versa. In this chapter, the potential role of glutamatergic and serotonergic neurotransmitter systems in the pathophysiology of schizophrenia is examined from the perspective of the psychotomimetic effects of i) phencyclidine (PCP) and ketamine, noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) glutamatergic receptor that bind at the intrachannel site of the receptor to prevent calciumion flux into the cell; ii) D-lysergic acid diethylamide (LSD), a serotonin-like hallucinogenic indoleamine that acts as an agonist at the serotonin-subtype-2A (5HT2A) receptor; and iii) 3, 4-methylenedioxy-methamphetamine (MDMA), an indirect serotonin agonist.
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
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The psychotomimetic effects of PCP, LSD and MDMA:
Pharmacological models of schizophrenia?
Vibeke S. Catts1, Stanley V. Catts1,2
1School of Medicine, The University of Queensland; 2Mental Health Centre, Royal
Brisbane and Women’s Hospital
In this Review the potential role of glutamatergic and serotonergic neurotransmitter
systems in the pathophysiology of schizophrenia is examined from the perspective of the
psychotomimetic effects of 1) phencyclidine (PCP) and ketamine, non-competitive
antagonists of the N-methyl-D-aspartate (NMDA) glutamatergic receptor that bind at the
intra-channel site of the receptor to prevent calcium ion flux into the cell 2) D-lysergic
acid diethylamide (LSD), a serotonin-like hallucinogenic indoleamine that acts as an
agonist at the serotonin-subtype-2A (5HT2A) receptor, and 3) 3,4-methylenedioxy-
methamphetamine (MDMA), an indirect serotonin agonist. These drugs, variously called
hallucinogens, schizophrenomimetics, psychotogens or psychotomimetics, have in
common reports that they can induce psychotic symptoms (hallucinations, delusions,
formal thought disorder, or catatonia-like abnormalities) in the absence of delirium. The
primary question addressed herein, whether PCP-induced psychosis is a valid model of
schizophrenia, gives rise to additional questions about the validity of ketamine challenge
at subanaesthetic doses in humans as a model of PCP psychosis, and in turn, questions
about the validity of drug-induced changes in non-human animals (rodents, monkeys)
treated with PCP and its analogues (ketamine or dizocilpine [MK-801]) as models of
PCP-induced psychosis.
A model is defined as any experimental preparation developed for the purpose of
studying a condition in the same or different species (1). In evaluating disease models the
following criteria (2) apply:
How similar phenomenologically is the behavioural performance of the model
compared to the symptoms of the disease? (face validity)
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How closely does the model replicate the hypothesised pathophysiology or
theoretical process underlying the disease? (construct validity)
How accurately can predictions be made about the disease based on performance
of the model? (predictive validity).
An extension of construct validity is aetiological validity, which refers to the degree of
equivalence between the model-inducing manipulation and the aetiological factors
causing the disease. Models must be reliable, in the sense that their performance can be
accurately measured. Ideally, models also display discriminant validity (measures of the
model’s performance are un-correlated with those of models of other diseases) and
convergent validity (multiple measures of the performance of the same model are highly
correlated). Hence, the validity of a model relies as much on aetiological validity (how
the model is induced or created) as on the validity of measures of its performance, which
in turn depend on the validity of measures of the disease itself.
Modelling schizophrenia is difficult at all levels (2, 3). There are no agreed upon
pathognomonic features; many of the symptoms are based on verbal report and cannot be
measured in animals; the aetiology is multi-factorial and specific factors are unknown;
the pathophysiology is ill-defined and may be heterogenous; and most disease measures
applicable to in vivo animal models, e.g. deficits in working memory or prepulse
inhibition (PPI), are not specific to schizophrenia. Rapid progress in therapeutics in other
complex diseases (e.g. cancer) has been attributed to availability of valid animal and
cellular models, and slow progress in schizophrenia attributed to the lack of these models
(4). Some argue that drug development in schizophrenia has not progressed appreciably
since the introduction of chlorpromazine (4-7). Others reason that only symptom
reducing, and not disease modifying, treatments will arise when disease models for
testing new drugs are based solely on symptom similarity and its behavioural
measurement, as is the case with amphetamine-induced hyperlocomotion in rodents (e.g.
8, 9). These considerations imply that a useful disease model of schizophrenia will have
more than face and construct validity by generating accurate predictions about the human
pathophysiology and likely clinical effectiveness of novel pharmacotherapies. This
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Review aims to assess the relative validity of NMDA antagonist models of schizophrenia
compared with serotonergic models based on LSD- and MDMA-induced psychosis.
Human studies
For each drug of interest, this Section reviews the evidence for psychotomimetic effects
in humans, in terms of induced transient symptoms with acute dosing, and the
epidemiological association between formal psychotic disorder and chronic abuse. The
phenomenological similarity of drug-induced symptoms and the clinical features of
schizophrenia is closely examined. Where available, human neuroimaging and clinical
biomarker studies are considered for comparison of drug-induced effects and deficits
seen in schizophrenia. Ketamine is included in the review because most experimental
evidence supporting the validity of the PCP model arose from studies using ketamine in
humans. The literature on LSD and MDMA is briefly reviewed for comparative purposes.
Phencyclidine (PCP)
Phencyclidine [1-(1-phenylcyclohexyl)piperidine hydrochloride] was synthesized in 1956
(10). Preclinical testing indicated that PCP might be a safe intravenous (IV) anaesthetic
because it induced analgesia and anaesthesia without circulatory or respiratory depression
(10). PCP was tested as an anaesthetic in about 3000 patients in the late 1950’s. The term
‘dissociative anaesthetic’ was coined because PCP induced a state of detachment, and
dissociation from painful and environmental stimuli, without causing unconsciousness:
during anaesthesia the patient remained immobile with fixed sightless staring, absent
facial expression, and open mouth (11). PCP is highly lipid soluble and readily crosses
the blood-brain barrier, inducing CNS effects within minutes of IV injection. The serum
half-life of PCP was reported to vary between 4 to 72 hours (12, 13). When PCP was
used as an IV anaesthetic, patients became responsive to auditory stimuli within 60
minutes (14) though orientation remained poor for up to 4 hours (15). Intravenous PCP
induced dose-dependent effects: at doses of about 0.25 mg/kg (about 0.2 μM serum
concentration), it produced complete insensibility to pain; at doses above 0.5 mg/kg
(about 0.4 μM serum concentration), patients became delirious; and when doses were
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increased towards 1 mg/kg (up to 0.8 μM serum concentration), severe rigidity, catatonia,
and convulsions ensued (14, 16-18).
Early clinical use revealed that many patients experienced psychotic symptoms as they
emerged from PCP anaesthesia (11, 14, 15, 19). Emergence phenomena included:
agitation, bizarre behaviour, paranoia, formal thought disorder, hallucinations, and
delusions, typically lasting for 12-72 hours but occasionally persisting for up to 10 days
(14, 19). Symptoms were schizophrenia-like, especially the motor changes (15). Flat
facies, fixed staring, manneristic grimacing, generalized rigidity, and plastic stiffness
very similar to ‘cerea flexibilitas’ occurred. Stereotypic verbalizations of select phrases
were uttered. PCP-induced agitation was associated with atypical movements: head
rolling or shaking the head from side to side was common. Attempts to prevent
emergence reactions by pre-treatment with haloperidol or diazepam were relatively
unsuccessful: diazepam (20) appeared to be as effective as haloperidol (21).
Phencyclidine was withdrawn from the market for human use in 1965. A veterinarian
formulation was introduced in 1967 but because of a growing abuse problem all legal
manufacture of the drug was ceased in 1979.
Despite its propensity to cause adverse reactions, PCP abuse became widespread. It was
relatively inexpensive to manufacture and the starting materials, used in many industrial
processes, were readily available (22). Illicit PCP use first appeared in 1965 on the West
Coast of the USA (13). Initially the drug was ingested orally (called the ‘PeaCe Pill’).
Slow oral absorption resulted in inadvertent high dosing and frequent adverse reactions,
limiting its appeal (22). Once street users discovered that the dose could be lowered and
self-titrated by smoking PCP added to cigarettes, illicit use escalated. National surveys in
the USA indicate that peak use of PCP occurred between 1977 and 1979 (23, 24).
Between 1976 and 1977 the National Institute of Drug Abuse (NIDA) reported a
doubling (from 3% to 5.8%) of the number of 12- to 17-year-old users of PCP, and a 50%
increase (from 9.5% to 13.9%) in 18- to 25-year-old users (22). A survey of 319 adult
users reported negative events on 100% of use occasions (25), including speech
difficulties (80%), perceptual disturbances (75%), restlessness (76%), disorientation
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(63%), anxiety (61%), paranoia (34%), hyper-excitability (27%), irritability (22%) and
mental confusion (22%). The extent to which PCP posed serious problems at that time
was indicated by the US Drug Abuse Warning Network (DAWN), a national reporting
system for drug-related deaths and hospital emergencies. Data from the 662 participating
emergency centres showed 111 events in October 1976 versus 54 events in October 1974;
and reports of PCP-related deaths increased over roughly the same period from 17 in
April 1976 to 30 in March 1977 (22). Undesirable psychological reactions were frequent.
In a 1978 study at one urban psychiatric hospital, PCP was detected by blood analysis in
78.5% of 150 consecutive involuntary admissions (26).
Because PCP abuse occurred as a regional epidemic clear evidence of an association with
formally diagnosable psychotic disorder emerged. In the mid- to late-1970’s many case
series reports of PCP-related psychotic disorder admitted to mental health services were
published (e.g. 27-42), describing close temporal and regional associations between
changes in illicit PCP production, levels of PCP abuse among young people, and changes
in rates of emergency presentation of PCP-related psychotic disorder in this age group.
Washington DC, a major centre for PCP production and abuse in the early 1970’s,
illustrates this point. The first hospital admissions for PCP psychosis occurred in late
1973. Thereafter, the admission rate increased rapidly to a peak in February 1974, when
one-third of all first psychiatric admissions were diagnosed with PCP psychosis. In
March 1974, police closure of a local illegal PCP laboratory resulted in a marked drop to
no more than three new cases of PCP-related psychosis per month in April, May, and
June 1974. A new epidemic of PCP psychosis occurred in 1975 and 1976. In early 1976
law enforcement agencies pronounced the Washington metropolitan area the PCP capital
of the country, and increased raids on local illegal PCP laboratories. Thereafter a slow but
steady decline in psychiatric admissions for PCP psychosis occurred (29).
Although a strong relationship between PCP abuse and psychotic disorder was evident,
the face validity of PCP-induced psychosis as a model for schizophrenia also requires
close phenomenological similarity between the two disorders. To make this comparison,
three types of PCP-related conditions need to be distinguished: acute intoxication without
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delirium (a ‘bad trip’); acute intoxication with delirium; and the more persistent drug-
induced psychotic disorder (38). Duration of acute PCP intoxication parallels the half-life
of the drug. Symptom severity is dose-dependent. Acute intoxication without delirium
lasts about 3-8 hours and presents with restlessness, agitation, hallucinations, delusions,
nystagmus, hypertension, tachycardia, ataxia, slurred speech, and hyper-reflexia (38, 43,
44). PCP-induced delirium represents a more profound degree of toxicity, which can
persist for a week. Dose-dependent clinical features include clouding of consciousness,
disorientation, toxic psychosis, vomiting, hyper-salivation, spasticity, EEG slowing or
seizures, and respiratory depression (33, 38, 43, 45, 46).
In addition to acute intoxication syndromes, PCP induces psychotic disorder that is very
similar to schizophrenia or schizoaffective disorder in the absence of delirium (22, 27-29,
31, 32, 34, 36-38, 40, 41, 47-49). The duration of PCP-related psychosis bears no
relationship to ingested dose or drug half-life. It characteristically shows sudden
resolution within 2 to 4 weeks (29, 41), though on occasion persists for months. Patients
with PCP-related psychosis could not be distinguished from schizophrenia patients on the
basis of presenting symptoms (31, 33). All domains of schizophrenic symptomatology
seemed to be represented. Prominent positive symptoms were reported: paranoia; and
persecutory and grandiose delusions (31, 34, 36, 37, 39, 48, 50) often with bizarre
Schneiderian qualities (33, 40, 51); and hallucinations in all modalities (31, 33-37, 39, 46,
48, 50). Formal thought disorder with loosening of associations, cognitive
disorganization, perseveration or thought blocking occurred (27, 33, 34, 36-39, 50).
Catatonic behaviour in a variety of forms was almost universally present with PCP-
psychosis: inappropriate and unpredictable behaviour; excitement and violence; nudism;
mannerisms and stereotypies; and catatonic posturing and mutism (13, 31, 33-41, 45, 46).
Features resembling negative symptoms also occurred: blunted affect (46); apathy and
emotional disengagement (38); social withdrawal and autistic behaviour (27, 31, 37); and
amotivation (27, 31, 37, 38, 46).
Despite marked similarities between PCP psychosis and schizophrenia, cross-sectionally
there were atypical features: a predominance of visual or haptic hallucinations over
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auditory hallucinations; distortion of time appreciation and body image disturbance; and
prominent somatosensory deficits, especially diminished proprioception and pain
perception (19, 51, 52). As well, there were differences in psychiatric history with a
relatively high proportion of patients not having a family history or personal history of
schizophrenia, and an absence of previous psychiatric history or evidence of prodromal
psychosocial deterioration (22, 28, 29, 38, 47, 49, 53). Although most cases of PCP-
psychosis resolved within two weeks without sequelae (29), about 25% of patients went
on to have a typical history of schizophrenia (37). This subgroup of patients took months
rather than weeks to recover from the first PCP-related psychotic episode, tended to have
a family history of schizophrenia, and a personal history of other psychiatric disorder (29,
31, 39).
A point of disagreement in the clinical literature concerns the effectiveness of dopamine
D2 receptor (D2R) antagonist antipsychotics in the treatment of acute PCP psychosis.
Some studies concluded benzodiazepines (13, 27, 33, 34, 45) were preferable to
haloperidol or chlorpromazine in PCP intoxication whilst others favoured haloperidol
(35, 42, 54, 55). Apart from one group (42, 55), most agreed that antipsychotic and
sedatives may reduce agitation, however no pharmacological treatments appeared to
shorten the course of the psychotic illness (13, 34). Luisada & Brown (37) noted that in
the cases subsequently re-diagnosed with schizophrenia, acute response to antipsychotic
drugs was faster and superior after re-diagnosis than during the first PCP-induced episode
of psychosis. The equivocable response of PCP psychosis to D2R antagonists was the
first clue that PCP psychosis may not be primarily linked to dopamine dysregulation.
Experimental studies using PCP in hospitalized patients with chronic schizophrenia
supported the view that the psychotomimetic effect of PCP was directly related to
mechanisms producing the symptoms of schizophrenia (56-58). Luby et al. (56) reported
that immediately after IV PCP, patients showed an acute intensification of thought
disorder and inappropriate affect: “it was as though … the acute phase of their illness had
been reinstated”. Chronic patients frequently manifested symptom relapses persisting for
more than a month after a single IV dose of PCP, indicating that PCP may act on a
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fundamental disease process. That is, PCP exaggerated pre-existing, or precipitated an
acute relapse of previously experienced, phenomenology rather than added qualitatively
different psychotic symptoms. Response to PCP in patients was distinctly different to that
with LSD or mescaline which produced a milder and brief change in the level of
symptoms, mainly by adding qualitatively different symptoms such as kaleidoscopic
visual hallucinations (49, 50, 56, 57). Providing the first suggestion that prefrontal
mechanisms were directly related to PCP effects, Itil et al. (58) found that leucotomised
patients with schizophrenia did not show as marked a response to PCP compared to un-
leucotomised patients.
Experimental studies using PCP in human volunteers (HVs) also supported the view that
PCP comprehensively induced symptoms resembling schizophrenia (52, 53, 56, 59, 60).
Luby et al. (56) gave 9 HVs PCP in a subanaesthetic dose (0.1 mg/kg IV). All subjects
experienced “body image changes” (impaired ability to distinguish between self and non-
self stimuli, feelings of depersonalization, and a sense of unreality), “estrangement”
(profound sense of aloneness or isolation, of being detached from the environment), and
“disorganization of thought” (inability to maintain a set, frequent loss of goal ideas,
impairment of abstract attitude, blocking, neologisms, word salad, and echolalia). Most
subjects experienced negativism and hostility (child-like oppositional behaviour and
catatonia-like reactions); and about one third showed repetitive motor behaviours
(rhythmic body movements, including rocking, head-rolling, and grimacing). In another
study of 12 HVs, PCP (0.075-0.1 mg/kg IV) induced positive symptoms (auditory
hallucinations and thought disorder), negative symptoms (blunting, apathy and
amotivation), catatonic features (psychomotor retardation, negativism and catatonic
immobility), and cognitive deficits (associative learning and abstract reasoning deficits)
(52). In contrast to LSD or mescaline, PCP in HVs induced perseveration and
concreteness, and nystagmus: in common with LSD and mescaline, PCP induced body
image disturbance, depersonalization, and disturbances in time appreciation (52). One
study of seven HVs given 12 mg PCP by slow IV injection provided detailed descriptions
of phenomenology (60). After a brief period of disorientation cleared, PCP caused
marked cognitive deficits affecting “the function that combines, unifies, and integrates all
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available information into a field which is meaningful” and preventing “goal-directed
behaviour”. Formal thought disorder (both loosening and concreteness) was apparent,
including “catatonic-like perseveration”. Sensory filtering deficits occurred so that the
subject “was unable to focus actively on particular areas of his perceptual field [and] had
become a victim of all inflowing stimuli but could not screen out the irrelevancies”. Also,
sensory distortions were experienced, like hearing your voice “seem to come from a
distance as if someone else were speaking” whilst intellectually knowing that it was
yourself speaking. Feelings of passivity emerged so that “the subject saw his arms and
legs move and yet did not have the feeling that he himself was making these
movements”. A profound sense of apathy and amotivation accompanied the PCP-induced
psychotomimetic effects. Bakker and Amini (60) hypothesized that PCP produced a
converse psychic state to that induced by LSD and psilocybin.
Moreover, early neurocognitive studies in HVs demonstrated PCP-induced deficits
resembling those seen in schizophrenia. Rosenbaum et al. (53) compared three groups of
HVs, 10 receiving PCP (0.1 mg/kg IV), 10 receiving LSD orally (1 ug/kg), and five
receiving 500 mg amobarbital sodium IV (amphetamine 15 mg added to counter
drowsiness associated with the barbiturate). Using a crude measure of attention, only PCP
(i.e. not LSD or barbiturate) produced a deficit equivalent to that observed on the same
test in patients with schizophrenia. On a motor learning task, the performance of only the
PCP treated HVs dropped to the level of patients with schizophrenia. Cohen et al. (59)
compared the effects of PCP, LSD and amobarbital sodium (amphetamine 15 mg added)
in three groups of HVs. In a test of symbolic thinking (proverb interpretation), only PCP
subjects (i.e. not LSD or barbiturate) showed deficits in symbolic thinking quantitatively
equivalent to those seen in groups of patients with schizophrenia. Similar findings were
made in relation to a test of sustained attention (serial sevens).
In summary, the psychotomimetic effects of PCP were first recognised as emergence
phenomena when it was used as an anaesthetic. During a PCP abuse epidemic in the
United States, it became evident that PCP induced formal psychotic disorder, even in
individuals without evidence of predisposition to schizophrenia. The phenomenology of
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the psychotomimetic effects of PCP were schizophrenia-like in range and quality,
whether observed as anaesthetic emergence phenomena, presenting symptoms of PCP-
induced psychotic disorder, or behavioural change induced by experimental use of PCP
in patients with schizophrenia or HVs. Clinicians who observed PCP-induced symptoms
recognised signs that Bleuler (‘loosening’ plus ‘concreteness’) and Kraepelin
(‘weakening…volition’ plus ‘loss of inner unity of the activities of intellect, emotion and
volition’) deemed primary to, and processes (e.g. sensorimotor gating, [61]) that
psychologists considered characteristic of, schizophrenia. Because PCP was made illegal
for use in human research in 1965, no studies measuring the effect of PCP on putative
biomarkers of schizophrenia (e.g. prepulse inhibition [PPI], smooth pursuit eye
movement [SPEM], P50 suppression or mismatch negativity [MMN]) or functional
neuroimaging measures, were carried out in patients with schizophrenia or HVs. This
type of human research had to await the introduction of ketamine, a safer and less potent
psychotomimetic analogue of PCP.
Ketamine
Analogues of PCP were researched as alternative dissociative anaesthetic agents that
might have fewer adverse reactions than PCP, the most important being ketamine [2-(2-
chlorophenyl)-2-(methylamino)-cyclohexanone]. Ketamine was first synthesised in 1961,
first tested in human volunteers in 1964 (62), and first approved for general clinical use in
1970. It is used intravenously (analgesic dose, 1-2 mg/kg; anaesthetic dose, 5-10 mg/kg),
intramuscularly (analgesic dose, 1.5-2mg/kg; anaesthetic dose, 4.0-6.0 mg/kg), and less
frequently as an oral (100-300 mg/kg) anaesthetic (63, 64). Ketamine is highly lipid
soluble and readily crosses the blood-brain barrier, inducing CNS effects within seconds
of IV injection. The plasma half-life of ketamine has been reported to be 1-2 hours (65).
When ketamine is used intravenously, duration of anaesthesia is dose-dependent and may
be as brief as 30 minutes (66, 67) with complete recovery taking several hours. Because
ketamine does not depress respiratory or cardiovascular systems, it was widely used as a
field anaesthetic by the US army during the Vietnam War and continues to be marketed
as a valuable anaesthetic for human procedures, especially in children, and in veterinarian
practice.
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While ketamine anaesthesia can produce emergence phenomena in up to 30% of
anaesthetised adults, the symptoms are not as severe as those produced by PCP (49, 68).
Emergence symptoms include alterations in mood state and body image, dissociative and
out of body experiences, floating sensations, vivid dreams or illusions, ‘weird trips’, and
occasionally delirium (64). Between 10-15% of post-operative patients show
hallucinatory reactions (69, 70). Ketamine emergence phenomena are dose-dependent
and age-related, with an incidence of less than 10% in patients less than 16 years old (64).
Compared to standard anaesthesia (halothane/nitrous oxide), ketamine does not cause an
excess of emergence reactions in children (71). In adults, pre-treatment with droperidol or
haloperidol is inferior to benzodiazepines in preventing vivid emergence reactions and
delirium following ketamine (reviewed in 64). In summary, when used as an anaesthetic
ketamine induces emergent psychotomimetic effects qualitatively similar to PCP but
quantitatively substantially less intense, in line with its more than 10-fold lower PCP-like
activity (72) and about 30-fold lower NMDA receptor complex binding affinity (73, 74).
Despite warnings about its abuse potential (75), ketamine eventually appeared on the
streets (known as ‘Special K’, ‘Vitamin K’ or ‘K’) in the early 1970’s (25, 76) in the
same way that PCP did in the 1960’s. Ketamine use was popularised by publication
accounts (77). In 1978 ketamine was authoritatively described as the “ultimate
psychedelic” (78). Ketamine is typically inhaled or injected intramuscularly (79).
Ketamine users try to achieve or ‘fall into’ a ‘k-hole’ of social detachment lasting up to
an hour. This experience includes a distorted sense of space, so that a small room appears
the size of a football field, and an indistinct awareness of time, so that a few minutes
seems like an hour (80). Physical immobilization and disengagement from time and space
is associated with psychedelic experiences such as spiritual journeys, interaction with
famous or fictitious people, and hallucinatory visions. The k-hole ends abruptly though
can quickly be re-entered with another injection of ketamine (79).
Unlike PCP, ketamine is difficult to manufacture and most recreational users acquire it
through diversion of prescription product or theft from veterinary supplies (81). In the
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1970’s and 80’s recreational use was restricted to a select group of the intelligentsia.
Expanded use emerged in the context of the subcultural music phenomenon known as
‘acid house music’ and large scale parties called ‘raves’ (76, 82). Although there has been
a growing number of reports of illicit use of ketamine in many countries (63), in
comparison to other club drugs such as Ecstasy (MDMA), its use remains restricted to a
small number of polysubstance abusers (81, 83). Currently, the lifetime prevalence of
ketamine use is in the order of 0.7 – 2.6%, depending on the age and nationality of the
study populations (83). Adverse events specifically related to illicit use of ketamine are
difficult to ascertain because 80% of patients presenting to hospital emergency
departments reporting ketamine use also report concurrent use of other drugs. Reasons
for going to the emergency department include overdose (47%), unexpected reaction
(28%), chronic effects (11%), or seeking detoxification (9%)(80).
Because there have been no regionally or temporally circumscribed epidemics of illicit
ketamine use, it has been difficult to establish the psychiatric consequences of its abuse.
The main evidence for a link between ketamine abuse and psychotic disorder is based on
the occasional psychiatric case series report (e.g. 77, 84, 85); survey data of ketamine
users who reported auditory hallucinations, paranoia, loose associations, and unusual
thought content among the behavioural effects of ketamine (86); and psychometric data
on small groups of ketamine users (87-90). Chronic ketamine abusers had higher scores
on tests of delusional ideation and schizotypal symptomatology, which increased with
acute dosing of ketamine (87-90), but also remained elevated at short-term follow-up (88,
89). The very limited literature on the neurocognitive effects of ketamine abuse suggests
acute induction of impairments of working, episodic and semantic memory (89), and with
chronic ketamine use, induction of chronic impairments in episodic memory (90). In
summary, there is evidence of an association between ketamine abuse and increased
proneness to quasi-psychotic symptoms and neurocognitive deficits, and psychotic
disorder resembling schizophrenia, however the research supporting these associations is
under-developed and does not define the strength of these associations.
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In contrast to patient studies using PCP, experimental use of ketamine in hospitalised
patients with chronic schizophrenia is considered ethically acceptable (91). This is partly
based on experience using ketamine as an anaesthetic for surgery in patients with
schizophrenia stabilised on antipsychotic medication, which was associated with only
brief mild post-operative disturbance and not major psychotic relapse (92). Lahti et al.
(93) gave subanaesthetic does of ketamine (0.1, 0.3 and 0.5 mg/kg IV) to 9 hospitalised
patients with schizophrenia stabilised on haloperidol (0.3 mg/kg/day for at least 12
weeks). Six of the 9 patients were withdrawn from haloperidol for more than 4 weeks
before being re-challenged with ketamine. In patients on haloperidol, ketamine induced
20 minutes post-injection about a 3-fold increase (dose-related) in BPRS psychosis
scores, which returned to baseline within 90 minutes (though four out of the 9 patients
reported delayed recurrence of psychotic symptoms for 24 hours after ketamine). In
patients off haloperidol, ketamine induced dose-dependent increases in BPRS psychosis
scores. Although ketamine-induced BPRS psychosis scores were slightly higher in
patients off haloperidol compared with the same patients on haloperidol, it was clear that
haloperidol provided little protection against the psychotomimetic effects of ketamine.
Qualitatively there was remarkable similarity between the themes and content of
psychotic symptoms induced by ketamine and symptoms associated with the patients’
schizophrenic illness (93). In a replication study, Malhotra et al. (94) gave ketamine (0.77
mg/kg IV over one hour) to 13 hospitalised patients with schizophrenia and neuroleptic
free for at least 2 weeks, and 16 HVs. In both unmedicated patients and HVs, ketamine
produced significant increases in total BPRS scores, reflecting increased thought disorder
and increased negative symptoms (withdrawal-retardation). Neurocognitive testing
showed unmedicated patients and HVs both had significant ketamine-induced
impairments in verbal recall and recognition memory, patients performing worse than
HVs. When re-challenged with ketamine, patients subsequently stabilised on clozapine
showed significantly blunted ketamine-induced increases in BPRS psychosis ratings (95).
In another replication, Lahti et al. (96) gave ketamine (0.1, 0.3 and 0.5 mg/kg IV) to 17
hospitalised patients with schizophrenia stabilised on haloperidol (0.3 mg/kg/day for at
least 12 weeks) and 18 HVs. Patients and HVs showed significant ketamine-induced
increases on the three components of the BPRS psychosis score (thought disorder,
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hallucinations, and delusions), and the BPRS withdrawal score, which reversed within 90
minutes post-injection. Approximately 70% of patients experienced ketamine-induced
symptoms strikingly reminiscent of their usual psychotic symptoms during an illness
exacerbation. In summary, unlike PCP the reaction to ketamine was mild and very brief
in medicated patients, and more pronounced though still brief in unmedicated patients.
Experimental studies using ketamine in HVs have mainly focused on neurocognitive
measurement. However, the recent challenge (97) to the view that ketamine is a
psychotomimetic agent demands a brief review of the symptom-based literature.
Ghoneim et al. (98) were the first to investigate the behavioural effects of subanaesthetic
doses of ketamine in 34 HVs. Intramuscular ketamine (0.25 and 0.5 mg/kg) induced self-
reported visual hallucinations (not auditory) in 75% of subjects at 0.25 mg/kg and 77% at
0.5 mg/kg. A minority of subjects also reported paranoid feelings of being manipulated or
controlled during the experiment. In the second study, 18 HVs were given ketamine IV
for 40 minutes (99). Ketamine 0.5 mg/kg (but not 0.1 mg/kg) induced significant
increases in BPRS psychosis score 10 minutes from onset of the infusion until 15 minutes
after the ketamine infusion was ceased. Ketamine significantly increased each of the four
positive symptom sub-component scores (thought disorder, hallucinatory behaviour,
suspiciousness, and unusual thought content or delusions). Hallucinatory behaviour was
limited to illusionary experiences. Ketamine also induced significant increases in the
BPRS hostility-suspiciousness factor score (hostility, suspiciousness, uncooperativeness,
and grandiosity), and significant increases in BPRS negative symptoms. Comparable
ketamine-induced symptoms to those noted in the two initial HVs studies have been
observed in the many subsequent challenge studies (100-107). This comparability
extended to the fine grained level of symptom structure, as was evident when the
component structure of ketamine-induced conceptual disorganization in HVs was shown
to closely overlap with the structure of formal thought disorder in patients with
schizophrenia (101, 102). In summary, ketamine induces attenuated rather than frank
hallucinations and delusions at the low doses typically used in experimental studies of
HVs, and the impression that it is not psychotomimetic is inconsistent with the high rates
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of emergence phenomena when used as an anaesthetic in adults and elicitation of frank
psychotic symptoms when studied in patients with schizophrenia.
Experimental studies of the effects of ketamine in HVs confirm that ketamine-induced
neurocognitive deficits show striking resemblance to those seen in schizophrenia (108,
109). In contrast to the crude assessments used in PCP studies, tests used in ketamine
studies have good psychometric properties and can differentiate types of deficits (e.g.,
episodic versus working memory) and cognitive dysfunctions (e.g., encoding versus
retrieval). Episodic memory (EM) refers to memory for events (sometimes called
declarative or explicit memory). EM can be tested at the level of recall (generating a list
of words or a story from memory) or recognition (deciding whether words have been
previously presented). Deficits in recall may be caused by impaired encoding or retrieval
of material; whilst deficits in recognition memory are caused by impaired encoding. EM
deficits implicate medial temporal lobe structures, including the hippocampal formation.
Prefrontal structures support higher order information processing such as: short-term
online memory used to maintain and manipulate information (called working memory);
executive functions (planning, decision making, and abstract reasoning); selective
attention and vigilance; and verbal fluency. Psychomotor speed is particularly sensitive to
prefrontal dysfunction. Inhibition is central to performing prefrontal-related tasks, which
is subserved by intracortical circuits, and feedback loops with subcortical structures,
especially the thalamus and basal ganglia (110-112).
Deficits in EM are consistently induced by ketamine in HVs (98, 99, 103, 107, 113-119),
a result not seen with acute amphetamine challenge (104). A substantial literature
indicates selective deficits at the level of encoding (recognition memory) rather than at
the level of retrieval (99, 103, 107, 114, 119-122), a selective effect consistent with
differential system dysfunction (123). Ketamine also induces deficits in working memory
in HVs (100, 104, 107, 121, 124), with greater impact on manipulation compared with
maintenance of information in working memory (108, 124), a distinction reviewed
elsewhere (123). Deficits in working memory are not observed in acute amphetamine
challenge (104). Ketamine induces deficits in other prefrontal functions including:
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abstraction deficits in relation to proverb interpretation (115, 116); perseverative errors in
sorting tasks (99, 115, 116); impaired response inhibition (119); and impaired vigilance
(104, 116), the latter not seen with acute amphetamine challenge (104). Most studies
show that ketamine induces deficits in selective attention (99, 103, 115, 125, 126), but
not all (100, 107). Although only some studies report verbal fluency deficits (99, 100,
114, 116) and others do not (107, 115, 119, 127, 128), verbal fluency deficits are found in
chronic ketamine recreational users (88, 89). Psychomotor speed is also slowed by
ketamine (113, 121, 129). In summary, the pattern of neurocognitive deficits induced by
ketamine resembles that seen in schizophrenia, and implicate dysfunction in the
prefrontal cortex (130) and medial temporal lobe (131).
More proximal evidence that ketamine induces dysfunction in brain systems affected by
schizophrenia has been provided by regional activation studies in HVs. Regional brain
activation changes can be assessed using functional Magnetic Resonance Imaging (fMRI)
to measure the Blood Oxygen Level Dependent (BOLD) effect, an index of regional
cerebral blood flow (rCBF) change, and Positron Emission Tomography (PET) to
measure changes in regional metabolic rate, either in terms of oxygen ([15O]water) or
glucose ([18F]flurodeoxyglucose: FDG) uptake. As functional imaging studies of
schizophrenia have more often than not found reduced activation prefrontally (e.g., 132,
133-135), especially in the cingulate cortex (e.g., 136, 137-140), and medial temporal
lobe (e.g., 133, 135, 141), it was predicted that ketamine would induce decreases in
regional brain activation in the same areas in HVs. However, contrary to hypothesis,
acute ketamine dosing increases activation prefrontally (106, 142-147) including the
cingulate cortex (106, 142, 147), and thalamus (106, 146-148). No studies reported
changes in the hippocampus or medial temporal lobe. Two functional imaging studies of
the effects of ketamine in patients with schizophrenia have been reported: one found
ketamine-induced blood flow increases in frontal and cingulate regions (142); the other
found ketamine-induced increases in rCBF in anterior cingulate and reduced rCBF in
hippocampus (93).
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Clinical biomarkers known to be abnormal in schizophrenia have also been assessed in
experimental studies of ketamine in HVs. Contrary to expectation, deficits in prepulse
inhibition (PPI) analogous to those seen in schizophrenia have not been observed in HVs
administered ketamine (149, 150). Indeed, three independent studies showed PPI
augmentation after ketamine administration to HVs (127, 151, 152). A single study of
schizophrenia-like oculomotor abnormalities in HVs administered ketamine showed
ketamine-induced smooth pursuit eye tracking deficits (114). Ketamine does not
significantly reduce P50 suppression (149, 150). Deficits in MMN analogous to those
observed in schizophrenia have been reported in HVs administered ketamine (153, 154).
To conclude, ketamine produces less potent PCP-like psychotomimetic effects
commensurate with its more than 30-fold lower NMDA receptor complex binding
activity (73, 74) compared with PCP. Qualitatively however, the two analogues induce
equivalent psychotomimetic phenomena at the level of symptoms, neurocognition, and
regional brain activation. It can be concluded therefore that ketamine challenge studies in
HVs have face (and to a degree, construct) validity as preclinical models of PCP
psychosis, and in turn as models of schizophrenia. Additional support for PCP-related
models may be offered by comparing them with serotonergic models to examine
evidence for discriminant validity. This will be sought by reviewing the psychotomimetic
effects of the 5HT2A agonist, LSD, and the indirect serotonergic agonist, MDMA.
Lysergic acid diethylamide (LSD)
LSD (D-lysergic acid diethyamide) was originally synthesised in 1938 but its
psychotomimetic effects were not discovered until 1943 when one of its co-discoverers
experienced “fantastic visions of extraordinary vividness accompanied by a kaleidoscopic
play of intense coloration” following inadvertent ingestion (155). LSD acts primarily as a
functional agonist at the 5HT2A receptor (156). LSD quickly distributes to the brain and
other body compartments, is metabolised in the liver and kidneys, and excreted in faeces.
Effects of LSD are felt within an hour after ingestion and can last from 6 to 12 hours,
although LSD cannot be detected in brain 20 minutes after ingestion. Oral
psychotomimetic dosages are in the 25-150 μg range. Sensory perceptions are altered and
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intensified so that colours appear brighter and sounds become magnified or perceived as
patterns; there is a merging of senses (synesthesia) so that sounds become whirling
patterns of vivid colour; perceptions of time and space are distorted, so that seconds may
seems like an eternity, and objects become fluid and shifting. Depersonalisation;
experience of feeling merged with another object or another person; hallucinations and
visions; and religious revelations and spiritual insights, have been reported (157-159).
That is, LSD intensifies emotional experience as much as perceptual experience (160).
Physical effects are few and the lethal dose of LSD is so high that it has not been
estimated. Psychological dependence is very uncommon (161). Physical dependence does
not develop with LSD (162) however if used daily, tolerance to the psychotomimetic
effects of LSD develops rapidly but disappears after a few days abstinence (157, 158).
Legal production of LSD during the late 1940s and 1950s was directed towards research
by the US Army (as a ‘truth serum’ or brain washing agent) and psychiatrists (as an
adjunct to psychotherapy).
Around 1962 progressive restriction of legal use of LSD led to a dramatic increase in
illegal production and illicit use throughout the US and internationally, promoted by the
writings of a Harvard University instructor who became a media figure popularising LSD
and the hippie movement with his catch phrase “Turn on, tune in and drop out” (155).
The use of LSD peaked in the late 1960s and then steadily declined to a low but stable
level in the 1970s. In the early to mid-1980s there appeared to be decreased interest in
LSD, possibly due to reports of negative drug effects (163). Like ketamine, LSD re-
emerged in the context of ‘acid house’ music and ‘rave’ parties (76, 82). In an European
(164) and an Australian (165) study, prevalence of use was over 30% amongst youth
attending rave or dance parties. Whilst the annual prevalence of illicit LSD use amongst
high school students in the USA decreased from 1980 to 1990, in the mid-1990s
prevalence again increased to almost 10% (163). However, probably due to efforts by law
enforcement, use of LSD decreased to its lowest level in 2005 (163), paralleled by a
significant decline in use among dance drug users, at least in the UK (166).
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No epidemiological study has determined the relationship between LSD use and the
incidence of psychotic disorder. Initially LSD was considered to have therapeutic value
and reviews of its use with psychiatric supervision concluded that prolonged psychosis
following LSD was rare (167-170). LSD therapy was initially applied to patients with an
established history of schizophrenia with only a small risk of causing relapse (171, 172).
However, following broader illicit use of LSD in the late 1960s a number of case series
reports of psychosis in patients using LSD were published (reviewed by 173, 174, 175).
Patients with psychotic disorder who had used LSD were said to present with
phenomenologically similar symptoms and outcome to those with schizophrenia who did
not take LSD (175-181). However, in contrast to patients with PCP-induced psychosis,
most individuals presenting with psychosis in the setting of LSD abuse showed poor
premorbid adjustment and/or prior psychiatric admissions (175-181) or family history of
psychotic or other serious psychiatric illness (179, 182). Contemporary clinicians could
not determine whether psychosis in the setting of LSD abuse was a separate diagnostic
entity or simply represented a subgroup of patients with schizophrenia who used LSD.
An important area of agreement in the clinical literature was the view that the symptoms
of acute LSD intoxication were phenomenologically different to the symptoms of
schizophrenia (183-186). LSD-induced perceptual disorders are visual rather than
auditory; the visual distortions are not frank hallucinations but have the character of
illusions; delusional ideation is not stable and usually insight is retained; negative
symptoms are at most mild; and, LSD-induced phenomenology is often distinguishable
by patients with schizophrenia from their primary symptoms (183-186). In marked
contrast to both schizophrenia and PCP psychosis, the hallucinogenic effects of acute
LSD intoxication subside rapidly with benzodiazepines (44) unless delirium is evident.
Other dissimilarities with schizophrenia were reported in LSD-related (N,N-
dimethyltryptamine [DMT] or psilocybin) challenge studies in HVs measuring PPI (151,
187, 188) or MMN (189, 190) which did not find deficits, although deficits in attention
(126) and P50 suppression (187) with DMT were reported.
In conclusion, although LSD has obvious hallucinogenic effects, it is debatable whether it
should be considered psychotogenic. Indeed, support for the existence of psychotic
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disorder specifically induced by LSD as a diagnostic entity is inconclusive. Despite
periods of relatively high and low rates of use of LSD in communities, no formal or
informal epidemiological data have linked fluctuations in community use to variations in
the incidence of psychotic disorder. In fact, only a total of 75 individual case reports of
putative LSD-psychosis were found in a recent world-wide review (175). The occurrence
of psychosis in the setting of LSD abuse appears to be more related to individual
vulnerabilities than specific drug actions. This does not mean that adverse events with
LSD do not occur (174). Acute LSD intoxication is associated with panic attacks and
harm from misadventure, and a long-term consequence, Hallucinogen Persisting
Perception Disorder (HPPD) or ‘flashbacks’, has diagnostic validity (191). Nonetheless,
models based on LSD-related drugs are not irrelevant to the study of schizophrenia,
especially to investigate disturbances in serotonergic regulation (192, 193), because of
the 5HT2A receptor antagonist actions of atypical antipsychotics (186, 194, 195), and the
potential relevance of interactions between glutamatergic and serotonergic systems in the
pathogenesis of schizophrenia (126, 156, 196-199). An example of this type of
interaction is the recent discovery that functional complexes form between 5HT2A
receptors and group II metabotropic glutamate receptors (mGluR2) in brain cortex,
complexes which are targeted by LSD (200). For the purposes of this review however at
this stage we conclude our formal consideration of LSD-induced psychotomimetic effects
as a model of schizophrenia.
Ecstasy
MDMA (3,4-methylenedioxy-methamphetamine) is a ring-substituted amphetamine
derivative. It was patented in 1914 but never made commercially available. MDMA was
classified a restricted drug in the United Kingdom in 1977 and in the United States in
1985. MDMA is almost always consumed orally, the psychoactive dose being about 100
mg. The primary effect of MDMA is to produce a positive mood state with feelings of
euphoria, intimacy and closeness to other people, an effect that distinguishes it from
amphetamine or hallucinogens (201). MDMA also has stimulant effects as well as mild
psychedelic effects on insight and perceptual and sensual enhancement. The peak
psychoactive effects last on average 4-6 hours, though the half-life of MDMA is
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approximately 9 hours in humans (202). Tolerance to the psychoactive effects develops
rapidly (203). No physical withdrawal syndrome has been described (204), but
psychological dependence is common (161, 205, 206). Illicit Ecstasy tablets often contain
compounds related to MDMA, such as MDE (3,4-methylenedioxy-methamphetamine).
The generic term ‘Ecstasy’ is now preferred because it may refer to MDMA, analogues
of MDMA, or a combination of these (207). Ecstasy use by young people has worldwide
popularity (208, 209). In the United Kingdom during the mid-1980s the drug of choice
for people attending raves was Ecstasy and the popularity of this youth culture resulted in
an explosion in recreational use. Among US college students there was a steady increase
in Ecstasy use from 2.0% in 1991 to 13.1% in 2000 (210). Similarly, in the Australian
general population there is a steady increase in the proportion of people who have ever
tried Ecstasy from 4.8% in 1998, 6.1% in 2001, to 7.5% in 2004 (211, 212). Amongst
dance or rave party attendees, the use of Ecstasy is far more common (up to 80%
prevalence) than the use of ketamine and PCP (83, 164, 165); however, polysubstance
abuse (especially methamphetamine, cannabis and hallucinogens) among Ecstasy users is
the norm (80, 213-215).
Public alarm concerning the dangers of Ecstasy use initially arose from reports of sudden
death in young healthy users, especially when ingestion occurred at dance parties which
were typically hot, crowded venues with loud repetitive music and light shows (216,
217). Cause of death was either cardiac arrhythmia or malignant hyperthermia, and
usually related to polysubstance ingestion (218). However, a direct link between the
fatalities and Ecstasy use is supported by a strong correlation between rates of Ecstasy
use and rates of fatalities (219). Milder effects of intoxication include nausea, loss of
appetite, tachycardia, hypertension, jaw tension, bruxism and sweating (215). Chronic
adverse events associated with Ecstasy use include extensive polydrug use, high rates of
intravenous drug use, and financial, relationship and occupational problems (214).
Of particular concern is evidence of associations between Ecstasy use and neurocognitive
deficits. These associations remain controversial. Although there are several cross-
sectional studies showing cognitive impairment in Ecstasy users (reviewed in 220), there
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is evidence that these impairments may be due to polysubstance abuse rather than Ecstasy
use itself (221, 222). Although the evidence from longitudinal studies for an association
between chronic Ecstasy use and long-term neurocognitive impairment is fairly
consistent (223), this association also remains controversial. In a major review, Morgan
(220) concluded that in many longitudinal studies the evidence for an association
between selective memory impairments and chronic heavy recreational use of Ecstasy
may be confounded by polysubstance abuse. There are studies showing a correlation
between the total dose of MDMA exposure and memory performance (224-226), but
again this association is open to confounding by polysubstance abuse. Moreover, a
consistent profile of neurocognitive deficits in Ecstasy users is not evident, some
reporting mainly prefrontal deficits (e.g. 227), others observing mainly hippocampal-
related memory deficits (228), whilst others find both (226). In summary, researchers
hold polarised views on the harm of Ecstasy use seemingly reflecting divided public
opinion, with some concluding evidence of harm is definitive (229, 230) whilst others are
equally certain that evidence of harm is inconclusive or absent (208).
Although there are many studies reporting an association between Ecstasy use and mental
disorder (especially depression and anxiety), it is impossible to determine in cross-
sectional studies whether this relationship is due to Ecstasy, associated polysubstance
abuse (208), and whether it pre- or post-dates Ecstasy use. In prospective (231) or
retrospective (232) comparisons of the age-of-onset of mental disorder and age-of-onset
of Ecstasy use, psychiatric disorder appeared to precede Ecstasy consumption. A meta-
analysis showed that the strength of the association between Ecstasy use and depressive
symptomatology was weak and unlikely to be clinically relevant (233).
Psychotic disorder as an adverse reaction to Ecstasy use appears to be rare and
idiosyncratic, mainly determined by user-related variables (familial predisposition;
previous psychotic episodes; very high dose exposure; and polysubstance abuse) rather
than be drug-related. Soar et al. (234) reviewed published psychiatric case studies from
the previous 10 years involving MDMA. Of the 38 cases, 22 had a psychotic disorder or
symptoms. Two of this subgroup had a family history of psychosis, an observed rate that
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is precisely comparable to the expected rate with schizophrenia itself. As well, in the
psychotic patients confounding arose from greater Ecstasy use being associated with
heavier polysubstance use. In an Italian series (235) of 32 cases of psychotic disorder in
Ecstasy users (patients with self-reported polysubstance abuse excluded),
symptomatology was not phenomenologically distinctive, and many cases had a family
history of psychiatric disorder or past personal history of non-psychotic psychiatric
disorder, making it impossible to determine whether Ecstasy was the primary cause of
psychosis or not. In a community sample, the occurrence of schizophrenia was not related
to heavy Ecstasy exposure (232). There is only a single case report in which experimental
MDMA intoxication produced an acute toxic hallucinosis lasting 2.5 hours (236),
emphasising the rarity and idiosyncratic nature of this adverse event. The lack of
evidence of an association between psychotic disorder and Ecstasy use described above
has not prevented opinion being published that Ecstasy “has a special risk for persistent
organic psychoses” (229). Clinical biomarker studies have not supported MDMA
challenge as a model of schizophrenia. Unexpected increases (i.e., not deficits) in PPI
have been observed after administration of MDMA in HVs (237, 238) and in chronic
ecstasy abusers (239). Therefore, for the purposes of this review at this stage we conclude
our formal consideration of MDMA-induced psychotomimetic effects as a model of
schizophrenia.
Animal studies
This Section reviews animal models induced by PCP and analogues to further assess the
construct and predictive validity of the PCP model of schizophrenia. We examine how
closely these animal models replicate pathophysiological and theoretical processes
hypothesised to underlie schizophrenia. Evidence of predictive validity is presented by
comparing the potency of novel compounds in reversing PCP-related psychotomimetic
effects in the model with their antipsychotic effect in patients with schizophrenia. First,
principles and constraints concerning disease modelling in animals are noted, and
illustrated by considering the amphetamine-induced model of psychosis.
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Animal modelling: Principles and constraints
Attempts at modelling psychiatric diseases in their entirety is futile because rodents have
much simpler brain structure than humans, making it impossible for rodents to display the
same kinds of complex symptoms as humans: it is unrealistic to expect homology on all
aspects of a disorder across two species (1, 240). A more feasible approach is to model
specific signs or symptoms of the disease, or neurobiological correlates, for which there
are relatively equivalent behaviours or measures in both humans and rodents. This
approach is illustrated by the dominant animal model for schizophrenia, amphetamine-
induced hyperlocomotion in rodents, a model that currently serves as the ‘gold standard’
in evaluating other models, especially the PCP model.
Amphetamine-induced hyperlocomotion in animals has face validity because the
stereotypic hyperactivation of the model bears ‘symptom similarity’ to the agitation seen
in patients with acute schizophrenia, and in turn, because amphetamine abuse is
associated with psychotic disorder resembling schizophrenia in humans (241). The model
also has high predictive validity because currently available antipsychotic drugs attenuate
amphetamine-induced hyperlocomotion in rodents. The limitation of using
hyperlocomotion as the measure of the model is that this behaviour is also reversed by
compounds that have no antipsychotic effect clinically, and the compound with superior
antipsychotic effect, clozapine, is no more effective in reversing hyperlocomotion than
the conventional D2R antagonist, haloperidol (242). The dangers of basing animal
models on symptom similarity using analogous behavioural measurement have been long
recognised (243). A limitation with using a model that has high predictive validity for a
single class of drugs is ‘pharmacological isomorphism’, the utility of the model being
limited to identifying only one class of (‘me-too’) drugs and not supporting the discovery
of drugs of a distinctly new class (9). The construct validity of amphetamine-induced
animal models of schizophrenia has been augmented by measurement of disease markers,
such as deficits in PPI. PPI is an example of reliable measurement of an indicator of
human disease (also putatively indexing a theoretical process, ‘sensorimotor gating’,
(61)) that has an equivalent measureable behaviour in the animal model ('homologous'
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measurement, 243). However, the disease non-specificity of PPI and hyperlocomotion
constrains their utility in animal studies of the pathophysiology of schizophrenia.
This constraint has been addressed in amphetamine-induced animal models by measuring
brain system/neuronal dysfunctions, in addition to assessing behavioural change. A step
in this direction was based on findings in rodents and primates that induction of
hyperlocomotion by dopamine agonists (e.g. amphetamine) is related to increased
subcortical dopamine release in ventral striatum (244-249). Notably, these preclinical
findings informed research that produced the first direct evidence in living patients of
significant dysregulation of subcortical dopamine neurotransmission in schizophrenia
using an in vivo receptor binding method (250), a consistently confirmed finding
(reviewed in 251). Patients show amphetamine-induced sensitivity to presynaptic
dopamine release resulting from inhibition of the dopamine transport (DAT) and the
vesicular monoamine transporter (VMAT). Increases in positive (but not negative)
symptoms in patients following amphetamine challenge were found to correlate with in
vivo dopamine release (252). That is, a neurobiological correlate of the animal model
correctly predicted the nature of the dopaminergic dysregulation later found in patients
with schizophrenia.
Recent research on amphetamine-induced animal models has revealed abnormalities at
the neuronal level in prefrontal cortex (253). Homayoun and Moghaddam (253)
investigated PFC neuronal activation in rats after amphetamine sensitisation (five days
repeated daily dosing). Emphasising the importance of specifying pharmacological
models in terms of exposure to single (acute) or repeated (subchronic or chronic) dosing,
this group reported that the electrophysiological responses of PFC neurons begin to
change after a few doses of amphetamine. Repeated amphetamine exposure had opposite
effects in two regions of prefrontal cortex – a progressive hyperactivation of orbitofrontal
cortex and hypoactivation of medial prefrontal cortex. These alterations were present
irrespective of whether the rats were behaving spontaneously or performing an operant
responding task, indicating they were not secondary to hyperlocomotion. The pattern of
prefrontal findings is homologous to prefrontal findings reported in human in vivo
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neuroimaging studies of schizophrenia (hypoactivation of dorsolateral PFC, 254) and
substance addiction (hyperactivation of orbitofrontal cortex, 255), another example of the
animal model informing human disease research. As only subchronic or chronic
amphetamine dosing (256-261), and not single dosing, induces psychosis in healthy or
substance-abusing volunteers, prefrontal neuronal dysfunction demonstrated in the
repeat-dosing amphetamine model (253) may be of pathophysiological importance to
schizophrenia, providing a marker for identifying novel and more specific
pharmacotherapies, as well as sign-posting future research into prefrontal neuronal
dysfunction in patients with schizophrenia. Linking the repeat-dosing amphetamine
model back to the PCP model of schizophrenia are studies showing that psychostimulant
sensitisation (both behavioural and neurochemical) is mediated by NMDA and non-
NMDA glutamate-dependent processes secondary to increased stimulant-induced
dopamine release (262-264).
In summary, lessons from the extensive characterisation of the amphetamine-induced
model of schizophrenia are relevant to evaluating other animal models. For example
PCP-related models are also sensitive to dosing schedule, with chronic (repeated daily)
dosing inducing hypoactivation (265), not hyperactivation as seen in acute (single) dosing
models. An issue of utmost importance is characterising an animal model at the neuronal
and brain tissue level (8, 266). This level of information is the basis of a model’s capacity
to generate predictions about human pathophysiology and likely clinical effectiveness of
novel pharmacotherapies (4, 7, 266, 267). These issues are as relevant to the burgeoning
literature on genetically modified models (1, 2, 4), as they are to the evaluation of PCP-
related animal models, the subject to which we now proceed.
Animal models and controversy about the pharmacology of PCP and
its analogues
Animal studies use a range of PCP analogues, all of which are considered to have their
primary pharmacological action at a binding site located within the ion channel formed
by the NMDA glutamatergic receptor (called ‘the PCP binding site’). PCP inhibits
NMDA receptor-mediated neurotransmitter release and therefore functions as an NMDA
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receptor antagonist. As PCP binds to a site of the NMDA receptor complex that is distinct
from the recognition site for the neurotransmitter glutamate, its inhibitory effects are non-
competitive in that they cannot be overcome by increased neurotransmitter
concentrations. PCP analogues, ketamine and MK-801 (dizocilpine), also have high
affinity for the PCP binding site and are NMDA antagonists. Compared to PCP, ketamine
has lower affinity and MK-801 higher affinity for the PCP binding site. Although PCP
and ketamine interacts with catecholamine re-uptake transporters at anaesthetic doses,
psychotomimetic effects occur at lower serum levels where these agents have appreciable
affinity only at the NMDA receptor complex (72).
A leading research group has argued that the psychotomimetic effects of PCP and
ketamine are primarily mediated by direct actions on dopaminergic transmission (268-
273). They propose that all psychotomimetic drugs exert this effect via D2R-related
action (274). This group presented in vitro experimental evidence that PCP and ketamine
are potent ligands at striatal D2R in the high-affinity state (269, 272, 273). No other
group has replicated these findings, which have been contradicted (275) or refuted either
in a functional assay (276) or other experiments (277, 278). Another source of evidence
that is in complete disagreement with the hypothesis that the psychotomimetic effects of
PCP analogues are directly caused by an amphetamine-like striatal dopaminergic
dysregulation, are the negative results reported in the substantial in vivo ligand binding
imaging literature (reviewed in 279). In contrast to PCP and ketamine, MK-801 is highly
selective for the PCP site even at very high concentrations, yet it has strong
psychotomimetic effects (72) as does the highly selective competitive NMDA antagonist,
CGS 19755 (Selfotel, 280). Moreover, drug discrimination studies, in which animals are
trained to recognise drugs with a common pharmacological effect, demonstrate that MK-
801 and ketamine have PCP–like effects directly proportional to their binding affinity
potency at the PCP site and these effects are not related to the differential affinity of these
drugs for catecholamine transporters, which are only evident at anaesthetic doses
(reviewed in 72). It can therefore be confidently concluded that the primary
pharmacological action responsible for the psychotomimetic effects of PCP and
analogues is non-competitive antagonism of the NMDA receptor complex, and any
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disturbance of dopaminergic systems is secondary to and downstream from,
glutamatergic antagonism.
Changes in behaviour and clinical biomarkers in PCP-related models
As discussed above, amphetamine-induced hyperlocomotion in animal models represents
analogous measurement of the psychotomimetic effects of amphetamine seen in humans.
It is assumed that hyperlocomotion in animal models of psychosis is analogous to the
positive symptoms of schizophrenia, an assumption supported by antipsychotic-induced
attenuation of hyperlocomotion in animal models, and positive symptoms in patients.
However, analogous measurement in models may have no relationship to disease
pathophysiology (9). PCP (e.g., 281, 282-286), ketamine (e.g., 287), and MK-801 (e.g.,
266, 288) also induce hyperlocomotion in animals, illustrating that two different
pharmacological models show the same analogous behaviour. However if a characteristic
sign of the human disease, such as a distinctive catatonia-like stereotopy, selective
impairment in working memory, or a specific deficit in sensorimotor gating, is assessed
across species using homologous measurement, it is more likely that aspects of construct
validity will be measured. PCP induces characteristic stereotypic head movements in
humans (see above), which are replicated in animal models treated with PCP (e.g., 281,
286), ketamine (e.g., 287, 289) or MK-801 (e.g., 266). That is, hyperlocomotion is
common to both PCP and amphetamine models, whereas only PCP and analogues induce
head movements that are identical to PCP-induced stereotopies in humans and similar to
catatonia-like motor changes in schizophrenia. Additional face validity for PCP-induced
animal models for schizophrenia relates to measurement of PCP-induced ‘negative’
symptoms. In contrast to acute amphetamine-induced models that do not show
homologous behaviour to negative symptoms (282, 284, 288), animal models induced by
PCP (282-285, 290) and MK-801 (288) show deficits in social interaction, considered to
be homologous to negative symptoms.
Neurocognitive testing of PCP-related animal models also supports the face (and to a
degree, construct) validity of these models, demonstrating homologous deficits to those
seen in PCP psychosis and schizophrenia. In particular, behavioural assessment of
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animals treated with PCP (281, 291-294) or MK-801 (266, 295, 296) reveal deficits on
prefrontal-related tests, such as spatial working memory tasks (266, 281, 291, 293, 294,
296) and executive function tasks, the latter eliciting perserverative responding and
difficulties in set shifting (292, 295). Moreover, measures of clinical biomarkers in
animal models induced by PCP (297-299), ketamine (300, 301) and MK-801 (297, 298)
have demonstrated deficits in PPI homologous to those found in schizophrenia. Whereas
pre-treatment of rats with haloperidol attenuates PPI deficits induced by dopamine
agonists (302, 303), haloperidol has no significant effect on the ability of PCP (299),
ketamine (300), or MK-801 (299) to disrupt PPI. Taken together, these findings indicate
that PPI deficits associated with the amphetamine-induced model are mediated by
subcortical D2R, and PPI deficits associated with PCP-related models are not, a form of
discriminant validity.
Increased regional brain activation in acute PCP-related animal
models
Face (and to a degree, construct) validity of PCP-related animal models would be
supported if homologous patterns of brain activation were seen across animal models,
PCP-induced psychosis, and schizophrenia. Homology of activation change could be
expected in terms of both regional distribution, and whether it is under- or over-activated.
Animal models induced by MK-801 (304) or ketamine (304-306) show altered 2DG
activation in: frontal regions, especially medial prefrontal and retrosplenial (cingulate)
cortex; medial temporal regions, especially the hippocampal formation; anterior ventral
thalamic nucleus; and subcortical limbic centres. Areas of altered BOLD contrast in
ketamine-induced animal models included frontal regions and the hippocampal formation
(307, 308). Against prediction, regional activation indexed by either BOLD contrast or
2DG autoradiography is increased in animal models induced by MK-801 and ketamine in
acute (single) doses (304-308). In summary, distribution of hyperactivation in PCP-
related animal models shows regional homology with activation abnormalities reported in
studies of patients with schizophrenia, implicating four specific brain regions, namely:
prefrontal cortex (309-312), hippocampal formation (313, 314), subcortical limbic nuclei
(315, 316), and thalamic nuclei (137, 139, 317).
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Paradoxical hyperactivation seen in PCP-related animal models, compared to the
hypoactivation usually reported in studies of patients, is of special interest. Possible
causes of animal model-human disease discrepancies include mismatch in a number of
areas 1) use of acute pharmacological challenges to model chronic brain disease 2) use of
neurochemical challenges to model neurodevelopmental disorder 3) modelling a different
stage of the human disease in an animal, compared to the disease stage in which human
findings were made (e.g. early-stage model versus late-stage disease) and 4) modelling
different phases of the disease (e.g. acute relapse versus inter-episode residua). Two lines
of evidence suggest that the direction-of-activation discrepancy may be due to
administration of an acute (single) dose of PCP or analogue to model chronic disease
findings. First, PET studies in humans show that a single dose of ketamine induced
increased brain activation (146, 147), whilst PET studies of subjects who chronically
abused PCP showed reduced brain activation (318, 319). Second, reduced prefrontal and
thalamic reticulate nucleus activation was found using 2DG in a repeat-dosing animal
model (320). Although these findings suggest that there is not a real discrepancy between
the clinical and preclinical models, the intriguing question remains as to why NMDA
antagonists should induce brain hyperactivation.
Increased prefrontal glutamate in PCP-related animal models
Using microdialysis in rats, Moghaddam and Adams (281, 321) showed that PCP induces
presynaptic release of glutamate and dopamine, both showing increased extracellular
levels in prefrontal cortex and nucleus accumbens. In this landmark study (see
commentary in 321) a single dose of PCP (5 mg/kg IP) elicited marked motor activity,
stereotopy with head rolling, and spatial working memory impairments. By manipulating
the level of extracellular glutamate (whilst not altering dopamine levels) with a mGluR
agonist (see next Section), these authors demonstrated that psychotomimetic behaviour of
the model (hyperlocomotion and stereotopy) were related to glutamate levels, not
dopamine levels. Increased prefrontal/hippocampal/subcortical glutamate efflux is a
consistent effect replicated with a range of NMDA antagonists, including ketamine (322),
PCP (323), and a competitive antagonist (324). Taken together, the work of Moghaddam
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and colleagues has characterised a key element of the neuronal dysfunction underlying
psychotomimetic behaviour in this animal model increased levels of extracellular
glutamate and dopamine. But is glutamate efflux related to prefrontal hyperactivation at
the neuronal level?
Increased prefrontal neuronal firing in PCP-related animal models
Another cornerstone in our understanding of the cellular mechanism of the PCP-induced
animal model concerns the firing rate of prefrontal neurons. Jackson et al. (266)
administered single systemic doses of MK-801 (0.01, 0.05, 0.1 and 0.3 mg/kg) to rats. At
the two highest doses of MK-801 sustained and substantial increases in prefrontal neuron
firing occurred, firing rates highly correlated with stereotopy counts. MK-801 also
induced spatial working memory deficits. These important in vivo findings,
demonstrating that MK-801-induced increases in firing rate in prefrontal neurons are
directly related to behavioural measures of the animal model, have been replicated (325-
327). Two other studies from the Fukushima Medical University, one of which
represented the first demonstration of the effect of PCP on prefrontal neuron firing rate
(328), add important detail to the description of the PCP-induced cellular dysfunction.
Suzuki et al. (328) found a differential effect on prefrontal neuronal firing between
systemic and locally (prefrontally) administered PCP, indicating that afferents
(presumably non-NMDA glutamate) from other brain regions partly drive the prefrontal
neuronal firing. This hypothesis was supported by a subsequent study showing that PCP
applied locally to the ventral hippocampus led to increased prefrontal neuronal firing
(329), apparently mediated by AMPA/kainate glutamate receptors (330). The
thalamocortical circuit may also be a major driver of pathological prefrontal activation
and increased cortical glutamate release. MK-801 injections into the anterior nucleus of
the thalamus induced cortical degeneration in a pattern indistinguishable from systemic
administration, while injection directly into cortical regions did not lead to degenerative
change (112). As glutamatergic systems are the major energy users in the brain, and
pyramidal cells are the major excitatory cell type, it is likely that PCP-induced regional
hyperactivation indexed by BOLD or 2DG uptake is related to increases in pyramidal cell
firing. The question as to how NMDA antagonism induces increased extracellular
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glutamate and dopamine, and increased prefrontal neuronal firing, remains to be
considered.
GABAergic interneuron deficits in PCP-related animal models
A long held assumption about the PCP model of psychosis is that deficits in GABAergic
interneuron transmission, presumed to be related to PCP-induced dysfunction of the
NMDA receptor complex on GABAergic neurons, results in disinhibition of pyramidal
cells (3, 109, 112, 156, 331-338). There is now a wealth of evidence to support this
assumption. Parvalbumin (PV) is a calcium binding protein located within a
subpopulation of GABAergic interneurons. PV interneurons receive the largest
glutamatergic input among all GABA-releasing neurons in cortex (339) and are highly
sensitive to NMDA antagonists (340), a property related to the role played by NMDA
receptors in control of basal synaptic activation of these interneurons (341). In an acute
PCP dosing rat study, expression of PV was decreased in the reticular nucleus of the
thalamus and substantia nigra pars reticulate (342). In repeat-dosing rat models, the
density or number of hippocampal GABAergic interneurons expressing PV was
decreased with PCP (296, 343) and with ketamine (344). In a repeat-dosing PCP monkey
model, the density of prefrontal PV containing axo-axonic structures was decreased
(345). Also, ketamine induced dose-dependent decreases in PV and GAD67 immuno-
reactivity in cultured PV interneurons specifically (346, 347). Because PV interneurons
are involved in the generation of gamma oscillations responsible for temporal encoding
and storage or recall of information required for working memory (348), alterations in
gamma frequencies have been used to index functional deficits in GABAergic
interneurons induced by ketamine (349). Juvenile rats given MK-801 for 14 days that
showed increased firing of pyramidal cells and deficits in spatial memory pre-mortem,
also showed decreased numbers of PV interneurons postmortem (296). A recent study
provided the first direct evidence of an inverse relationship between MK-801-induced
increases in prefrontal pyramidal cell firing rate and decreases in activity of GABAergic
interneurons (326). This important study (326) demonstrated that NMDA receptors
preferentially drive the activity of cortical inhibitory interneurons, and that NMDA
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receptor antagonism causes cortical excitation by disinhibition of prefrontal pyramidal
neurons.
The significance of the cellular dysfunctions affecting GABAergic interneurons in PCP-
related animal models pertains to reports of homologous changes in prefrontal PV
interneurons in postmortem studies of schizophrenia (309-312, 350). Moreover,
disturbances in the gamma frequency band of scalp-recorded EEG, considered to reflect
gamma oscillations arising from PV interneuron cortical synchronisation, are evident in
schizophrenia and correlated with prefrontal-related cognitive deficits in patients (351-
354). That is, the PCP model of schizophrenia offers sufficient construct validity at the
level of cellular dysfunction to inform hypotheses about the pathophysiology of
schizophrenia that can be tested in the model. An example of such a hypothesis concerns
the possibility that reduced nicotinamide adenine dinucleotide phosphate (NADPH)
oxidase activation may be involved in the loss of PV expression in prefrontal cortex in
schizophrenia (346). This hypothesis arose directly from a study of the animal model, and
awaits investigation in studies of the human disease itself.
Secondary monoaminergic system disturbances in PCP-related
animal models
Another component of the cellular dysfunction related to the PCP model concerns
secondary effects of NMDA antagonism on catecholaminergic and serotonergic
pathways. As noted above, there is little evidence of direct action on these
neurotransmitter systems. However, there is a wealth of evidence that glutamatergic
systems closely interact with dopaminergic (293, 294, 336, 355) and serotonergic (156,
196, 197, 199, 356) pathways. In a series of ground-breaking studies Jentsch and
colleagues showed that acute PCP dosing induces marked increases in prefrontal
dopamine turnover (355), whilst daily chronic (14 days) dosing causes significantly
reduced prefrontal dopamine utilisation (293) that persists up to four weeks after ceasing
PCP administration (294). This laboratory showed that chronic PCP-induced decreased
dopamine utilisation was associated with deficits in spatial learning memory in rats (293),
and with deficits in perseverative learning in monkeys (294). These findings illustrate the
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importance of specifying acute or chronic exposure to PCP and analogues in describing
the animal model (265). Glutamatergic-serotonergic system interactions are also of
relevance, increased prefrontal glutamate efflux being induced by 5HT2A receptor
activation presynaptically (126, 194, 357, 358) and the psychotomimetic effects of LSD
being reversed by mGluR2 agonist reduction of glutamate efflux (200).
In summary, the PCP model of schizophrenia is now supported by an extensive literature
describing model-induced animal behaviour and neurocognitive deficits, regional brain
activation patterns, and a comprehensive range of cellular dysfunctions. Advanced in
vitro and in vivo assays applied to this animal model permit a high level of homologous
measurement. Novel hypotheses about pathogenesis and pathophysiology have been
generated based on the model, which now go well beyond generalisations about
hypoglutamatergic function in schizophrenia (359-363). Ultimately however, the most
important form of validity is whether the model can predict antipsychotic efficacy in the
development of new medications for schizophrenia.
Drug development using PCP-related animal models
Animal models with predictive validity, coupled with knowledge of drug action, are
powerful combinations in the study of schizophrenia and drug development (338). For
the purposes of this Section, mainly drugs that have been tested in patients to determine
efficacy will be reviewed. Predictive validity will be assessed on the basis of whether
PCP-related models can differentiate between clozapine and other available
antipsychotics; and whether the model is predictive of novel treatments that are not based
on D2R antagonism.
There are now several studies that demonstrate differential response to clozapine
compared to other antipsychotic agents using the PCP animal model. To illustrate, in an
acute ketamine-induced model, clozapine completely blocked all ketamine-induced
regional brain activation (indexed by 2DG uptake), an effect not seen with haloperidol
(305); and in a PCP repeat–dosing model, clozapine but not haloperidol reversed PCP-
induced prelimbic reductions in PV staining (320). The reader is reminded that
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amphetamine-induced models did not behaviourally differentiate the effect of clozapine
and haloperidol (242). Of greater importance however, is the predictive validity of the
model in relation to novel drug development, drugs that are not simply variations of those
based on D2R antagonism.
The first indication that the PCP-induced model might have predictive validity for agents
with novel modes of action concerns the anticonvulsant, lamotrigine. Lamotrigine
inhibits glutamate release via blockade of sodium channels. When tested in a ketamine-
induced mouse model, lamotrigine reversed ketamine-induced PPI deficits, an effect it
did not have on amphetamine-induced PPI deficits (301). Moreover, lamotrigine reduced
ketamine-induced perceptual abnormalities in HVs (364). Although lamotrigine is not
effective as monotherapy in patients with schizophrenia, when used in treatment-resistant
patients to augment D2R antagonist antipsychotics (365-367), lamotrigine does have
modest beneficial effects that are evident to a greater extend when used in conjunction
with clozapine (368-370). Carbamazapine, which does not appreciably reduce glutamate
release despite its similar action to lamotrigine in blocking sodium channels (371), is
ineffective as an augmenting agent in treatment-resistant schizophrenia (372).
Of greater interest is the predictive validity of the PCP animal model in relation to new
drugs that act directly on glutamate. Preliminary evidence that NMDA receptor complex
modulators might be efficacious in schizophrenia came from studies demonstrating small
beneficial effects of augmenting antipsychotic treatment with glycine or serine (reviewed
in 360). Based on the PCP model, researchers have now identified and tested a range of
new and promising compounds. Amongst these is sarcosine, a glycine transporter 1
(Glyt-1) inhibitor, which increases glycine at the NMDA receptor complex, thereby
facilitating NMDA transmission. Preclinical testing on PCP-induced models showed
reversal of PCP effects (373), not as apparent in the amphetamine-induced model.
Subsequent clinical testing revealed that sarcosine was ineffective as monotherapy (374),
but that it shows a significant beneficial effect when used as an augmenting agent with
conventional antipsychotic treatment (375). Sarcosine did not offer additional benefit as
an adjunct treatment with clozapine (376), suggesting that clozapine may have direct
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action at Glyt-1. Another example of drug development based on the PCP model is the
preclinical testing of N-acetylaspartylglutamate (NAAG) peptidase inhibitors. These
compounds are selective mGluR2 agonists, which inhibit presynaptic glutamate release
(377). Preclinical testing of the NAAG peptidase inhibitor, ZJ43, showed that it reduced
MK-801-induced hyperlocomotion and PCP-induced stereotypic movements (378),
effects due to the mGluR3 agonist action of ZJ43 (379). Interestingly, a recent report
demonstrated that an mGluR2 agonist abolished LSD-induced psychotomimetic
signalling and behavioural responses (200). The field awaits the results of clinical trials
of this class of agents.
The most important example of predictive validity of the PCP model concerns the
development of the mGluR3 agonist, LY354740, which acts to reduce release of
presynaptic glutamate (380). Preclinical testing in an acute PCP-induced model
demonstrated that LY354740 reduced PCP-induced stereotypic movement,
hyperlocomotion, and spatial working memory deficits (281). Significantly these effects
were associated with reversal of increased glutamate and dopamine effluxes prefrontally
(281). Interestingly, preclinical testing of LY354740 in HVs did not significantly
improve ketamine-induced psychosis ratings but it did improve ketamine-induced
working memory deficits (381). Based on these results, LY354740 has been subjected to
clinical trial in patients with schizophrenia. In a landmark study, acute ill patients were
randomised to LY2140023 (an orally absorbable analogue of LY354740), olanzapine, or
placebo. This study demonstrated that LY2140023 was effective against the positive and
negative symptoms of schizophrenia and had few side-effects (382). Hence, the PCP
model showed accurate predictive validity in the case of the first effective novel
antipsychotic since the introduction of chlorpromazine.
The PCP model of schizophrenia: An integration
When the psychotomimetic effect of PCP was first proposed as a model of schizophrenia
(383) the pharmacological actions of PCP were unknown. Although an early report
hypothesised impaired function of glutamatergic neurons as a model of schizophrenia
(384), it was not until the PCP binding site was localised to the NMDA receptor complex
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(385) that NMDA receptor hypofunction could be incorporated into the PCP model (362,
363). A ‘thalamic filter dysfunction’ was proposed (362): pathological activation of the
cortico-striato-thalamo-cortical feedback loop was hypothesised to cause information
overload in the cortex (reviewed in 386). Strengthening evidence that the
psychotomimetic effects of PCP were directly related to NMDA receptor complex
antagonism challenged the highly influential dopamine hypothesis of schizophrenia (72).
An important element of the PCP model, glutamatergic neuronal disinhibition due to
functional antagonism of NMDA receptors on GABAergic interneurons that normally
place excitatory pyramidal neurons under inhibitory control, was added more recently
(387, 388). The putative role of cortical pruning (389) and evidence of reduced prefrontal
neuropil (390, 391) in schizophrenia have also been incorporated into the model (361).
A number of neuropharmacological descriptions of the PCP model (hypoglutamatergic
model) of schizophrenia have been published (109, 112, 332-334, 336-338, 359, 360,
392-396). Central to these models is a PCP-induced deficit of GABAergic interneurons,
which results in disinhibition of glutamatergic pyramidal cells (see Figure 1, Panel A).
Although this disinhibition is assumed to be widespread throughout grey matter, models
emphasise its impact on prefrontal cortex in accounting for psychotomimetic effects.
Increased levels of extracellular glutamate in acute PCP models are thought to result from
local collateral feedback by disinhibited pyramidal neurons onto presynaptic terminals,
and increased non-NMDA glutamatergic efferent feedback from thalamus, other
subcortical centres, and the hippocampal formation (see Figure 1, Panel B). Completing
the PCP model are descriptions of increased dopamine efflux in the prefrontal cortex and
ventral pallidum, resulting from greater cortical drive to striatal/limbic subcortical
centres. Increased cortical drive to the median raphe results in increased prefrontal
serotonin concentrations, which augment glutamate efflux via presynaptic 5HT2A
receptor activation. Importantly, ventral pallidal stimulation of the dorsomedial thalamic
nucleus, and hippocampal-limbic stimulation of the anterior nucleus of the thalamus,
provides an explanation for excessive subcortical-cortical glutamatergic feedback drive to
the prefrontal cortex (see Figure 1, Panel B).
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PLACE FIGURE 1 NEAR HERE
The acute model described above has been supplemented by a chronic PCP model, which
includes reduced prefrontal extracellular glutamate and dopamine (294). A number of
cellular mechanisms have been advanced to link these surface receptor-focussed models
to intracellular final common pathway models. Svenningson et al. (277, 278) have
implicated a common signalling pathway in the mediation of the psychotomimetic effects
of glutamatergic antagonists (such as PCP), serotonergic agonists (such as LSD) and
dopaminergic agonists (such as amphetamine). In this pathway, phosphorylation status of
Dopamine- and an Adenosine 3’,5’monophosphate (cAMP)-Regulated PhosphoProtein of
32 kilodaltons (DARPP-32) regulates downstream effector proteins, glycogen synthesis
kinase-3 (GSK-3), cAMP response element-binding proteins (CREP) and c-Fos, thereby
influencing electrophysiological, transcriptional, and behavioural responses. An
alternative mechanism for linking the PCP model to intracellular signalling pathways is
via glutamate-mediated excitotoxicity, which has been found to induce apoptotic loss of
dendrites and synapses without cell body death or gliosis (reviewed in 336). Postmortem
studies have reported elevated Bax:Bcl-2 ratio (a marker of increased propensity for
apoptosis) in the temporal cortex (397, 398), comparable to functional findings in
cultured fibroblasts from patients with schizophrenia (399). Taken together, these
proposals provide a rich source of hypotheses for testing in studies into the pathogenesis
of schizophrenia.
Summary and conclusion
It is concluded that although PCP, LSD and MDMA have well-documented
psychotomimetic effects, only for PCP is there abundant evidence that it induced
psychotic disorder beyond the acute symptoms of intoxication. In fact, there is no clear
evidence that either LSD or MDMA induces psychotic disorder independent of
toxication, let alone schizophrenia, in individuals who do not have vulnerability to
schizophrenia premorbidly. Impressive qualitative similarity between PCP-induced
symptoms and those of schizophrenia, both in range and nature, was shown by detailed
examination of first-hand clinical descriptions of phenomenology. This examination was
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only possible by review of primary source publications written by trained clinicians who
personally observed patients and HVs experiencing PCP-related symptoms.
Although inducing quantitatively less intense psychotomimetic effects, ketamine is
considered a safe and valid model of PCP psychosis, and applicable to preclinical human
studies. We also concluded that rodent and primate models induced by PCP and
analogues have construct validity, showing homologous behaviour, cognitive deficits,
alterations in regional brain activation, and underlying neuronal dysfunction, to those
observed in patients with schizophrenia. Most importantly, animal models demonstrated
predictive validity at the level of hypothesis-generation about human pathophysiology
and efficacy of novel drug therapies. Indeed, it could be said that PCP-related animal
models have been instrumental in the discovery of the first novel class of antipsychotic
drug treatments (i.e. mGluR2/3 agonists) without D2R antagonist action since the
introduction of chlorpromazine. The relative merits of PCP-related and amphetamine-
induced models of schizophrenia have been discussed elsewhere (3). We considered both
models to have high predictive validity when descriptions and measurement are carried
out at the level of neuronal dysfunction. Amphetamine-induced models highlight the
importance of dosing schedules to describing models because only sensitisation induced
by repeated dosing mimics schizophrenia (e.g. 253, 400-402). This issue is also relevant
to PCP-related models (294). A notable limitation of neurochemical models is that they
usually do not incorporate a neurodevelopmental perspective (403). This implies that
developmental models will be required to complement pharmacological models
(reviewed in 4), either aetiologically linked to the occurrence of schizophrenia (e.g.,
prenatal viral infection mimicked using poly I:C, 404), induced by a prenatal
hippocampal lesion (403, 405), or based on a specific genetic alteration, exemplified by
mouse models of velo-cardio-facial syndrome (406), DISC1 (407) or neuregulin-1 Type
III (408).
In a more general sense this review reminds us of our field’s historic dependence on
research using patients. Preclinical models, especially in animals, release research from
the inevitable confounding factors related to illness experience and treatment. Most
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importantly animal models allow direct observation of neuronal dysfunction that models
the human pathophysiology. Without this opportunity, major improvements in the drug
treatment of schizophrenia will not be possible. This review also highlights the need for
excellence in clinical observation and measurement in developing adequately valid
animal models, which rely on the clinical insights of well-trained clinicians who are
interested in the neurobiology of psychiatric disorder. Communication between the clinic
and the preclinical behavioural laboratory will enable the refinement of established
models and the creation of new ones (1). Insufficient well validated, objective, and
reliable measures of psychopathology is a barrier to the development of homologous
measurement in animal models. The validation of an animal model can only be as good
as the information available in the relevant preclinical human research and the clinical
literature (409). Clinical studies need to be informed by results from animal studies as
much as the reverse is true. More translational science is needed to relate animal findings
to humans and vice versa (1).
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41
References
1. Geyer MA, Markou A: The role of preclinical models in the development of
psychotropic drugs, in Neuropsychopharmacology: The Fifth Generation of
Progress. Edited by Davis KL, Charney D, Coyle JT, Nemeroff C, Lippincott
Williams & Wilkins, 2002, pp 445-455
2. Robbins TW: Animal models of psychosis, in Neurobiology of Mental Illness.
Edited by Charney DS, Nestler EJ. New York, Oxford University Press, 2004, pp
263-286
3. Krystal JH, Abi-Dargham A, Laruelle M, Moghaddam B: Pharmacological
models of psychoses, in Neurobiology of Mental Illness. Edited by Charney DS,
Nestler EJ. New York, Oxford University Press, 2004, pp 287-298
4. Carpenter WT, Koenig JI: The evolution of drug development in schizophrenia:
Past issues and future opportunities. Neuropsychopharmacology 2008; online
advanced copy
5. Adams CE, Rathbone J, Thornley B, Clarke M, Borrill J, Wahlbeck K, Awad AG:
Chlorpromazine for schizophrenia: a Cochrane systematic review of 50 years of
randomised controlled trials. BMC Medicine 2005; 3:15-21
6. Insel TR, Scolnick EM: Cure therapeutics and strategic prevention: raising the bar
for mental health research. Molecular Psychiatry 2006; 11(1):11-17
7. Agid Y, Buzsaki G, Diamond DM, Frackowiak R, Giedd J, Girault JA, Grace A,
Lambert JJ, Manji H, Mayberg H, Popoli M, Prochiantz A, Richter-Levin G,
Somogyi P, Spedding M, Svenningsson P, Weinberger D: Viewpoint - How can
drug discovery for psychiatric disorders be improved? Nature Reviews Drug
Discovery 2007; 6(3):189-201
8. Sams-Dodd F: Strategies to optimize the validity of disease models in the drug
discovery process. Drug Discovery Today 2006; 11(7-8):355-363
9. Mathysse S: Animal models in psychiatric research, in Progress in Brain
Research, vol 65. Edited by van Ree JM, Mathysse S, Elsevier Science, 1986, pp
259-270
10. Maddox VH: The historical development of phencyclidine, in PCP
(Phencyclidine): Historical and current perspectives. Edited by Domino EF.
Detroit, Ann Arbor, 1981, pp 1-8
11. Johnstone M, Evans V, Baigel S: Sernyl (Cl-395) in clinical anaesthesia. British
Journal of Anaesthesia 1959; 31(10):433-439
12. Cook CE, Brine DR, Jeffcoat AR, Hill JM, Wall ME, Perezreyes M, Diguiseppi
SR: Phencyclidine disposition after intravenous and oral doses. Clinical
Pharmacology & Therapeutics 1982; 31(5):625-634
13. Sioris LJ, Krenzelok EP: Phencyclidine Intoxication – Literature Review.
American Journal of Hospital Pharmacy 1978; 35(11):1362-1367
14. Griefenstein FE, Yoshitake J, Devault M, Gajewski JE: A study of a 1-Aryl cyclo
hexyl amine for anesthesia. Anesthesia & Analgesia 1958; 37(5):283-294
15. Collins VJ, Gorospe CA, Rovenstine EA: Intravenous nonbarbiturate, nonnarcotic
analgesics: Preliminary studies. Cyclohexylamines. Anesthesia & Analgesia
1960; 39:302-306
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
42
16. Burns RS, Lerner SE: The effects of phencyclidine in man: A review, in PCP
(Phencyclidine): Historical and current perspectives. Edited by Domino EF.
Detroit, Ann Arbor, 1981, pp 449-470
17. Zukin SR, Lowinson JH, Zylberman I: Substance abuse: Phencyclidine use
disorder, in Psychiatry, Volume 1. Edited by Tasman A, Kay J, Lieberman JA.
West Sussex, John Wiley & Sons, 2004, pp 1010-1045
18. Walberg CB, McCarron MM, Schlulze BW: Quantitation of phencyclidine in
serum by enzyme immunoassay: Results in 405 patients. Journal of Analytical
Toxicology 1983; 7:106-110
19. Meyer JS, Greifenstein F, Devault M: A new drug causing symptoms of sensory
deprivation - neurological, electroencephalographic and pharmalogical effects of
Sernyl. Journal of Nervous and Mental Disease 1959; 129(1):54-61
20. Kothary SP, Zsigmond EK: A double-blind study of the effective
antihallucinatory doses of diazepam prior to ketamine anesthesia. Clinical
Pharmacology and Therapeutics 1977; 21:108-109
21. Helrich M, Atwood JM: Modification of Sernyl anesthesia with haloperidol.
Anesthesia and Aanalgesia 1964; 43(5):471-474
22. Petersen RC, Stillman RC: Phencyclidine: An overview, in Phencyclidine (PCP)
Abuse: An Appraisal, Monograph 21. Edited by Petersen RC, Stillman RC.
Rockville, Maryland, National Institute on Drug Abuse, 1978, pp 1-17
23. Newmeyer JA: The epidemiology of PCP use in the late 1970s. Journal of
Psychedelic Drugs 1980; 12(3-4):211-215
24. Stillman R, Petersen RC: Paradox of phencyclidine (PCP) abuse. Annals of
Internal Medicine 1979; 90(3):428-430
25. Siegel RK: Phencyclidine and ketamine intoxication: A study of four populations
of recreational users, in Phencyclidine (PCP) Abuse: An Appraisal, Monograph
21. Edited by Petersen RC, Stillman RC. Rockville, Maryland, National Institute
on Drug Abuse, 1978, pp 119-147
26. Aniline O, Allen RE, Pitts FN, Yago LS, Pitts AF: The urban epidemic of
phencyclidine use - laboratory evidence from a public psychiatric hospital
inpatient service. Biological Psychiatry 1980; 15(5):813-817
27. Fauman B, Baker F, Coppleson LW, Rosen P, Segal MB: Psychosis induced by
phencyclidine. Concepts, Components and Configurations 1975; 4(3):223-225
28. Fauman MA, Fauman B: The psychiatric aspects of chronic phencyclidine use: A
study of chronic PCP users, in Phencyclidine (PCP) Abuse: An Appraisal,
Monograph 21. Edited by Petersen RC, Stillman RC. Rockville, Maryland,
National Institute on Drug Abuse, 1978, pp 183-200
29. Luisada PV: The phencyclidine psychosis: Phenomenology and treatment, in
Phencyclidine (PCP) Abuse: An Appraisal, Monograph 21. Edited by Petersen
RC, Stillman RC. Rockville, Maryland, National Institute on Drug Abuse, 1978,
pp 241-253
30. Smith DE, Wesson DR, Buxton ME, Seymour R, Kramer HM: The diagnosis and
treatment of the PCP abuse syndrome, in Phencyclidine (PCP) Abuse: An
Appraisal, Monograph 21. Edited by Petersen RC, Stillman RC. Rockville,
Maryland, National Institute on Drug Abuse, 1978, pp 229-240
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
43
31. Erard R, Luisada PV, Peele R: The PCP psychosis - prolonged intoxication or
drug precipitated functional illness. Journal of Psychedelic Drugs 1980; 12(3-
4):235-251
32. Yago KB, Pitts FN, Burgoyne RW, Aniline O, Yago LS, Pitts AF: The urban
epidemic of phencyclidine (PCP) use - Clinical and laboratory evidence from a
public psychiatric hospital emergency service. Journal of Clinical Psychiatry
1981; 42(5):193-196
33. Yesavage JA, Freman AM: Acute phencyclidine (PCP) intoxication -
Psychopathology and prognosis. Journal of Clinical Psychiatry 1978; 39(8):664-
666
34. Allen RM, Young SJ: Phencyclidine-induced psychosis. American Journal of
Psychiatry 1978; 135(9):1081-1084
35. Gwirtsman HE, Wittkop W, Gorelick D, Lemberg A, Motis G: Phencyclidine
intoxication - Incidence, clinical patterns and course of treatment. Research
Communications in Psychology Psychiatry and Behavior 1984; 9(4):405-410
36. McCarron MM, Schulze BW, Thompson GA, Conder MC, Goetz WA: Acute
phencyclidine intoxication - Incidence of clinical findings in 1,000 cases. Annals
of Emergency Medicine 1981; 10(5):237-242
37. Luisada PV, Brown BI: Clinical management of phencyclidine psychosis. Clinical
Toxicology 1976; 9(4):539-545
38. Pearlson GD: Psychiatric and medical syndromes associated with phencyclidine
(PCP) abuse. Johns Hopkins Medical Journal 1981; 148(1):25-33
39. Wright HH, Cole EA, Batey SR, Hanna K: Phencyclidine-induced psychosis - 8-
year follow-up of 10 cases. Southern Medical Journal 1988; 81(5):565-567
40. Burns RS, Lerner SE: Perspectives - Acute phencyclidine intoxication. Clinical
Toxicology 1976; 9(4):477-501
41. Rainey JM, Crowder MK: Prevalence of phencyclidine in street drug
preparations. New England Journal of Medicine 1974; 290(8):466-467
42. Giannini AJ, Eighan MS, Loiselle RH, Giannini MC: Comparison of haloperidol
and chlorpromazine in the treatment of phencyclidine psychosis. Journal of
Clinical Pharmacology 1984; 24(4):202-204
43. Lerner SE, Burns RS: Phencyclidine use among youth: History, epidemiology,
and acute and chronic intoxication, in Phencyclidine (PCP) Abuse: An Appraisal,
Monograph 21. Edited by Petersen RC, Stillman RC. Rockville, Maryland,
National Institute on Drug Abuse, 1978, pp 66-118
44. Kay J, Tasman A: Essentials of Psychiatry. West Sussex, John Wiley and Sons,
2006
45. Liden CB, Lovejoy FH, Costello CE: Phencyclidine - 9 Cases of poisoning.
JAMA Journal of the American Medical Association 1975; 234(5):513-516
46. Burns RS, Lerner SE, Corrado R, James SH, Schnoll SH: Phencyclidine - States
of acute intoxication and fatalities. Western Journal of Medicine 1975;
123(5):345-349
47. Fauman MA, Fauman BJ: The differential diagnosis of organic based psychiatric
disturbance in the emergency department. Concepts, Components and
Configurations 1977; 6(7):315-323
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
44
48. Smith DE: A clinical approach to the treatment of PCP abuse, in PCP
(phencyclidine): Historical and current perspectives. Edited by Domino EF.
Detroit, Ann Arbor, 1981, pp 471-486
49. Domino EF, Luby ED: Abnormal mental states induced by phencyclidine as a
model of schizophrenia, in PCP (phencyclidine): Historical and current
perspectives. Edited by Domino EF. Detroit, Ann Arbor, 1981, pp 401-419
50. Ban TA, Lohrenz JJ, Lehmann HE: Observations on the action of sernyl - a new
psychotropic drug. Canadian Psychiatric Association Journal 1961; 6(3):150-157
51. Rosse RB, Collins JP, Faymccarthy M, Alim TN, Wyatt RJ, Deutsch SI:
Phenomenological comparison of the idiopathic psychosis of schizophrenia and
drug-induced cocaine and phencyclidine psychoses - a retrospective study.
Clinical Neuropharmacology 1994; 17(4):359-369
52. Davies BM, Beech HR: The effect of 1-arylcyclohexylamine (Sernyl) on 12
normal volunteers. Journal of Mental Science 1960; 106(444):912-924
53. Rosenbaum G, Cohen BD, Luby ED, Gottlieb JS, Yelen D: Comparison of Sernyl
with other drugs - simulation of schizophrenic performance with Sernyl, LSD-25,
and amobarbital (Amytal) sodium. 1. Attention, motor function, and
proprioception. Archives of General Psychiatry 1959; 1(6):651-656
54. Carls KA, Ruehter VL: An evaluation of phencyclidine (PCP) psychosis: A
retrospective analysis at a state facility. American Journal of Drug and Alcohol
Abuse 2006; 32(4):673-678
55. Giannini AJ, Nageotte C, Loiselle RH, Malone DA, Price WA: Comparison of
chlorpromazine, haloperidol and pimozide in the treatment of phencyclidine
psychosis - D2 receptor specificity. Journal of Toxicology - Clinical Toxicology
1984; 22(6):573-579
56. Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R: Study of a new
schizophrenomimetic drug - Sernyl. Archives of Neurology and Psychiatry 1959;
81(3):363-369
57. Levy L, Cameron DE, Aitken RCB: Observation on 2 psychotomimetic drugs of
piperidine derivation-Ci-395 (Sernyl) and Ci-400. American Journal of Psychiatry
1960; 116(9):843-844
58. Itil T, Keskiner A, Kiremitci N, Holden JMC: Effect of phencyclidine in chronic
schizophrenics. Canadian Psychiatric Association Journal 1967; 12(2):209-212
59. Cohen BD, Rosenbaum G, Gottlieb JS, Luby ED: Comparison of phencyclidine
hydrochloride (Sernyl) with other drugs - Simulation of schizophrenic
performance with phencyclidine hydrochloride (Sernyl), lysergic-acid
diethylamide (LSD-25), and amobarbital (Amytal) sodium. 2. Symbolic and
sequential thinking. Archives of General Psychiatry 1962; 6(5):395-401
60. Bakker CB, Amini FB: Observations on the psychotomimetic effects of Sernyl.
Comprehensive Psychiatry 1961; 2:269-280
61. Braff DL, Geyer MA, Swerdlow NR: Human studies of prepulse inhibition of
startle: normal subjects, patient groups, and pharmacological studies.
Psychopharmacology 2001; 156(2-3):234-258
62. Domino EF, Chodoff P, Corssen G: Pharmacologic effects of Cl-581 a new
dissociative anesthetic in man. Clinical Pharmacology & Therapeutics 1965;
6(3):279-291
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
45
63. Wolff K, Winstock AR: Ketamine - From medicine to misuse. CNS Drugs 2006;
20(3):199-218
64. White PF, Way WL, Trevor AJ: Ketamine - Its pharmacology and therapeutic
uses. Anesthesiology 1982; 56(2):119-136
65. Idvall J, Ahlgren I, Aronsen KF, Stenberg P: Ketamine infusions -
Pharmacokinetics and clinical effects. British Journal of Anaesthesia 1979;
51(12):1167-1173
66. Bennett JA, Bullimore JA: Use of ketamine hydrochloride anesthesia for
radiotherapy in young children. British Journal of Anaesthesia 1973; 45(2):197-
201
67. Slogoff S, Allen GW, Wessels JV, Cheney DH: Clinical experience with
subanesthetic ketamine. Anesthesia and Analgesia 1974; 53(3):354-358
68. White JM, Ryan CF: Pharmacological properties of ketamine. Drug and Alcohol
Review 1996; 15(2):145-155
69. Reier CE: Ketamine - Dissociative agent or hallucinogen? New England Journal
of Medicine 1971; 284(14):791-792
70. Collier BB: Ketamine and conscious mind. Anaesthesia 1972; 27(2):120-134
71. Modvig KM, Nielsen SF: Psychological changes in children after anesthesia -
Comparison between halothane and ketamine. Acta Anaesthesiologica
Scandinavica 1977; 21(6):541-544
72. Javitt DC, Zukin SR: Recent advances in the phencyclidine model of
schizophrenia. American Journal of Psychiatry 1991; 148(10):1301-1308
73. Vincent JP, Kartalovski B, Geneste P, Kamenka JM, Lazdunski M: Interaction of
phencyclidine (angel dust) with a specific receptor in rat brain membranes.
Proceedings of the National Academy of Sciences of the United States of America
1979; 76(9):4678-4682
74. Hampton RY, Medzihradsky F, Woods JH, Dahlstrom PJ: Stereospecific binding
of H-3-labeled phencyclidine in brain membranes. Life Sciences 1982;
30(25):2147-2154
75. FDA Drug Bulletin: Ketamine abuse. FDA Drug Bulletin 1979; 9(4):24
76. Dotson JW, Ackerman DL, West LJ: Ketamine abuse. Journal of Drug Issues
1995; 25(4):751-757
77. Jansen KLR: A review of the nonmedical use of ketamine: Use, users and
consequences. Journal of Psychoactive Drugs 2000; 32(4):419-433
78. Stafford P: Psychedelics Encyclopedia. Berkeley, California, Ronin Publishing,
1992
79. Lankenau SE, Clatts MC: Ketamine injection among high risk youth: Preliminary
findings from New York City. Journal of Drug Issues 2002; 32(3):893-905
80. Maxwell JC: Party drugs: Properties, prevalence, patterns, and problems.
Substance Use & Misuse 2005; 40(9-10):1203-1240
81. Maxwell JC: The response to club drug use. Current Opinion in Psychiatry 2003;
16(3):279-289
82. Lyttle T, Montagne M: Drugs, music, and ideology - a social pharmacological
interpretation of the acid house movement. International Journal of the Addictions
1992; 27(10):1159-1177
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
46
83. Degenhardt L, Copeland J, Dillon P: Recent trends in the use of "club drugs": An
Australian review. Substance Use & Misuse 2005; 40(9-10):1241-1256
84. Weiner AL, Vieira L, McKay CA, Bayer MJ: Ketamine abusers presenting to the
emergency department: A case series. Journal of Emergency Medicine 2000;
18(4):447-451
85. Lim DK: Ketamine associated psychedelic effects and dependence. Singapore
Medical Journal 2003; 44(1):31-34
86. Dillon P, Copeland J, Jansen K: Patterns of use and harms associated with non-
medical ketamine use. Drug and Alcohol Dependence 2003; 69(1):23-28
87. Uhlhaas PJ, Millard I, Muetzelfeldt L, Curran HV, Morgan CJA: Perceptual
organization in ketamine users: preliminary evidence of deficits on night of drug
use but not 3 days later. Journal of Psychopharmacology 2007; 21(3):347-352
88. Curran HV, Monaghan L: In and out of the K-hole: a comparison of the acute and
residual effects of ketamine in frequent and infrequent ketamine users. Addiction
2001; 96(5):749-760
89. Curran HV, Morgan C: Cognitive, dissociative and psychotogenic effects of
ketamine in recreational users on the night of drug use and 3 days later. Addiction
2000; 95(4):575-590
90. Morgan CJA, Riccelli M, Maitland CH, Curran HV: Long-term effects of
ketamine: evidence for a persisting impairment of source memory in recreational
users. Drug and Alcohol Dependence 2004; 75(3):301-308
91. Carpenter WT: The schizophrenia ketamine challenge study debate. Biological
Psychiatry 1999; 46(8):1081-1091
92. Kudoh A, Katagai H, Takazawa T: Anesthesia with ketamine, propofol, and
fentanyl decreases the frequency of postoperative psychosis emergence and
confusion in schizophrenic patients. Journal of Clinical Anesthesia 2002;
14(2):107-110
93. Lahti AC, Holcomb HH, Medoff DR, Tamminga CA: Ketamine Activates
Psychosis and Alters Limbic Blood-Flow in Schizophrenia. Neuroreport 1995;
6(6):869-872
94. Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, Breier A:
Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment
in neuroleptic-free schizophrenics. Neuropsychopharmacology 1997; 17(3):141-
150
95. Malhotra AK, Adler CM, Kennison SD, Elman I, Pickar D, Breier A: Clozapine
blunts N-methyl-D-aspartate antagonist-induced psychosis: A study with
ketamine. Biological Psychiatry 1997; 42(8):664-668
96. Lahti AC, Weiler MA, Michaelidis T, Parwani A, Tamminga CA: Effects of
ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology
2001; 25(4):455-467
97. Pomarol-Clotet E, Honey GD, Murray GK, Corlett PR, Absalom AR, Lee M,
McKenna PJ, Bullmore ET, Fletcher PC: Psychological effects of ketamine in
healthy volunteers - Phenomenological study. British Journal of Psychiatry 2006;
189:173-179
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
47
98. Ghoneim MM, Hinrichs JV, Mewaldt SP, Petersen RC: Ketamine - Behavioral-
effects of subanesthetic doses. Journal of Clinical Psychopharmacology 1985;
5(2):70-77
99. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD,
Heninger GR, Bowers MB, Charney DS: Subanesthetic effects of the non-
competitive NMDA antagonist, ketamine, in humans - Psychotomimetic,
perceptual, cognitive, and neuroendocrine responses. Archives of General
Psychiatry 1994; 51(3):199-214
100. Adler CM, Goldberg TE, Malhotra AK, Pickar D, Breier A: Effects of ketamine
on thought disorder, working memory, and semantic memory in healthy
volunteers. Biological Psychiatry 1998; 43(11):811-816
101. Adler CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D, Breier A:
Comparison of ketamine-induced thought disorder in healthy volunteers and
thought disorder in schizophrenia. American Journal of Psychiatry 1999;
156(10):1646-1649
102. Covington MA, Riedel WJ, Brown C, He CZ, Morris E, Weinstein S, Semple J,
Brown J: Does ketamine mimic aspects of schizophrenic speech? Journal of
Psychopharmacology 2007; 21(3):338-346
103. Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D, Breier
A: NMDA receptor function and human cognition: The effects of ketamine in
healthy volunteers. Neuropsychopharmacology 1996; 14(5):301-307
104. Krystal JH, Perry EB, Gueorguieva R, Belger A, Madonich SH, Abi-Dargham A,
Cooper TB, MacDougall L, Abi-Saab W, D'Souza DC: Comparative and
interactive human psychopharmacologic effects of ketamine and amphetamine -
Implications for glutamatergic and dopaminergic model psychoses and cognitive
function. Archives of General Psychiatry 2005; 62(9):985-995
105. Gouzoulis-Mayfrank E, Heekeren K, Neukirch A, Stoll M, Stock C, Obradovic
M, Kovar KA: Psychological effects of (S)-ketamine and N,N-
dimethyltryptamine (DMT): A double-blind, cross-over study in healthy
volunteers. Pharmacopsychiatry 2005; 38(6):301-311
106. Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J: Differential
psychopathology and patterns of cerebral glucose utilisation produced by (S)- and
(R)-ketamine in healthy volunteers using positron emission tomography (PET).
European Neuropsychopharmacology 1997; 7(1):25-38
107. Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey
T, Craft S, Olney JW: Ketamine-induced NMDA receptor hypofunction as a
model of memory impairment and psychosis. Neuropsychopharmacology 1999;
20(2):106-118
108. Morgan CJA, Curran HV: Acute and chronic effects of ketamine upon human
memory: a review. Psychopharmacology 2006; 188(4):408-424
109. Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R: NMDA
receptor antagonist effects, cortical glutamatergic function, and schizophrenia:
toward a paradigm shift in medication development. Psychopharmacology 2003;
169(3-4):215-233
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
48
110. McFarland NR, Haber SN: Thalamic relay nuclei of the basal ganglia form both
reciprocal and nonreciprocal cortical connections, linking multiple frontal cortical
areas. Journal of Neuroscience 2002; 22(18):8117-8132
111. Pantelis C, Barnes TRE, Nelson HE, Tanner S, Weatherley L, Owen AM,
Robbins TW: Frontal-striatal cognitive deficits in patients with chronic
schizophrenia. Brain 1997; 120:1823-1843
112. Sharp FR, Tomitaka M, Bernaudin M, Tomitaka S: Psychosis: pathological
activation of limbic thalamocortical circuits by psychomimetics and
schizophrenia? Trends in Neurosciences 2001; 24(6):330-334
113. Harborne GC, Watson FL, Healy DT, Groves L: The effects of sub-anaesthetic
doses of ketamine on memory, cognitive performance and subjective experience
in healthy volunteers. Journal of Psychopharmacology 1996; 10(2):134-140
114. Radant AD, Bowdle TA, Cowley DS, Kharasch ED, Roy-Byrne PP: Does
ketamine-mediated N-methyl-D-aspartate receptor antagonism cause
schizophrenia-like oculomotor abnormalities? Neuropsychopharmacology 1998;
19(5):434-444
115. Krystal JH, D'Souza DC, Karper LP, Bennett A, Abi-Dargham A, Abi-Saab D,
Cassello K, Bowers MB, Vegso S, Heninger GR, Charney DS: Interactive effects
of subanesthetic ketamine and haloperidol in healthy humans.
Psychopharmacology 1999; 145(2):193-204
116. Krystal JH, Karper LP, Bennett A, D'Souza DC, Abi-Dargham A, Morrissey K,
Abi-Saab D, Bremner JD, Bowers MB, Suckow RF, Stetson P, Heninger GR,
Charney DS: Interactive effects of subanesthetic ketamine and subhypnotic
lorazepam in humans. Psychopharmacology 1998; 135(3):213-229
117. Parwani A, Weiler MA, Blaxton TA, Warfel D, Hardin M, Frey K, Lahti AC: The
effects of a subanesthetic dose of ketamine on verbal memory in normal
volunteers. Psychopharmacology 2005; 183(3):265-274
118. LaPorte DJ, Blaxton TA, Michaelidis T, Robertson DU, Weiler MA, Tamminga
CA, Lahti AC: Subtle effects of ketamine on memory when administered
following stimulus presentation. Psychopharmacology 2005; 180(3):385-390
119. Morgan CJA, Mofeez A, Brandner B, Bromley L, Curran HV: Ketamine impairs
response inhibition and is positively reinforcing in healthy volunteers: a dose-
response study. Psychopharmacology 2004; 172(3):298-308
120. Hetem LAB, Danion JM, Diemunsch P, Brandt C: Effect of a subanesthetic dose
of ketamine on memory and conscious awareness in healthy volunteers.
Psychopharmacology 2000; 152(3):283-288
121. Lofwall MR, Griffiths RR, Mintzer MZ: Cognitive and subjective acute dose
effects of intramuscular ketamine in healthy adults. Experimental and Clinical
Psychopharmacology 2006; 14(4):439-449
122. Honey GD, O'Loughlin C, Turner DC, Pomarol-Clotet E, Corlett PR, Fletcher
PC: The effects of a subpsychotic dose of ketamine on recognition and source
memory for agency: Implications for pharmacological modelling of core
symptoms of schizophrenia. Neuropsychopharmacology 2006; 31(2):413-423
123. Fletcher PC, Honey GD: Schizophrenia, ketamine and cannabis: Evidence of
overlapping memory deficits. Trends in Cognitive Sciences 2006; 10(4):167-174
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
49
124. Honey RAE, Turner DC, Honey GD, Sharar SR, Kumaran D, Pomarol-Clotet E,
McKenna P, Sahakian B, Robbins TW, Fletcher P: Subdissociative dose ketamine
produces a deficit in manipulation but not maintenance of the contents of working
memory. Neuropsychopharmacology 2003; 28(11):2037-2044
125. Passie T, Karst M, Wiese B, Emrich HM, Schneider U: Effects of different
subanesthetic doses of (S)-ketamine on neuropsychology, psychopathology, and
state of consciousness in man. Neuropsychobiology 2005; 51(4):226-233
126. Gouzoulis-Mayfrank E, Heekeren K, Neukirch A, Stoll M, Stock C, Daumann J,
Obradovic M, Kovar KA: Inhibition of return in the human 5HT(2A) agonist and
NMDA antagonist model of psychosis. Neuropsychopharmacology 2006;
31(2):431-441
127. Abel KM, Allin MPG, Hemsley DR, Geyer MA: Low dose ketamine increases
prepulse inhibition in healthy men. Neuropharmacology 2003; 44(6):729-737
128. Krystal JH, Bennett A, Abi-Saab D, Belger A, Karper LP, D'Souza DC, Lipschitz
D, Abi-Dargham A, Charney DS: Dissociation of ketamine effects on rule
acquisition and rule implementation: Possible relevance to NMDA receptor
contributions to executive cognitive functions. Biological Psychiatry 2000;
47(2):137-143
129. Morgan CJA, Mofeez A, Brandner B, Bromley L, Curran HV: Acute effects of
ketamine on memory systems and psychotic symptoms in healthy volunteers.
Neuropsychopharmacology 2004; 29(1):208-218
130. Fletcher PC, Henson RNA: Frontal lobes and human memory - Insights from
functional neuroimaging. Brain 2001; 124:849-881
131. Henson R: A mini-review of fMRI studies of human medial temporal lobe activity
associated with recognition memory. Quarterly Journal of Experimental
Psychology Section B-Comparative and Physiological Psychology 2005; 58(3-
4):340-360
132. Ragland JD, Gur RC, Valdez J, Turetsky BI, Elliott M, Kohler C, Siegel S, Kanes
S, Gur RE: Event-related fMRI of frontotemporal activity during word encoding
and recognition in schizophrenia. American Journal of Psychiatry 2004;
161(6):1004-1015
133. Hofer A, Weiss EM, Golaszewski SM, Siedentopf CM, Brinkhoff C, Kremser C,
Felber S, Fleischhacker WW: Neural correlates of episodic encoding and
recognition of words in unmedicated patients during an acute episode of
schizophrenia: A functional MRI study. American Journal of Psychiatry 2003;
160(10):1802-1808
134. Glahn DC, Ragland JD, Abramoff A, Barrett J, Laird AR, Bearden CE, Velligan
DI: Beyond hypofrontality: A quantitative meta-analysis of functional
neuroimaging studies of working memory in schizophrenia. Human Brain
Mapping 2005; 25(1):60-69
135. Ragland JD, Gur RC, Raz J, Schroeder L, Kohler CG, Smith RJ, Alavi A, Gur
RE: Effect of schizophrenia on frontotemporal activity during word encoding and
recognition: A PET cerebral blood flow study. American Journal of Psychiatry
2001; 158(7):1114-1125
136. Tamminga CA, Thaker GK, Buchanan R, Kirkpatrick B, Alphs LD, Chase TN,
Carpenter WT: Limbic system abnormalities identified in schizophrenia using
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
50
positron emission tomography with fluorodeoxyglucose and neocortical
alterations with deficit syndrome. Archives of General Psychiatry 1992;
49(7):522-530
137. Andreasen NC, Oleary DS, Cizadlo T, Arndt S, Rezai K, Ponto LLB, Watkins
GL, Hichwa RD: Schizophrenia and cognitive dysmetria: A positron-emission
tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry.
Proceedings of the National Academy of Sciences of the United States of America
1996; 93(18):9985-9990
138. Andreasen NC, Rezai K, Alliger R, Swayze VW, Flaum M, Kirchner P, Cohen G,
Oleary DS: Hypofrontality in neuroleptic-naive patients and in patients with
chronic schizophrenia - Assessment with Xe-133 single photon emission
computed tomography and the Tower of London. Archives of General Psychiatry
1992; 49(12):943-958
139. Haznedar MM, Buchsbaum MS, Luu C, Hazlett EA, Siegel BV, Lohr J, Wu J,
Haier RJ, Bunney WE: Decreased anterior cingulate gyrus metabolic rate in
schizophrenia. American Journal of Psychiatry 1997; 154(5):682-684
140. Siegel BV, Buchsbaum MS, Bunney WE, Gottschalk LA, Haier RJ, Lohr JB,
Lottenberg S, Najafi A, Nuechterlein KH, Potkin SG, Wu JC: Cortical-striatal-
thalamic circuits and brain glucose metabolic activity in 70 unmedicated male-
schizophrenic patients. American Journal of Psychiatry 1993; 150(9):1325-1336
141. Jessen F, Scheef L, Germeshausen L, Tawo Y, Kockler M, Kuhn KU, Maier W,
Schild HH, Heun R: Reduced hippocampal activation during encoding and
recognition of words in schizophrenia patients. American Journal of Psychiatry
2003; 160(7):1305-1312
142. Holcomb HH, Lahti AC, Medoff DR, Cullen T, Tamminga CA: Effects of
noncompetitive NMDA receptor blockade on anterior cingulate cerebral blood
flow in volunteers with schizophrenia. Neuropsychopharmacology 2005;
30(12):2275-2282
143. Honey GD, Honey RAE, O'Loughlin C, Sharar SR, Kumaran D, Suckling J,
Menon DK, Sleator C, Bullmore ET, Fletcher PC: Ketamine disrupts frontal and
hippocampal contribution to encoding and retrieval of episodic memory: An fMRI
study. Cerebral Cortex 2005; 15(6):749-759
144. Honey RAE, Honey GD, O'Loughlin C, Sharar SR, Kumaran D, Bullmore ET,
Menon DK, Donovan T, Lupson VC, Bisbrown-Chippendale R, Fletcher PC:
Acute ketamine administration alters the brain responses to executive demands in
a verbal working memory task: an fMRI study. Neuropsychopharmacology 2004;
29(6):1203-1214
145. Fu CHY, Abel KM, Allin MPG, Gasston D, Costafreda SG, Suckling J, Williams
SCR, McGuire PK: Effects of ketamine on prefrontal and striatal regions in an
overt verbal fluency task: a functional magnetic resonance imaging study.
Psychopharmacology 2005; 183(1):92-102
146. Langsjo JW, Salmi E, Kaisti KK, Aalto S, Hinkka S, Aantaa R, Oikonen V,
Viljanen T, Kurki T, Silvanto M, Scheinin H: Effects of subanesthetic ketamine
on regional cerebral glucose metabolism in humans. Anesthesiology 2004;
100(5):1065-1071
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
51
147. Langsjo JW, Kaisti KK, Aalto S, Hinkka S, Aantaa R, Oikonen V, Sipila H, Kurki
T, Silvanto M, Scheinin H: Effects of subanesthetic doses of ketamine on regional
cerebral blood flow, oxygen consumption, and blood volume in humans.
Anesthesiology 2003; 99(3):614-623
148. Stone JM, Erlandsson K, Arstad E, Bressan RA, Squassante L, Teneggi V, Ell PJ,
Pilowsky LS: Ketamine displaces the novel NMDA receptor SPET probe [I-
123]CNS-1261 in humans in vivo. Nuclear Medicine and Biology 2006;
33(2):239-243
149. van Berckel BNM, Oranje B, van Ree JM, Verbaten MN, Kahn RS: The effects of
low dose ketamine on sensory gating, neuroendocrine secretion and behavior in
healthy human subjects. Psychopharmacology 1998; 137(3):271-281
150. Oranje B, Gispen-de Wied CC, Verbaten MN, Kahn RS: Modulating sensory
gating in healthy volunteers: The effects of ketamine and haloperidol. Biological
Psychiatry 2002; 52(9):887-895
151. Heekeren K, Neukirch A, Daumann J, Stoll M, Obradovic M, Kovar KA, Geyer
MA, Gouzoulis-Mayfrank E: Prepulse inhibition of the startle reflex and its
attentional modulation in the human S-ketamine and N,N-dimethyltryptamine
(DMT) models of psychosis. Journal of Psychopharmacology 2007; 21(3):312-
320
152. Duncan EJ, Madonick SH, Parwani A, Angrist B, Rajan R, Chakravorty S,
Efferen TR, Szilagyi S, Stephanides M, Chappell PB, Gonzenbach S, Ko GN,
Rotrosen JP: Clinical and sensorimotor gating effects of ketamine in normals.
Neuropsychopharmacology 2001; 25(1):72-83
153. Umbricht D, Schmid L, Koller R, Vollenweider FX, Hell D, Javitt DC: Ketamine-
induced deficits in auditory and visual context-dependent processing in healthy
volunteers - Implications for models of cognitive deficits in schizophrenia.
Archives of General Psychiatry 2000; 57(12):1139-1147
154. Sauer H, Kreitschmann-Andermahr I, Gaser E, Nowak H, Demme U, Rosburg T:
Ketamine reduces the neuromagnetic mismatch reaction. Schizophrenia Research
2000; 41(1):148-148
155. O'Brien R, Cohen S: Encyclopedia of drug abuse. New York, Facts on File, 1984
156. Aghajanian GK, Marek GJ: Serotonin model of schizophrenia: emerging role of
glutamate mechanisms. Brain Research Reviews 2000; 31(2-3):302-312
157. Henderson LA, Glass WJ: LSD: Still with us after all these years. San Francisco,
Jossey-Bass Publishers, 1998
158. Grinspoon L, Bakalar JB: Psychedelic drugs reconsidered. New York, The
Lindesmith Center, 1998
159. Houston J: Phenomenology of the psychedelic experience, in Psychodelic Drugs.
Edited by Hicks RE, Fink PJ. New York, Grune & Stratton, 1969, pp 1-7
160. Katz MM, Waskow IE, Olsson J: Characterizing Psychological State Produced by
LSD. Journal of Abnormal Psychology 1968; 73(1):1-14
161. Stone AL, O'Brien MS, De la Torre A, Anthony JC: Who is becoming
hallucinogen dependent soon after hallucinogen use starts? Drug and Alcohol
Dependence 2007; 87(2-3):153-163
162. Siegel RK, West LJ: Hallucinations. Behavior, experience & theory. New York,
John Wiley & Sons, 1975
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
52
163. Johnston LD, O'Malley PM, Bachman JG, Schulenberg JE: Monitoring the
Future. National results on adolescent drug use. Overview of key findings, 2005.
Bethesda, MD, National Institute on Drug Abuse, 2006
164. Riley SCE, James C, Gregory D, Dingle H, Cadger M: Patterns of recreational
drug use at dance events in Edinburgh, Scotland. Addiction 2001; 96(7):1035-
1047
165. Lenton S, Boys A, Norcross K: Raves, drugs and experience: drug use by a
sample of people who attend raves in Western Australia. Addiction 1997;
92(10):1327-1337
166. McCambridge J, Winstock A, Hunt N, Mitcheson L: 5-year trends in use of
hallucinogens and other adjunct drugs among UK dance drug users. European
Addiction Research 2007; 13(1):57-64
167. Halpern JH: The use of hallucinogens in the treatment of addiction. Addiction
Research 1996; 4(2):177-189
168. Cohen S: Lysergic acid diethylamide - Side-effects and complications. Journal of
Nervous and Mental Disease 1960; 130(1):30-40
169. Levine J, Ludwig AM: The LSD controversy. Comprehensive Psychiatry 1964;
5(5):314-321
170. Cohen S, Ditman KS: Prolonged adverse reactions to lysergic acid diethylamide.
Archives of General Psychiatry 1963; 8(5):475-480
171. Cholden LS, Kurland A, Savage C: Clinical reactions and tolerance to LSD in
chronic schizophrenia. Journal of Nervous and Mental Disease 1955; 122(3):211-
221
172. Fink M, Simeon J, Haque W, Itil T: Prolonged adverse reactions to LSD in
psychotic subjects. Archives of General Psychiatry 1966; 15(5):450-454
173. Abraham HD, Aldridge AM: Adverse consequences of lysergic acid
diethylamide. Addiction 1993; 88(10):1327-1334
174. Strassman RJ: Adverse reactions to psychedelic drugs - a review of the literature.
Journal of Nervous and Mental Disease 1984; 172(10):577-595
175. Abraham HD, Aldridge AM, Gogia P: The psychopharmacology of
hallucinogens. Neuropsychopharmacology 1996; 14(4):285-298
176. Glass GS, Bowers MB: Chronic psychosis associated with long-term
psychotomimetic drug abuse. Archives of General Psychiatry 1970; 23(2):97-103
177. Hays P, Tilley JR: Differences between LSD psychosis and schizophrenia.
Canadian Psychiatric Association Journal 1973; 18(4):331-333
178. Sedman G, Kenna JC: The use of LSD-25 as a diagnostic aid in doubtful cases of
schizophrenia. British Journal of Psychiatry 1965; 111(470):96-100
179. Vardy MM, Kay SR: LSD psychosis or LSD induced schizophrenia - A
multimethod inquiry. Archives of General Psychiatry 1983; 40(8):877-883
180. Ungerlei.Jt, Fisher DD, Fuller M: Dangers of LSD - Analysis of 7 months
experience in a university hospitals psychiatric service. Journal of the American
Medical Association 1966; 197(6):389-392
181. Frosch WA, Robbins ES, Stern M: Untoward reactions to lysergic acid
diethylamide (LSD) resulting in hospitalization. New England Journal of
Medicine 1965; 273(23):1235-1239
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
53
182. Bowers MB, Swigar ME: Vulnerability to psychosis associated with hallucinogen
use. Psychiatry Research 1983; 9(2):91-97
183. Potvin S, Stip E, Roy J-Y: Toxic psychoses as pharmacological models of
schizophrenia. Current Psychiatry Review 2005; 1:23-32
184. Langs RJ, Barr HL: Lysergic acid diethylamide (LSD-25) and schizophrenic
reactions - A comparative study. Journal of Nervous and Mental Disease 1968;
147(2):163-172
185. Hollister LE: Clinical syndrome from LSD-25 compared with epinephrine.
Diseases of the Nervous System 1964; 25(7):427-429
186. Breier A: Serotonin, Schizophrenia and antipsychotic drug action. Schizophrenia
Research 1995; 14(3):187-202
187. Riba J, Rodriguez-Fornells A, Barbanoj MJ: Effects of ayahuasca on sensory and
sensorimotor gating in humans as measured by P50 suppression and prepulse
inhibition of the startle reflex, respectively. Psychopharmacology 2002;
165(1):18-28
188. Gouzoulis-Mayfrank E, Heekeren K, Thelen B, Lindenblatt H, Kovar KA, Sass
H, Geyer MA: Effects of the hallucinogen psilocybin on habituation and prepulse
inhibition of the startle reflex in humans. Behavioural Pharmacology 1998;
9(7):561-566
189. Umbricht D, Koller R, Vollenweider FX, Schmid L: Mismatch negativity predicts
psychotic experiences induced by NMDA receptor antagonist in healthy
volunteers. Biological Psychiatry 2002; 51(5):400-406
190. Umbricht D, Vollenweider FX, Schmid L, Grubel C, Skrabo A, Huber T, Koller
R: Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation
and AX-continuous performance task: Implications for the neuropharmacology of
cognitive deficits in schizophrenia. Neuropsychopharmacology 2003; 28(1):170-
181
191. Halpern JH, Pope HG: Hallucinogen persisting perception disorder: what do we
know after 50 years? Drug and Alcohol Dependence 2003; 69(2):109-119
192. AbiDargham A, Laruelle M, Charney D, Krystal J: Serotonin and schizophrenia:
A review. Drugs of Today 1996; 32(2):171-185
193. Iqbal N, vanPraag HM: The role of serotonin in schizophrenia. European
Neuropsychopharmacology 1995; 5:11-23
194. Amargos-Bosch M, Lopez-Gil X, Artigas F, Adell A: Clozapine and olanzapine,
but not haloperidol, suppress serotonin efflux in the medial prefrontal cortex
elicited by phencyclidine and ketamine. International Journal of
Neuropsychopharmacology 2006; 9(5):565-573
195. Lopez-Gil X, Babot Z, Amargos-Bosch M, Sunol C, Artigas F, Adell A:
Clozapine and haloperidol differently suppress the MK-801 increased
glutamatergic and serotonergic transmission in the medial prefrontal cortex of the
rat. Neuropsychopharmacology 2007; 32(10):2087-2097
196. Breese GR, Knapp DJ, Moy SS: Integrative role for serotonergic and
glutamatergic receptor mechanisms in the action of NMDA antagonists: potential
relationships to antipsychotic drug actions on NMDA antagonist responsiveness.
Neuroscience and Biobehavioral Reviews 2002; 26(4):441-455
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
54
197. Noda Y, Kamei H, Mamiya T, Furukawa H, Nabeshima T: Repeated
phencyclidine treatment induces negative symptom-like behavior in forced
swimming test in mice: Imbalance of prefrontal serotonergic and dopaminergic
functions. Neuropsychopharmacology 2000; 23(4):375-387
198. Martin P, Carlsson ML, Hjorth S: Systemic PCP treatment elevates brain
extracellular 5-HT: a microdialysis study in awake rats. Neuroreport 1998;
9(13):2985-2988
199. Nichols CD, Sanders-Bush E: A single dose of lysergic acid diethylamide
influences gene expression patterns within the mammalian brain.
Neuropsychopharmacology 2002; 26(5):634-642
200. Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF,
Zhou M, Okawa Y, Calldo LF, Milligan G, Gingrich JA, Filizola M, Meana JJ,
Sealfon SC: Identification of a serotonin/glutamate receptor complex implicated
in psychosis. Nature 2008:doi:10.1038/nature06612
201. Solowij N: Ecstasy (3,4-methylenedioxymethamphetamine). Current Opinion in
Psychiatry 1993; 6:411-415
202. Gamma A, Buck A, Berthold T, Hell D, Vollenweider FX: 3,4-
methylenedioxymethamphetamine (MDMA) modulates cortical and limbic brain
activity as measured by [(H2O)-O-15]-PET in healthy humans.
Neuropsychopharmacology 2000; 23(4):388-395
203. Parrott AC: Human psychopharmacology of Ecstasy (MDMA): a review of 15
years of empirical research. Human Psychopharmacology-Clinical and
Experimental 2001; 16(8):557-577
204. Bialer PA: Designer drugs in the general hospital. Psychiatric Clinics of North
America 2002; 25(1):231-243
205. Thomasius R, Petersen KU, Zapletalova P, Wartberg L, Zeichner D, Schmoldt A:
Mental disorders in current and former heavy ecstasy (MDMA) users. Addiction
2005; 100(9):1310-1319
206. Cottler LB, Womack SB, Compton WM, Ben-Abdallah A: Ecstasy abuse and
dependence among adolescents and young adults: applicability and reliability of
DSM-IV criteria. Human Psychopharmacology-Clinical and Experimental 2001;
16(8):599-606
207. World Health Organization: Amphetamine like stimulants. Report from the WHO
meeting on amphetamines, MDMA and other psychostimulants. Geneva, WHO,
1996
208. Cole JC, Sumnall HR: Altered states: the clinical effects of ecstasy.
Pharmacology & Therapeutics 2003; 98(1):35-58
209. Green AR, Mechan AO, Elliott JM, O'Shea E, Colado MI: The pharmacology and
clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA,
"ecstasy"). Pharmacological Reviews 2003; 55(3):463-508
210. Landry MJ: MDMA: A review of epidemiologic data. Journal of Psychoactive
Drugs 2002; 34(2):163-169
211. Australian Institute of Health and Welfare: 2004 National Drug Strategy
Household Survey: Detailed Findings. AIHW cat. no. PHE 66. Canberra, AIHW,
2005
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
55
212. Australian Institute of Health and Welfare: 2001 National Drug Strategy
Household Survey; First results. AIHW cat. no. PHE 35. Canberra, AIHW, 2002
213. Wish ED, Fitzelle DB, O'Grady KE, Hsu MH, Arria AM: Evidence for significant
polydrug use among ecstasy-using college students. Journal of American College
Health 2006; 55(2):99-104
214. Topp L, Hando J, Dillon P, Roche A, Solowij N: Ecstasy use in Australia:
patterns of use and associated harm. Drug and Alcohol Dependence 1999; 55(1-
2):105-115
215. Solowij N, Hall W, Lee N: Recreational MDMA use in Sydney - A profile of
ecstasy users and their experiences with the drug. British Journal of Addiction
1992; 87(8):1161-1172
216. Schifano F: A bitter pill. Overview of ecstasy (MDMA, MDA) related fatalities.
Psychopharmacology 2004; 173(3-4):242-248
217. Henry JA, Jeffreys KJ, Dawling S: Toxicity and deaths from 3,4-
methylenedioxymethamphetamine (ecstasy). Lancet 1992; 340(8816):384-387
218. Schifano F, Oyefeso A, Corkery J, Cobain K, Jambert-Gray R, Martinotti G,
Ghodse AH: Death rates from ecstasy (MDMA, MDA) and polydrug use in
England and Wales 1996-2002. Human Psychopharmacology-Clinical and
Experimental 2003; 18(7):519-524
219. Schifano F, Corkery J, Deluca P, Oyefeso A, Ghodse AH: Ecstasy (MDMA,
MDA, MDEA, MBDB) consumption, seizures, retated offences, prices, dosage
levels and deaths in the UK (1994-2003). Journal of Psychopharmacology 2006;
20(3):456-463
220. Morgan MJ: Ecstasy (MDMA): a review of its possible persistent psychological
effects. Psychopharmacology 2000; 152(3):230-248
221. Medina KL, Shear PK: Anxiety, depression, and behavioral symptoms of
executive dysfunction in ecstasy users: Contributions of polydrug use. Drug and
Alcohol Dependence 2007; 87(2-3):303-311
222. Roiser JP, Rogers RD, Sahakian BJ: Neuropsychological function in ecstasy
users: a study controlling for polydrug use. Psychopharmacology 2007;
189(4):505-516
223. Kalechstein AD, De La Garza R, Mahoney JJ, Fantegrossi WE, Newton TF:
MDMA use and neurocognition: a meta-analytic review. Psychopharmacology
2007; 189(4):531-537
224. Thomasius R, Petersen K, Buchert R, Andresen B, Zapletalova P, Wartberg L,
Nebeling B, Schmoldt A: Mood, cognition and serotonin transporter availability
in current and former ecstasy (MDMA) users. Psychopharmacology 2003;
167(1):85-96
225. Parrott AC, Buchanan T, Scholey AB, Heffernan T, Ling J, Rodgers J:
Ecstasy/MDMA attributed problems reported by novice, moderate and heavy
recreational users. Human Psychopharmacology - Clinical and Experimental
2002; 17(6):309-312
226. Quednow BB, Jessen F, Kuhn KU, Maier W, Daum I, Wagner M: Memory
deficits in abstinent MDMA (ecstasy) users: neuropsychological evidence of
frontal dysfunction. Journal of Psychopharmacology 2006; 20(3):373-384
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
56
227. Zakzanis KK, Young DA: Memory impairment in abstinent MDMA ("ecstasy")
users: A longitudinal investigation. Neurology 2001; 56(7):966-969
228. Fox HC, McLean A, Turner JJD, Parrott AC, Rogers R, Sahakian BJ:
Neuropsychological evidence of a relatively selective profile of temporal
dysfunction in drug-free MDMA ("ecstasy") polydrug users.
Psychopharmacology 2002; 162(2):203-214
229. Schuler S: Early recognition and early intervention in drug-induced psychoses.
Neurology Psychiatry and Brain Research 1998; 5(4):197-204
230. Yucel M, L:ubman DI, Solowij N, Brewer WJ: Understanding drug addiction: a
neuropsychological perspective. Australian and New Zealand Journal of
Psychiatry 2007; 41:957-968
231. Lieb R, Schuetz CG, Pfister H, von Sydow K, Wittchen HU: Mental disorders in
ecstasy users: a prospective-longitudinal investigation. Drug and Alcohol
Dependence 2002; 68(2):195-207
232. Falck RS, Carlson RG, Wang JC, Siegal HA: Psychiatric disorders and their
correlates among young adult MDMA users in Ohio. Journal of Psychoactive
Drugs 2006; 38(1):19-29
233. Sumnell HR, Cole JC: Self-reported depressive symptomatology in community
samples of polysubstance misusers who report ecstasy use: a meta-analysis.
Journal of Psychopharmacology 2005; 19(1):84-92
234. Soar K, Turner JJD, Parrott AC: Psychiatric disorders in ecstasy (MDMA) users:
a literature review focusing on personal predisposition and drug history. Human
Psychopharmacology - Clinical and Experimental 2001; 16(8):641-645
235. Landabaso MA, Iraurgi I, Jimenez-Lerma JM, Calle R, Sanz J, Gutierrez-Fraile
M: Ecstasy-induced psychotic disorder: Six-month follow-up study. European
Addiction Research 2002; 8(3):133-140
236. Gouzoulis E, Borchardt D, Hermle L: A case of toxic psychosis induced by Eve
(3,4-Methylene-Dioxyethylam-Phetamine). Archives of General Psychiatry 1993;
50(1):75-75
237. Liechti ME, Geyer MA, Hell D, Vollenweider FX: Effects of MDMA (ecstasy)
on prepulse inhibition and habituation of startle in humans after pretreatment with
citalopram, haloperidol, or ketanserin. Neuropsychopharmacology 2001;
24(3):240-252
238. Vollenweider FX, Remensberger S, Hell D, Geyer MA: Opposite effects of 3,4-
methylenedioxymethamphetamine (MDMA) on sensorimotor gating in rats versus
healthy humans. Psychopharmacology 1999; 143(4):365-372
239. Quednow BB, Kuhn KU, Hoenig K, Maier W, Wagner M: Prepulse inhibition and
habituation of acoustic startle response in male MDMA ('ecstasy') users, cannabis
users, and healthy controls. Neuropsychopharmacology 2004; 29(5):982-990
240. van den Buuse M, Garner B, Gogos A, Kusljic S: Importance of animal models in
schizophrenia research. Australian and New Zealand Journal of Psychiatry 2005;
39(7):550-557
241. Boutros NN, Galloway M, Pihlgren EM: Stimulants and Psychosis, in Secondary
Schizophrenia. Edited by Sachdev PS, Keshavan MS. Cambridge, Cambridge
University Press, in press
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
57
242. O'Neill MF, Shaw G: Comparison of dopamine receptor antagonists on
hyperlocomotion induced by cocaine, amphetamine, MK-801 and the dopamine
D-1 agonist C-APB in mice. Psychopharmacology 1999; 145(3):237-250
243. Russell RW: Extrapolation from animals to man, in Animal behavior and drug
action. Edited by Steinberg H. Boston, Little, Brown, 1964, pp 410-418
244. Creese I, Iversen SD: Pharmacological and anatomical substrates of amphetamine
response in rat. Brain Research 1975; 83(3):419-436
245. Kohler C, Fuxe K, Ross SB: Regional in vivo binding of [3H]N-
Propylnorapomorphine in the mouse brain - Evidence for labeling of central
dopamine receptors. European Journal of Pharmacology 1981; 72(4):397-402
246. Van der werf JF, Sebens JB, Vaalburg W, Korf J: In vivo binding of N-N-
Propylnorapomorphine in the rat brain - Regional localization, quantification in
striatum and lack of correlation with dopamine metabolism. European Journal of
Pharmacology 1983; 87(2-3):259-270
247. Logan J, Dewey SL, Wolf AP, Fowler JS, Brodie JD, Angrist B, Volkow ND,
Gatley SJ: Effects of endogenous dopamine on measures of [F-18] N-
Methylspiroperidol binding in the basal ganglia - Comparison of simulations and
experimental results from PET studies in baboons. Synapse 1991; 9(3):195-207
248. Dewey SL, Smith GS, Logan J, Brodie JD, Fowler JS, Wolf AP: Striatal binding
of the PET ligand C-11 raclopride is altered by drugs that modify synaptic
dopamine levels. Synapse 1993; 13(4):350-356
249. Innis RB, Malison RT, Altikriti M, Hoffer PB, Sybirska EH, Seibyl JP, Zoghbi
SS, Baldwin RM, Laruelle M, Smith EO, Charney DS, Heninger G, Elsworth JD,
Roth RH: Amphetamine stimulated dopamine release competes in vivo for [I-123]
IBZM binding to the D2-receptor in nonhuman primates. Synapse 1992;
10(3):177-184
250. Laruelle M, AbiDargham A, vanDyck CH, Gil R, Dsouza CD, Erdos J, McCance
E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH,
Charney DS, Innis RB: Single photon emission computerized tomography
imaging of amphetamine-induced dopamine release in drug-free schizophrenic
subjects. Proceedings of the National Academy of Sciences of the United States
of America 1996; 93(17):9235-9240
251. Javitt DC, Laruelle M: Neurochemical theories, in Textbook of Schizophrenia.
Edited by Lieberman JA, Stroup ST, Perkins DO. Washington DC, American
Psychiatric Publishing, 2006, pp 85-116
252. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, van Dyck
CH, Charney DS, Innis RB, Laruelle M: Increased striatal dopamine transmission
in schizophrenia: Confirmation in a second cohort. American Journal of
Psychiatry 1998; 155(6):761-767
253. Homayoun H, Moghaddam B: Progression of cellular adaptations in medial
prefrontal and orbitofrontal cortex in response to repeated amphetamine. Journal
of Neuroscience 2006; 26(31):8025-8039
254. Hill K, Mann L, Laws KR, Stephenson ME, Nimmo-Smith I, McKenna PJ:
Hypofrontality in schizophrenia: a meta-analysis of functional imaging studies.
Acta Psychiatrica Scandinavica 2004; 110:243-256
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
58
255. Dom G, Sabbe B, Hulstijn W, van den Brink W: Substance use disorders and the
orbitofrontal cortex. British Journal of Psychiatry 2005; 187:209-220
256. McLellan AT, Woody GE, Obrien CP: Development of psychiatric illness in drug
abusers - Possible role of drug preference. New England Journal of Medicine
1979; 301(24):1310-1314
257. Angrist B, Sathananthan G, Wilk S, Gershon S: Amphetamine psychosis -
Behavioral and biochemical aspects. Journal of Psychiatric Research 1974; 11:13-
23
258. Bell DS: Experimental reproduction of amphetamine psychosis. Archives of
General Psychiatry 1973; 29(1):35-40
259. Griffith JD, Oates JA, Cavanaug.J, Held J: Dextroamphetamine - Evaluation of
psychomimetic properties in man. Archives of General Psychiatry 1972; 26(2):97-
100
260. Ellinwood EH: Amphetamine psychosis. I. Description of individuals and
process. Journal of Nervous and Mental Disease 1967; 144(4):273-283
261. Angrist BM, Gershon S: The phenomenology of experimentally induced
amphetamine psychosis - preliminary observations. Biological Psychiatry 1970;
2:95-107
262. Steketee JD: Neurotransmitter systems of the medial prefrontal cortex: potential
role in sensitization to psychostimulants. Brain Research Reviews 2003; 41(2-
3):203-228
263. Wolf ME: The role of excitatory amino acids in behavioral sensitization to
psychomotor stimulants. Progress in Neurobiology 1998; 54(6):679-720
264. Kalivas PW: Interactions between dopamine and excitatory amino acids in
behavioral sensitization to psychostimulants. Drug and Alcohol Dependence
1995; 37(2):95-100
265. Jentsch JD, Roth RH: The neuropsychopharmacology of phencyclidine: From
NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.
Neuropsychopharmacology 1999; 20(3):201-225
266. Jackson ME, Homayoun H, Moghaddam B: NMDA receptor hypofunction
produces concomitant firing rate potentiation and burst activity reduction in the
prefrontal cortex. Proceedings of the National Academy of Sciences of the United
States of America 2004; 101(22):8467-8472
267. MacDonald AW, Chafee MV: Translational and developmental perspective on N-
methyl-D-aspartate synaptic deficits in schizophrenia. Development and
Psychopathology 2006; 18(3):853-876
268. Kapur S, Seeman P: Ketamine has equal affinity for NMDA receptors and the
high-affinity state of the dopamine D-2 receptor. Biological Psychiatry 2001;
49(11):954-955
269. Kapur S, Seeman P: NMDA receptor antagonists ketamine and PCP have direct
effects on the dopamine D-2 and serotonin 5-HT2 receptors - implications for
models of schizophrenia. Molecular Psychiatry 2002; 7(8):837-844
270. Seeman P, Ko F, Tallerico T: Dopamine receptor contribution to the action of
PCP, LSD and ketamine psychotomimetics. Molecular Psychiatry 2005;
10(9):877-883
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
59
271. Seeman P, Lasaga M: Dopamine agonist action of phencyclidine. Synapse 2005;
58(4):275-277
272. Seeman P, Weinshenker D, Quirion R, Srivastava IAK, Bhardwaj SK, Grandy
DK, Premont RT, Sotnikova TD, Boksa P, El-Ghundi M, O'Dowd BF, George
SR, Perreault ML, Mannisto PT, Robinson S, Palmiter RD, Tallerico T:
Dopamine supersensitivity correlates with D2(High) states, implying many paths
to psychosis. Proceedings of the National Academy of Sciences of the United
States of America 2005; 102(9):3513-3518
273. Seeman P: Comment on "diverse psychotomimetics act through a common
signaling pathway". Science 2004; 305(5681)
274. Seeman P, Schwarz J, Chen JF, Szechtman H, Perreault M, McKnight GS, Roder
JC: Psychosis pathways converge via D2(High) dopamine receptors. Synapse
2006; 60(4):319-346
275. Svenningsson P, Nomikos GG, Greengard P: Response to comment on "Diverse
psychotomimetics act through a common signaling pathway". Science 2004;
305(5681)
276. Jordan S, Chen R, Fernalld R, Johnson J, Regardie K, Kambayashi J, Tadori Y,
Kitagawa H, Kikuchi T: In vitro biochemical evidence that the psychotomimetics
phencyclidine, ketamine and dizocilpine (MK-801) are inactive at cloned human
and rat dopamine D-2 receptors. European Journal of Pharmacology 2006; 540(1-
3):53-56
277. Svenningsson P, Nishi A, Fisone G, Girault JA, Nairn AC, Greengard P: DARPP-
32: An integrator of neurotransmission. Annual Review of Pharmacology and
Toxicology 2004; 44:269-296
278. Svenningsson P, Tzavara ET, Carruthers R, Rachleff I, Wattler S, Nehls M,
McKinzie DL, Fienberg AA, Nomikos GG, Greengard P: Diverse
psychotomimetics act through a common signaling pathway. Science 2003;
302(5649):1412-1415
279. Rabiner EA: Imaging of striatal dopamine release elicited with NMDA
antagonists: there anything there to be seen? Journal of Psychopharmacology
2007; 21(3):253-258
280. Davis SM, Lees KR, Albers GW, Diener HC, Markabi S, Karlsson G, Norris J:
Selfotel in acute ischemic stroke - Possible neurotoxic effects of an NMDA
antagonist. Stroke 2000; 31(2):347-354
281. Moghaddam B, Adams BW: Reversal of phencyclidine effects by a group II
metabotropic glutamate receptor agonist in rats. Science 1998; 281(5381):1349-
1352
282. Sams-Dodd F: Distinct Effects of D-amphetamine and phencyclidine on the social
behavior of rats. Behavioural Pharmacology 1995; 6(1):55-65
283. Sams-Dodd F: Phencyclidine-induced stereotyped behaviour and social isolation
in rats: A possible animal model of schizophrenia. Behavioural Pharmacology
1996; 7(1):3-23
284. Sams-Dodd F: Effects of continuous D-amphetamine and phencyclidine
administration on social behaviour, stereotyped behaviour, and locomotor activity
in rats. Neuropsychopharmacology 1998; 19(1):18-25
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
60
285. Sams-Dodd F: Effects of dopamine agonists and antagonists on PCP-induced
stereotyped behaviour and social isolation in the rat social interaction test.
Psychopharmacology 1998; 135(2):182-193
286. Ealster RL, Chait LD: The behavioral effects of phencyclidine in animals, in
Phencyclidine (PCP) Abuse: An Appraisal, Monograph 21. Edited by Petersen
RC, Stillman RC. Rockville, Maryland, National Institute on Drug Abuse, 1978,
pp 53-65
287. Hetzler BE, Wautlet BS: Ketamine-induced locomotion in rats in an open field.
Pharmacology Biochemistry and Behavior 1985; 22(4):653-655
288. Rung JP, Carlsson A, Markinhuhta KR, Carlsson ML: (+)-MK-801 induced social
withdrawal in rats; a model for negative symptoms of schizophrenia. Progress in
Neuro-Psychopharmacology & Biological Psychiatry 2005; 29(5):827-832
289. Duncan GE, Miyamoto S, Lieberman JA: Chronic administration of haloperidol
and olanzapine attenuates ketamine-induced brain metabolic activation. Journal of
Pharmacology and Experimental Therapeutics 2003; 305(3):999-1005
290. Sams-Dodd F: Phencyclidine in the social interaction test: An animal model of
schizophrenia with face and predictive validity. Reviews in the Neurosciences
1999; 10(1):59-90
291. Stefani MR, Moghaddam B: Effects of repeated treatment with amphetamine or
phencyclidine on working memory in the rat. Behavioural Brain Research 2002;
134(1-2):267-274
292. Egerton A, Reid L, McKerchar CE, Morris BJ, Pratt JA: Impairment in perceptual
attentional set-shifting following PCP administration: a rodent model of set-
shifting deficits in schizophrenia. Psychopharmacology 2005; 179(1):77-84
293. Jentsch JD, Tran A, Le D, Youngren KD, Roth RH: Subchronic phencyclidine
administration reduces mesoprefrontal dopamine utilization and impairs
prefrontal cortical-dependent cognition in the rat. Neuropsychopharmacology
1997; 17(2):92-99
294. Jentsch JD, Redmond DE, Elsworth JD, Taylor JR, Youngren KD, Roth RH:
Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after
long-term administration of phencyclidine. Science 1997; 277(5328):953-955
295. Stefani MR, Groth K, Moghaddam B: Glutamate receptors in the rat medial
prefrontal cortex regulate set-shifting ability. Behavioral Neuroscience 2003;
117(4):728-737
296. Rujescu D, Bender A, Keck M, Hartmann AM, Ohl F, Raeder H, Giegling I,
Genius J, McCarley RW, Moller HJ, Grunze H: A pharmacological model for
psychosis based on N-methyl-D-aspartate receptor hypofunction: Molecular,
cellular, functional and Behavioral abnormalities. Biological Psychiatry 2006;
59(8):721-729
297. Geyer MA, Swerdlow NR, Mansbach RS, Braff DL: Startle response models of
sensorimotor gating and habituation deficits in schizophrenia. Brain Research
Bulletin 1990; 25(3):485-498
298. Mansbach RS, Geyer MA: Effects of phencyclidine and phencyclidine analogues
on sensorimotor gating in the rat. Neuropsychopharmacology 1989; 2(4):299-308
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
61
299. Geyer MA, Braff DL, Mansbach RS: Failure of haloperidol to block the
disruption of sensory gating induced by phencyclidine and MK-801. Biological
Psychiatry 1989; 25:169A
300. Cilia J, Hatcher P, Reavill C, Jones DNC: (+/-) ketamine-induced prepulse
inhibition deficits of an acoustic startle response in rats are not reversed by
antipsychotics. Journal of Psychopharmacology 2007; 21(3):302-311
301. Brody SA, Geyer MA, Large CH: Lamotrigine prevents ketamine but not
amphetamine-induced deficits in prepulse inhibition in mice.
Psychopharmacology 2003; 169(3-4):240-246
302. Mansbach RS, Geyer MA, Braff DL: Dopaminergic stimulation disrupts
sensorimotor gating in the rat. Psychopharmacology 1988; 94(4):507-514
303. Geyer MA, Braff DL: Startle habituation and sensorimotor gating in
schizophrenia and related animal models. Schizophrenia Bulletin 1987;
13(4):643-668
304. Duncan GE, Miyamoto S, Leipzig JN, Lieberman JA: Comparison of brain
metabolic activity patterns induced by ketamine, MK-801 and amphetamine in
rats: support for NMDA receptor involvement in responses to subanesthetic dose
of ketamine. Brain Research 1999; 843(1-2):171-183
305. Duncan GE, Leipzig JN, Mailman RB, Lieberman JA: Differential effects of
clozapine and haloperidol on ketamine-induced brain metabolic activation. Brain
Research 1998; 812(1-2):65-75
306. Duncan GE, Moy SS, Knapp DJ, Mueller RA, Breese GR: Metabolic mapping of
the rat brain after subanesthetic doses of ketamine: potential relevance to
schizophrenia. Brain Research 1998; 787(2):181-190
307. Littlewood CL, Jones N, O'Neill MJ, Mitchell SN, Tricklebank M, Williams
SCR: Mapping the central effects of ketamine in the rat using pharmacological
MRI. Psychopharmacology 2006; 186(1):64-81
308. Burdett NG, Menon DK, Carpenter TA, Jones JG, Hall LD: Visualization of
changes in regional cerebral blood flow (rCBF) produced by ketamine using long
TE gradient echo sequences Preliminary results. Magnetic Resonance Imaging
1995; 13(4):549-553
309. Lewis DA, Gonzalez-Burgos G: Pathophysiologically based treatment
interventions in schizophrenia. Nature Medicine 2006; 12(9):1016-1022
310. Lewis DA, Hashimoto T: Deciphering the disease process of schizophrenia: The
contribution of cortical GABA neurons. Integrating the Neurobiology of
Schizophrenia 2007; 78:109-+
311. Lewis DA, Hashimoto T, Volk DW: Cortical inhibitory neurons and
schizophrenia. Nature Reviews Neuroscience 2005; 6(4):312-324
312. Lewis DA, Gonzalez-Burgos G: Neuroplasticity of neocortical circuits in
schizophrenia. Neuropsychopharmacology 2008; 33:141-165
313. Harrison PJ: The hippocampus in schizophrenia: a review of the
neuropathological evidence and its pathophysiological implications.
Psychopharmacology 2004; 174(1):151-162
314. Weinberger DR: Cell biology of the hippocampal formation in schizophrenia.
Biological Psychiatry 1999; 45(4):395-402
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
62
315. Shenton ME, Dickey CC, Frumin M, McCarley RW: A review of MRI findings in
schizophrenia. Schizophrenia Research 2001; 49(1-2):1-52
316. Bogerts B: Recent Advances in the neuropathology of schizophrenia.
Schizophrenia Bulletin 1993; 19(2):431-445
317. Buchsbaum MS, Someya T, Teng CY, Abel L, Chin S, Najafi A, Haier RJ, Wu J,
Bunney WE: PET and MRI of the thalamus in never-medicated patients with
schizophrenia. American Journal of Psychiatry 1996; 153(2):191-199
318. Wu JC, Buchsbaum MS, Potkin SG, Wolf MJ, Bunney WE: Positron emission
tomography study of phencyclidine users. Schizophrenia Research 1991;
4(3):415-415
319. Hertzman M, Reba RC, Kotlyarov EV: Single photon emission computed
tomography in phencyclidine and related drug abuse. American Journal of
Psychiatry 1990; 147(2):255-256
320. Cochran SM, Kennedy M, McKerchar CE, Steward LJ, Pratt JA, Morris BJ:
Induction of metabolic hypofunction and neurochemical deficits after chronic
intermittent exposure to phencyclidine: Differential modulation by antipsychotic
drugs. Neuropsychopharmacology 2003; 28(2):265-275
321. Wickelgren I: Neurobiology - A new route to treating schizophrenia? Science
1998; 281(5381):1264-1265
322. Moghaddam B, Adams B, Verma A, Daly D: Activation of glutamatergic
neurotransmission by ketamine: A novel step in the pathway from NMDA
receptor blockade to dopaminergic and cognitive disruptions associated with the
prefrontal cortex. Journal of Neuroscience 1997; 17(8):2921-2927
323. Adams B, Moghaddam B: Corticolimbic dopamine neurotransmission is
temporally dissociated from the cognitive and locomotor effects of phencyclidine.
Journal of Neuroscience 1998; 18(14):5545-5554
324. Liu J, Moghaddam B: Regulation of glutamate efflux by excitatory amino acid
receptors - Evidence for tonic inhibitory and phasic excitatory regulation. Journal
of Pharmacology and Experimental Therapeutics 1995; 274(3):1209-1215
325. Homayoun L, Jackson ME, Moghaddam B: Activation of metabotropic glutamate
2/3 receptors reverses the effects of NMDA receptor hypofunction on prefrontal
cortex unit activity in awake rats. Journal of Neurophysiology 2005; 93(4):1989-
2001
326. Homayoun H, Moghaddam B: Fine-tuning of awake prefrontal cortex neurons by
clozapine: Comparison with haloperidol and N-desmethylclozapine. Biological
Psychiatry 2007; 61(5):679-687
327. Homayoun H, Moghaddam B: NMDA receptor hypofunction produces opposite
effects on prefrontal cortex Interneurons and pyramidal neurons. Journal of
Neuroscience 2007; 27(43):11496-11500
328. Suzuki Y, Jodo E, Takeuchi S, Niwa S, Kayama Y: Acute administration of
phencyclidine induces tonic activation of medial prefrontal cortex neurons in
freely moving rats. Neuroscience 2002; 114(3):769-779
329. Jodo E, Suzuki Y, Katayama T, Hoshino KY, Takeuchi S, Niwa SI, Kayama Y:
Activation of medial prefrontal cortex by phencyclidine is mediated via a
hippocampo-prefrontal pathway. Cerebral Cortex 2005; 15(5):663-669
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
63
330. Katayama T, Jodo E, Suzuki Y, Hoshino KY, Takeuchi S, Kayama Y: Activation
of medial prefrontal cortex neurons by phencyclidine is mediated via
AMPA/kainate glutamate receptors in anesthetized rats. Neuroscience 2007;
150(2):442-448
331. Olney JW, Newcomer JW, Farber NB: NMDA receptor hypofunction model of
schizophrenia. Journal of Psychiatric Research 1999; 33(6):523-533
332. Halberstadt AL: The phencyclidine glutamate model of schizophrenia. Clinical
Neuropharmacology 1995; 18(3):237-249
333. Tsai GC, Coyle JT: Glutamatergic mechanisms in schizophrenia. Annual Review
of Pharmacology and Toxicology 2002; 42:165-179
334. Hirsch SR, Das I, Garey LJ, deBelleroche J: A pivotal role for glutamate in the
pathogenesis of schizophrenia, and its cognitive dysfunction. Pharmacology
Biochemistry and Behavior 1997; 56(4):797-802
335. Vollenweider FX, Geyer MA: A systems model of altered consciousness:
Integrating natural and drug-induced psychoses. Brain Research Bulletin 2001;
56(5):495-507
336. Stone JM, Morrison PD, Pilowsky LS: Glutamate and dopamine dysregulation in
schizophrenia - A synthesis and selective review. Journal of Psychopharmacology
2007; 21(4):440-452
337. Morris BJ, Cochran SM, Pratt JA: PCP: from pharmacology to modelling
schizophrenia. Current Opinion in Pharmacology 2005; 5(1):101-106
338. Large CH: Do NMDA receptor antagonist models of schizophrenia predict the
clinical efficacy of antipsychotic drugs? Journal of Psychopharmacology 2007;
21(3):283-301
339. Gulyas AI, Megias M, Emri Z, Freund TF: Total number and ratio of excitatory
and inhibitory synapses converging onto single interneurons of different types in
the CA1 area of the rat hippocampus. Journal of Neuroscience 1999;
19(22):10082-10097
340. Jones RSG, Buhl EH: Basket-like interneurons in layer II of the entorhinal cortex
exhibit a powerful NMDA-mediated synaptic excitation. Neuroscience Letters
1993; 149(1):35-39
341. Goldberg JH, Yuste R, Tamas G: Ca2+ imaging of mouse neocortical interneurone
dendrites: Contribution of Ca2+-permeable AMPA and NMDA receptors to
subthreshold Ca2+ dynamics. Journal of Physiology-London 2003; 551(1):67-78
342. Cochran SM, Fujimura M, Morris BJ, Pratt JA: Acute and delayed effects of
phencyclidine upon mRNA levels of markers of glutamatergic and GABAergic
neurotransmitter function in the rat brain. Synapse 2002; 46(3):206-214
343. Abdul-Monim Z, Neill JC, Reynolds GP: Sub-chronic psychotomimetic
phencyclidine induces deficits in reversal learning and alterations in parvalbumin-
immunoreactive expression in the rat. Journal of Psychopharmacology 2007;
21(2):198-205
344. Keilhoff G, Becker A, Grecksch G, Wolf G, Bernstein HG: Repeated application
of ketamine to rats induces changes in the hippocampal expression of
parvalbumin, neuronal nitric oxide synthase and cFOS similar to those found in
human Schizophrenia. Neuroscience 2004; 126(3):591-598
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
64
345. Morrow BA, Elsworth JD, Roth RH: Repeated phencyclidine in monkeys results
in loss of parvalbumin-containing axo-axonic projections in the prefrontal cortex.
Psychopharmacology 2007; 192(2):283-290
346. Behrens MM, Ali SS, Dao DN, Lucero J, Shekhtman G, Quick KL, Dugan LL:
Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by
NADPH-oxidase. Science 2007; 318(5856):1645-1647
347. Kinney JW, Davis CN, Tabarean I, Conti B, Bartfai T, Behrens MM: A specific
role for NR2A-containing NMDA receptors in the maintenance of parvalbumin
and GAD67 immunoreactivity in cultured interneurons. Journal of Neuroscience
2006; 26(5):1604-1615
348. Bartos M, Vida I, Jonas P: Synaptic mechanisms of synchronized gamma
oscillations in inhibitory interneuron networks. Nature Reviews Neuroscience
2007; 8(1):45-56
349. Cunningham MO, Hunt J, Middleton S, LeBeau FEN, Gillies MG, Davies CH,
Maycox PR, Whittington MA, Racca C: Region-specific reduction in entorhinal
gamma oscillations and parvalbumin-immunoreactive neurons in animal models
of psychiatric illness. Journal of Neuroscience 2006; 26(10):2767-2776
350. Reynolds GP, Harte MK: The neuronal pathology of schizophrenia: molecules
and mechanisms. Biochemical Society Transactions 2007; 35:433-436
351. Basar-Eroglu C, Brand A, Hildebrandt H, Kedzior KK, Mathes B, Schmiedt C:
Working memory related gamma oscillations in schizophrenia patients.
International Journal of Psychophysiology 2007; 64(1):39-45
352. Symond MB, Harris AWF, Gordon E, Williams LM: "Gamma synchrony" in
first-episode schizophrenia: A disorder of temporal connectivity? American
Journal of Psychiatry 2005; 162(3):459-465
353. Light GA, Hsu JL, Hsieh MH, Meyer-Gomes K, Sprock J, Swerdlow NR, Braff
DL: Gamma band oscillations reveal neural network cortical coherence
dysfunction in schizophrenia patients. Biological Psychiatry 2006; 60(11):1231-
1240
354. Spencer KM: Abnormal neural synchrony in schizophrenia. Psychophysiology
2003; 40:S17-S17
355. Jentsch JD, Elsworth JD, Redmond DE, Roth RH: Phencyclidine increases
forebrain monoamine metabolism in rats and monkeys: Modulation by the
isomers of HA966. Journal of Neuroscience 1997; 17(5):1769-1775
356. Kusljic S, Copolov DL, van den Buuse M: Differential role of serotonergic
projections arising from the dorsal and median raphe nuclei in locomotor
hyperactivity and prepulse inhibition. Neuropsychopharmacology 2003;
28(12):2138-2147
357. Rabin RA, Doat M, Winter JC: Role of serotonergic 5-HT2A receptors in the
psychotomimetic actions of phencyclidine. International Journal of
Neuropsychopharmacology 2000; 3(4):333-338
358. Farber NB, Hanslick J, Kirby C, McWilliams L, Olney JW: Serotonergic agents
that activate 5HT(2A) receptors prevent NMDA antagonist neurotoxicity.
Neuropsychopharmacology 1998; 18(1):57-62
359. Kristiansen LV, Huerta I, Beneyto M, Meador-Woodruff JH: NMDA receptors
and schizophrenia. Current Opinion in Pharmacology 2007; 7(1):48-55
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
65
360. Javitt DC: Glutamate and schizophrenia: Phencyclidine, N-methyl-D-aspartate
receptors, and dopamine-glutamate interactions, in Integrating the Neurobiology
of Schizophrenia, vol 78, 2007, pp 69-+
361. Catts SV, Ward PB, Lloyd A, Huang XF, Dixon G, Chahl L, Harper C, Wakefield
D: Molecular biological investigations into the role of the NMDA receptor in the
pathophysiology of schizophrenia. Australian and New Zealand Journal of
Psychiatry 1997; 31(1):17-26
362. Carlsson A: The current status of the dopamine hypothesis of schizophrenia.
Neuropsychopharmacology 1988; 1(3):179-186
363. Carlsson M, Carlsson A: Schizophrenia – A subcortical neurotransmitter
imbalance syndrome. Schizophrenia Bulletin 1990; 16(3):425-432
364. Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A, Krystal JH:
Attenuation of the neuropsychiatric effects of ketamine with lamotrigine - Support
for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists.
Archives of General Psychiatry 2000; 57(3):270-276
365. Large CH, Webster EL, Goff DC: The potential role of lamotrigine in
schizophrenia. Psychopharmacology 2005; 181(3):415-436
366. Kremer I, Vass A, Gorelik I, Bar G, Blanaru M, Javitt DC, Heresco-Levy U:
Placebo-controlled trial of lamotrigine added to conventional and atypical
antipsychotics in schizophrenia. Biological Psychiatry 2004; 56(6):441-446
367. Dursun SM, Deakin JFW: Augmenting antipsychotic treatment with lamotrigine
or topiramate in patients with treatment-resistant schizophrenia: a naturalistic
caseseries outcome study. Journal of Psychopharmacology 2001; 15(4):297-301
368. Dursun SM, McIntosh D: Clozapine plus lamotrigine in treatment-resistant
schizophrenia. Archives of General Psychiatry 1999; 56(10):950-950
369. Zoccali R, Muscatello MR, Bruno A, Cambria R, Mico U, Spina E, Meduri M:
The effect of lamotrigine augmentation of clozapine in a sample of treatment-
resistant schizophrenic patients: A double-blind, placebo-controlled study.
Schizophrenia Research 2007; 93(1-3):109-116
370. Tiihonen J, Hallikainen T, Ryynanen OP, Repo-Tiihonen E, Kotilainen I, Eronen
M, Toivonen P, Wahlbeck K, Putkonen A: Lamotrigine in treatment-resistant
schizophrenia: A randomized placebo-controlled crossover trial. Biological
Psychiatry 2003; 54(11):1241-1248
371. Ahmad S, Fowler LJ, Whitton PS: Lamotrigine, carbamazepine and phenytoin
differentially alter extracellular levels of 5-hydroxytryptamine, dopamine and
amino acids. Epilepsy Research 2005; 63(2-3):141-149
372. Leucht S, Kissling W, McGrath J, White P: Carbamazepine for schizophrenia.
Cochrane Database of Systematic Reviews 2007(3):Art. No.: CD001258. DOI:
10.1002/14651858.CD001258.pub2
373. Harsing LG, Gacsalyi I, Szabo G, Schmidt E, Sziray N, Sebban C, Tesolin-Decros
B, Matyus P, Egyed A, Spedding M, Levay G: The glycine transporter-1
inhibitors NFPS and Org 24461: a pharmacological study. Pharmacology
Biochemistry and Behavior 2003; 74(4):811-825
374. Lane HY, Liu YC, Huang CL, Chang YC, Liau CH, Perng CH, Tsai GE:
Sarcosine (N-Methylglycine) treatment for acute schizophrenia: A randomized,
double-blind study. Biological Psychiatry 2008; 63(1):9-12
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
66
375. Tsai GC, Lane HY, Yang PC, Chong MY, Lange N: Glycine transporter I
inhibitor, N-methylglycine (Sarcosine), added to antipsychotics for the treatment
of schizophrenia. Biological Psychiatry 2004; 55(5):452-456
376. Lane HY, Huang CL, Wu PL, Liu YC, Chang YC, Lin PY, Chen PW, Tsai G:
Glycine transporter I inhibitor, N-methylglycine (Sarcosine), added to clozapine
for the treatment of schizophrenia. Biological Psychiatry 2006; 60(6):645-649
377. Neale JH, Olszewski RT, Gehl LM, Wroblewska B, Bzdega T: The
neurotransmitter N-acetylaspartylglutamate in models of pain, ALS, diabetic
neuropathy, CNS injury and schizophrenia. Trends in Pharmacological Sciences
2005; 26(9):477-484
378. Olszewski RT, Bukhari N, Zhou J, Kozikowski AP, Wroblewski JT, Shamimi-
Noori S, Wroblewska B, Bzdega T, Vicini S, Barton FB, Neale JH: NAAG
peptidase inhibition reduces locomotor activity and some stereotypes in the PCP
model of schizophrenia via group II mGluR. Journal of Neurochemistry 2004;
89(4):876-885
379. Olszewski RT, Wegorzewska MM, Monteiro AC, Krolikowski KA, Zhou J,
Kozikowski AP, Long K, Mastropaolo J, Deutsch SI, Neale JH: Phencyclidine
and dizocilpine induced behaviors reduced by N-acetylaspartylglutamate
peptidase inhibition via metabotropic glutamate receptors. Biological Psychiatry
2008; 63(1):86-91
380. Schoepp DD, Johnson BG, Wright RA, Salhoff CR, Mayne NG, Wu S,
Cockerham SL, Burnett JP, Belegaje R, Bleakman D, Monn JA: LY354740 is a
potent and highly selective group II metabotropic glutamate receptor agonist in
cells expressing human glutamate receptors. Neuropharmacology 1997; 36(1):1-
11
381. Krystal JH, Abi-Saab W, Perry E, D'Souza D, Liu NJ, Gueorguieva R,
McDougall L, Hunsberger T, Belger A, Levine L, Breier A: Preliminary evidence
of attenuation of the disruptive effects of the NMDA glutamate receptor
antagonist, ketamine, on working memory by pretreatment with the group II
metabotropic glutamate receptor agonist, LY354740, in healthy human subjects.
Psychopharmacology 2005; 179(1):303-309
382. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova
AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG,
Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD:
Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a
randomized Phase 2 clinical trial. Nature Medicine 2007; 13(9):1102-1107
383. Luby ED, Cohen BD, Domino EF, Rosenbaum G, Gottlieb JS: Model psychoses
and schizophrenia. American Journal of Psychiatry 1962; 119(1):61-67
384. Kim JS, Kornhuber HH, Schmidburgk W, Holzmuller B: Low cerebrospinal fluid
glutamate in schizophrenic patients and a new hypothesis on schizophrenia.
Neuroscience Letters 1980; 20(3):379-382
385. Lodge D, Anis NA: Effects of phencyclidine on excitatory amino acid activation
of spinal interneurones in the cat. European Journal of Pharmacology 1982; 77(2-
3):203-204
386. Wachtel H, Turski L: Glutamate A new target in schizophrenia. Trends in
Pharmacological Sciences 1990; 11(6):219-220
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
67
387. Farber NB, Wozniak DF, Price MT, Labruyere J, Huss J, Peter HS, Olney JW:
Age-specific neurotoxicity in the rat associated with NMDA receptor blockade:
Potential relevance to schizophrenia? Biological Psychiatry 1995; 38(12):788-796
388. Olney JW, Farber NB: Glutamate Receptor Dysfunction and Schizophrenia.
Archives of General Psychiatry 1995; 52(12):998-1007
389. Keshavan MS, Anderson S, Pettegrew JW: Is schizophrenia due to excessive
synaptic pruning in the prefrontal cortex - The Feinberg hypothesis revisited.
Journal of Psychiatric Research 1994; 28(3):239-265
390. Glantz LA, Lewis DA: Decreased dendritic spine density on prefrontal cortical
pyramidal neurons in schizophrenia. Archives of General Psychiatry 2000;
57(1):65-73
391. Selemon LD, Rajkowska G, Goldmanrakic PS: Abnormally high neuronal density
in the schizophrenic cortex A morphometric analysis of prefrontal area 9 and
occipital area 17. Archives of General Psychiatry 1995; 52(10):805-818
392. Coyle JT: Substance use disorders and schizophrenia: A question of shared
glutamatergic mechanisms. Neurotoxicity Research 2006; 10(3-4):221-233
393. Tamminga CA, Lahti AC, Medoff DR, Gao XM, Holcomb HH: Evaluating
glutamatergic transmission in schizophrenia, in Glutamate and Disorders of
Cognition and Motivation, vol 1003, 2003, pp 113-118
394. Lewis DA, Moghaddam B: Cognitive dysfunction in schizophrenia - Convergence
of gamma-aminobutyric acid and glutamate alterations. Archives of Neurology
2006; 63(10):1372-1376
395. Abi-Saab WM, D'Souza DC, Moghaddam B, Krystal JH: The NMDA antagonist
model for schizophrenia: Promise and pitfalls. Pharmacopsychiatry 1998; 31:104-
109
396. Farber NB: The NMDA receptor hypofunction model of psychosis, in Glutamate
and Disorders of Cognition and Motivation, vol 1003, 2003, pp 119-130
397. Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF: Apoptotic mechanisms and
the synaptic pathology of schizophrenia. Schizophrenia Research 2006; 81(1):47-
63
398. Jarskog LF, Glantz LA, Gilmore JH, Lieberman JA: Apoptotic mechanisms in the
pathophysiology of schizophrenia. Progress in Neuro-Psychopharmacology &
Biological Psychiatry 2005; 29(5):846-858
399. Catts VS, Catts SV, McGrath JJ, Feron F, McLean D, Coulson EJ, Lutze-Mann
LH: Apoptosis and schizophrenia: A pilot study based on dermal fibroblast cell
lines. Schizophrenia Research 2006; 84(1):20-28
400. Castner SA, Goldman-Rakic PS: Long-lasting psychotomimetic consequences of
repeated low-dose amphetamine exposure in rhesus monkeys.
Neuropsychopharmacology 1999; 20(1):10-28
401. Selemon LD, Begovic A, Goldman-Rakic PS, Castner SA: Amphetamine
sensitization alters dendritic morphology in prefrontal cortical pyramidal neurons
in the non-human primate. Neuropsychopharmacology 2007; 32(4):919-931
402. Robinson TE, Kolb B: Alterations in the morphology of dendrites and dendritic
spines in the nucleus accumbens and prefrontal cortex following repeated
treatment with amphetamine or cocaine. European Journal of Neuroscience 1999;
11(5):1598-1604
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
68
403. Lipska BK: Using animal models to test a neurodevelopmental hypothesis of
schizophrenia. Journal of Psychiatry & Neuroscience 2004; 29(4):282-286
404. Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M: Immune
activation during pregnancy in mice leads to dopaminergic hyperfunction and
cognitive impairment in the offspring: A neurodevelopmental animal model of
schizophrenia. Biological Psychiatry 2006; 59(6):546-554
405. Moore H, Jentsch JD, Ghajarnia M, Geyer MA, Grace AA: A neurobehavioral
systems analysis of adult rats exposed to methylazoxymethanol acetate on E17:
Implications for the neuropathology of schizophrenia. Biological Psychiatry 2006;
60(3):253-264
406. Paylor R, McIlwain KL, McAninch R, Nellis A, Yuva-Paylor LA, Baldini A,
Lindsay EA: Mice deleted for the DiGeorge/velocardiofacial syndrome region
show abnormal sensorimotor gating and learning and memory impairments.
Human Molecular Genetics 2001; 10(23):2645-2650
407. Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, Wu D, Xue
R, Andrade M, Tankou S, Mori S, Gallagher M, Ishizuka K, Pletnikov M, Kida S,
Sawa A: Dominant-negative DISC1 transgenic mice display schizophrenia-
associated phenotypes detected by measures translatable to humans. Proceedings
of the National Academy of Sciences of the United States of America 2007;
104(36):14501-14506
408. Chen YJJ, Johnson MA, Lieberman MD, Goodchild RE, Schobel S,
Lewandowski N, Rosoklija G, Liu RC, Gingrich JA, Small S, Moore H, Dwork
AJ, Talmage DA, Role LW: Type III neuregulin-1 is required for normal
sensorimotor gating, memory-related behaviors, and corticostriatal circuit
components. Journal of Neuroscience 2008; 28(27):6872-6883
409. Segal DS, Geyer MA: Animal models of psychopathology, in Psychobiological
foundations of clinical psychiatry. Edited by Judd LL, Groves PM. Philadelphia,
JB Lippincott, 1985, pp 1-14
Catts & Catts: The psychotomimetic effects of PCP, LSD, MDMA: Pharmacological models of schizophrenia?
Unabridged manuscript, in press February 2008. Review obtained from www.qsrf.com.au
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Figure 1.
Panel A: Site of action of PCP. G: GABAergic interneuron; P: pyramidal neuron.
Panel B: Circuits of the brain relevant to the PCP model of schizozphrenia.
Black unbroken lines indicate glutamatergic neurotransmission, the strength of which is
indicated by the number of + signs.
Black dotted lines indicate dopaminergic neurotransmission.
Grey unbroken lines indicate serotonergic neurotransmission.
PFC: prefrontal cortex; AMG: amygdala; V. STRIATUM: ventral striatum; VP: ventral
pallidum; THAL: thalamus; DMn: dorsomedial nucleus of thalamus; An: anterior nucleus
of thalamus; HC: hippocampus; MR: median raphe.
MR
VP
V.
STRIATUM
AMG
HC
PFC
THAL
DMn An
AMG
+
+
B
PCP
P
G
A
* = blocked inhibitory
feedback to
pyramidal neurons
= NMDA receptor
l
... Both pyramidal cells and interneurons express functional NMDA receptors (Monyer, Burnashev, Laurie, Sakmann, & Seeburg, 1994). Animals administered non-competitive NMDA receptor antagonists show homologous behavior and cognitive deficits to the PCP-induced psychotomimetic effects observed in healthy human volunteers and individuals with schizophrenia (reviewed in Catts & Catts, 2010). Insights into the neuronal mechanisms underlying PCP-induced psychotomimetic effects have been obtained from in vivo electrophysiological studies, which demonstrate that single dose administration of NMDA receptor antagonists induces sustained large increases in prefrontal excitatory firing and release of glutamate by blocking the activity of inhibitory interneurons (Homayoun & Moghaddam, 2007;Moghaddam & Javitt, 2012). ...
... Converging evidence from several distinct lines of research suggests that NMDA receptor hypofunction may contribute to the expression of schizophrenia. Firstly, there are clinical studies of the deleterious behavioral effects of non-competitive NMDA receptor antagonists, with evidence of chronic use of PCP inducing psychotic disorder beyond the acute symptoms of intoxication (reviewed in Catts & Catts, 2010). Epidemics of PCP abuse in the U.S.A. during the 1960s and 1970s were regionally and temporally discrete, demonstrating a consistent association between heavy PCP use and epidemics of first admission schizophrenia, with most admissions occurring in young people with neither family history of schizophrenia nor displaying other premorbid risk factors (Fauman & Fauman, 1978;Luisada, 1978;Pearlson, 1981;Peterson and Stillman, 1978). ...
... Validated models are now available to assess the NMDA receptor hypofunction across both interneurons and pyramidal cells (Featherstone et al., 2015b), in interneurons only (Billingslea et al., 2014;Carlen et al., 2012;Korotkova et al., 2010) or in pyramidal cells only (Tatard-Leitman et al., 2015). Our review also highlights the importance of stage of illness effects: in clinical studies, with contrasting results for deviance type elicitation of MMN (Michie et al., 2000); resting state gamma band connectivity studies (Andreou et al., 2015); source modelling of MMN (Fulham et al., 2014); and in pharmacological models of early-stage (single dose NMDA receptor antagonist) and late-stage (repeated dose NMDA receptor antagonist) disease (Catts & Catts 2010). Importantly, stage-of-illness appears to affect therapeutic response to glutamatergic therapy (Kinon et al., 2015). ...
Article
Full-text available
Background: There is converging evidence of involvement of N-methyl-d-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Our group recently identified a decrease in total NR1 mRNA and protein expression in the dorsolateral prefrontal cortex in a case-control study of individuals with schizophrenia (n=37/group). The NR1 subunit is critical to NMDA receptor function at the postsynaptic density, a cellular structure rich in the scaffolding protein, PSD-95. The extent to which the NMDA receptor NR1 subunit is altered at the site of action, in the postsynaptic density, is not clear. Aims: To extend our previous results by measuring levels of NR1 and PSD-95 protein in postsynaptic density-enriched fractions of prefrontal cortex from the same individuals in the case-control study noted above. Methods: Postsynaptic density-enriched fractions were isolated from fresh-frozen prefrontal cortex (BA10) and subjected to western blot analysis for NR1 and PSD-95. Results: We found a 20% decrease in NR1 protein (t(66)=-2.874, P=0.006) and a 30% decrease in PSD-95 protein (t(63)=-2.668, P=0.010) in postsynaptic density-enriched fractions from individuals with schizophrenia relative to unaffected controls. Conclusions: Individuals with schizophrenia have less NR1 protein, and therefore potentially fewer functional NMDA receptors, at the postsynaptic density. The associated decrease in PSD-95 protein at the postsynaptic density suggests that not only are glutamate receptors compromised in individuals with schizophrenia, but the overall spine architecture and downstream signaling supported by PSD-95 may also be deficient.
... Both pyramidal cells and interneurons express functional NMDA receptors (Monyer, Burnashev, Laurie, Sakmann, & Seeburg, 1994). Animals administered non-competitive NMDA receptor antagonists show homologous behavior and cognitive deficits to the PCP-induced psychotomimetic effects observed in healthy human volunteers and individuals with schizophrenia (reviewed in Catts & Catts, 2010). Insights into the neuronal mechanisms underlying PCP-induced psychotomimetic effects have been obtained from in vivo electrophysiological studies, which demonstrate that single dose administration of NMDA receptor antagonists induces sustained large increases in prefrontal excitatory firing and release of glutamate by blocking the activity of inhibitory interneurons (Homayoun & Moghaddam, 2007;Moghaddam & Javitt, 2012). ...
... Converging evidence from several distinct lines of research suggests that NMDA receptor hypofunction may contribute to the expression of schizophrenia. Firstly, there are clinical studies of the deleterious behavioral effects of non-competitive NMDA receptor antagonists, with evidence of chronic use of PCP inducing psychotic disorder beyond the acute symptoms of intoxication (reviewed in Catts & Catts, 2010). Epidemics of PCP abuse in the U.S.A. during the 1960s and 1970s were regionally and temporally discrete, demonstrating a consistent association between heavy PCP use and epidemics of first admission schizophrenia, with most admissions occurring in young people with neither family history of schizophrenia nor displaying other premorbid risk factors (Fauman & Fauman, 1978;Luisada, 1978;Pearlson, 1981;Peterson and Stillman, 1978). ...
... Validated models are now available to assess the NMDA receptor hypofunction across both interneurons and pyramidal cells (Featherstone et al., 2015b), in interneurons only (Billingslea et al., 2014;Carlen et al., 2012;Korotkova et al., 2010) or in pyramidal cells only (Tatard-Leitman et al., 2015). Our review also highlights the importance of stage of illness effects: in clinical studies, with contrasting results for deviance type elicitation of MMN (Michie et al., 2000); resting state gamma band connectivity studies (Andreou et al., 2015); source modelling of MMN (Fulham et al., 2014); and in pharmacological models of early-stage (single dose NMDA receptor antagonist) and late-stage (repeated dose NMDA receptor antagonist) disease (Catts & Catts 2010). Importantly, stage-of-illness appears to affect therapeutic response to glutamatergic therapy (Kinon et al., 2015). ...
Article
Full-text available
Evidence suggests that anomalous mismatch negativity (MMN) in schizophrenia is related to glutamatergic abnormalities, possibly involving N-methyl-D-aspartate (NMDA) receptors. Decreased cortical expressions of NMDA receptor subunits have been observed in schizophrenia, though not consistently. To aid with integration and interpretation of previous work, we performed a meta-analysis of effect sizes of mRNA or protein levels of the obligatory NR1 subunit in prefrontal cortex from people with schizophrenia. In schizophrenia compared to unaffected controls the pooled effect size was -0.64 (95% confidence interval: -1.08 to -0.20) for NR1 mRNA reduction and -0.44 (95% confidence interval: -0.80 to -0.07) for NR1 protein reduction. These results represent the first step to a deeper understanding of the region-specific, cell-specific, and stage-specific NMDA receptor hypofunction in schizophrenia, which could be linked to mismatch negativity deficits via transgenic and pharmacological animal models.
... Glutamatergic N-Methyl-D-Aspartate receptor (NMDAR) hypofunction is widely agreed to recapitulate or exaggerate the symptoms of schizophrenia. Some of the earliest clues arose from the observations that non-competitive NMDAR antagonists produce behaviors indistinguishable from the symptoms and cognitive deficits characteristic of schizophrenia [reviewed in (Catts and Catts, 2010)]. Further, NMDAR autoantibody-mediated encephalitis can induce psychiatric symptoms, and autoantibodies that target NMDARs induce receptor internalisation thus reducing NMDAR function (Dalmau et al., 2007;Dalmau et al., 2011). ...
Article
Lower N-methyl-d-aspartate receptor (NMDAR) GluN1 subunit levels and heightened neuroinflammation are found in the cortex in schizophrenia. Since neuroinflammation can lead to changes in NMDAR function, it is possible that these observations are linked in schizophrenia. We aimed to extend our previous studies by measuring molecular indices of NMDARs that define key functional properties of this receptor — particularly the ratio of GluN2A and GluN2B subunits — in dorsolateral prefrontal cortex (DLPFC) from schizophrenia and control cases (37/37). We sought to test whether changes in these measures are specific to the subset of schizophrenia cases with high levels of inflammation-related mRNAs, defined as a high inflammatory subgroup. Quantitative autoradiography was used to detect ‘functional’ NMDARs ([³H]MK-801), GluN1-coupled-GluN2A subunits ([³H]CGP-39653), and GluN1-coupled-GluN2B subunits ([³H]Ifenprodil). Quantitative RT-PCR was used to measure NMDAR subunit transcripts (GRIN1, GRIN2A and GRIN2B). The ratios of GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNAs were calculated as an index of putative NMDAR composition. We found: 1) GluN2A binding, and 2) the ratios of GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNAs were lower in schizophrenia cases versus controls (p < 0.05), and 3) lower GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNA ratios were exaggerated in the high inflammation/schizophrenia subgroup compared to the low inflammation/control subgroup (p < 0.05). No other NMDAR-related indices were significantly changed in the high inflammation/schizophrenia subgroup. This suggests that neuroinflammation may alter NMDAR stoichiometry rather than targeting total NMDAR levels overall, and future studies could aim to determine if anti-inflammatory treatment can alleviate this aspect of NMDAR-related pathology.
... PCP, ketamine, and dizocilpine (MK-801) essentially bind at the intrachannel site of the NMDAr preventing Ca 2+ influx into the cell (Catts, Lai, Weickert, Weickert, & Catts, 2016). Administration of non-competitive NMDAr antagonists to animals have demonstrated corresponding cognitive deficits and behavior seen in healthy human controls as well as individuals with SCZ showcasing PCP-induced psychotomimetic effects (Catts & Catts, 2010). Currently, there exists a common recognition that NMDA receptorrelated neurotansmission is essential for the generation of MMN and that pre-clinical models of NMDAr hypofunction are associated with MMN deficits comparable to those found in schizophrenia (Catts et al., 2016). ...
Thesis
Full-text available
Background:Dysfunctional synaptic plasticity is one of the leading candidate mechanisms in schizophrenia(SCZ). Mismatch negativity (MMN), prepulse inhibition (PPI), and plasticity of the visual evoked potential (VEP) are electroencephalographic (EEG) indices of short-and long-term synaptic plasticity which may help clarify the role of synaptic dysfunction in SCZ. However, whether MMN, PPI, and VEP plasticity index distinct or overlapping synaptic processes remains unknown.Objectives: To evaluate a test battery of brain plasticity in a large sample ofhealthy controls in order to (i)determine the robustness of the different electrophysiological indices, and (ii) to test their degree of overlap/independence.Method:113 healthycontrols were measured using EEG and electromyography. Utilizing the modulation of the VEP using a checkerboard reversal task, the 'roving' standard implementation of the MMN, and the PPI of startle reflex, analyses were performed using SPSS and JASP. Correlation and exploratory factor analyses were used to explore thehypothesis that the paradigms may be related by a similar underlying neural mechanism.Results:As predicted, the MMN and PPI showcased robust effects with medium to very large effect sizes. The VEP paradigm also yielded medium to large effect sizes and also revealed a significant potentiation of the N145, P100, and P2P measures. Correlational analysis found weak tendencies between the paradigms however they did not reach significanceupon correction for multiple comparisons. An exploratory factor analysis was performed resulting in orthogonality between the paradigms.Conclusion:Results indicate that these paradigms indeed reflect independent neural systems that can be indexed via EEG indices of brain plasticity.
... The important role of hippocampi, cingulate cortex, and basal ganglia in a ketamine model of schizophrenia was confirmed as well. Ketamine is just one of the tools for understanding schizophrenia: its acute administration is better for modeling positive symptoms of the diseases, while a more chronic administration/abuse replicates cognitive and even some negative symptoms (Catts and Catts, 2010;Fletcher and Honey, 2006;Krystal et al., 1994). The main pharmacological target of ketamine are NMDA receptors. ...
Article
Ketamine is a noncompetitive antagonist of glutamatergic N-methyl-d-aspartate receptors. Its acute effects on healthy volunteers and schizophrenia patients mimic some acute psychotic, but also cognitive and negative symptoms of schizophrenia, and subchronic treatment with ketamine has been used as an animal model of psychotic disorders. Glutamatergic neurotransmission is tightly coupled to oxidative metabolism in the brain. Quantitative histochemical mapping of cytochrome c oxidase (COX) activity, which reflect long-term energy metabolism, was carried out in rats that received a daily subanaesthetic dose (30 mg/kg) of ketamine for 10 days. In total, COX activity was measured in 190 brain regions to map out metabolic adaptations to the subchronic administration of ketamine. Ketamine treatment was associated with elevated COX activity in nine brain sub-regions in sensory thalamus, basal ganglia, cortical areas, hippocampus and superior colliculi. Changes in pairwise correlations between brain regions were studied with differential correlation analysis. Ketamine treatment was associated with the reduction of positive association between brain regions in 66 % of the significant comparisons. Different layers of the superior colliculi showed the strongest effects. Changes in other visual and auditory brain centres were also of note. The locus coeruleus showed opposite pattern of increased coupling to mainly limbic brain regions in ketamine-treated rats. Our study replicated commonly observed activating effects of ketamine in the hippocampus, cingulate cortex, and basal ganglia. The current study is the first to extensively map the oxidative metabolism in the CNS in the ketamine model of schizophrenia. It shows that ketamine treatment leads to the re-organization of activity in sensory and memory-related brain circuits.
... Numerous reports describe psychosis and psychotic episodes associated with MDMA use [228][229][230][231][232], and Duman et al. [233] reported that MDMA and cannabis use interact additively in elevation of subclinical psychotic trait scores. However, given that most MDMA users commonly use various other psychoactive drugs, it remains unclear to what degree MDMA in particular is involved in these cases and effects [234]. ...
Article
Full-text available
The first treatments showing effectiveness for some psychiatric disorders, such as lithium for bipolar disorder and chlorpromazine for schizophrenia, were discovered by accident. Currently, psychiatric drug design is seen as a scientific enterprise, limited though it remains by the complexity of brain development and function. Relatively few novel and effective drugs have, however, been developed for many years. The purpose of this article is to demonstrate how evolutionary biology can provide a useful framework for psychiatric drug development. The framework is based on a diametrical nature of autism, compared with psychotic-affective disorders (mainly schizophrenia, bipolar disorder and depression). This paradigm follows from two inferences: (i) risks and phenotypes of human psychiatric disorders derive from phenotypes that have evolved along the human lineage and (ii) biological variation is bidirectional (e.g. higher vs lower, faster vs slower, etc.), such that dysregulation of psychological traits varies in two opposite ways. In this context, the author review the evidence salient to the hypothesis that autism and psychotic-affective disorders represent diametrical disorders in terms of current, proposed and potential psychopharmacological treatments. Studies of brain-derived neurotrophic factor, the PI3K pathway, the NMDA receptor, kynurenic acid metabolism, agmatine metabolism, levels of the endocannabinoid anandamide, antidepressants, anticonvulsants, antipsychotics, and other treatments, demonstrate evidence of diametric effects in autism spectrum disorders and phenotypes compared with psychotic-affective disorders and phenotypes. These findings yield insights into treatment mechanisms and the development of new pharmacological therapies, as well as providing an explanation for the longstanding puzzle of antagonism between epilepsy and psychosis. Lay Summary: Consideration of autism and schizophrenia as caused by opposite alterations to brain development and function leads to novel suggestions for pharmacological treatments.
... Overall, there is a lack of evidence that psychedelics increase the rate of mental health problems on a population level (Bonson, 2012;Catts and Catts, 2010). As Jorgen Bramness said in response to our population study of psychedelics and mental health: "The study shows, in agreement with previous studies, that we probably have exaggerated the danger of the use of psychedelics in general, and LSD in particular, at least if we are to judge on the basis of drug laws" (Tveito, 2013). ...
... Overall, there is a lack of evidence that psychedelics increase the rate of mental health problems on a population level (Bonson, 2012;Catts and Catts, 2010). As Jorgen Bramness said in response to our population study of psychedelics and mental health: "The study shows, in agreement with previous studies, that we probably have exaggerated the danger of the use of psychedelics in general, and LSD in particular, at least if we are to judge on the basis of drug laws" (Tveito, 2013). ...
Chapter
The categorization of autoimmune encephalitis associated with antibodies against cell surface or synaptic proteins has progressively widened with the discovery of new antibodies. Many patients suffering from autoimmune encephalitis show core symptoms such as psychosis, seizures, and abnormal movement, which usually respond to the immune therapies. The clinical spectrum of autoimmune encephalitis has been expanding, following several atypical cases that require specific antibody tests. Among the antibodies, those against the N-methyl-D-aspartate receptor (NMDAR) and voltage-gated potassium channel complex (leucine-rich glioma-inactivated protein 1) have attracted considerable attention. Some patients have an underlying tumor, and the occurrence of an ovarian teratoma has been highly reported in young female patients with anti-NMDAR encephalitis. These diseases are often treatable, and the good outcomes have been reported in patients who have had an early resection of the teratoma and received extensive immune therapies. In this review, anti-NMDAR antibody-associated encephalitis will be discussed with a focus on the underlying cellular and synaptic mechanisms of the disease considering the antibody roles on its pathogenesis.
Article
Increasing abuse of halluzinogens, stimulants and other psychoactive substances will lead to an increasing prevalence of drug-induced psychoses. These drugs are also risk factors to other neuropsychiatric health disturbances. Phenomenological similar symptoms, e.g. in schizophrenics, masking of psychiatric and neurological diseases, make early diagnosis and appropriate treatment in drug addicts difficult. To ease the diagnostic dilemma, advices are given to identify subchronic and chronic drug-induced psychoses and drug-precipitated schizophrenias. If there are different consequences for treatment, precise diagnosis is important. Especially is to note the course after detoxification with observing daily routine and maximum load of these patients and their family history. Drug-induced chronic psychoses often seem more organic. The pharmacotherapy of drug-induced psychoses bases on case reports. Nonmedical therapeutic measures are of priority in mild cases with health education and avoiding reintoxication. Continuous drug ingestion can change episodical psychoses in a chronic course. It is suggested, that drug-induced chronic psychiatric disturbances are based on neuro-toxic effects.
Article
Prepulse inhibition is a cross-species phenomenon in which reflex responses to discrete sensory events are modified by weak prestimulation. In experiments designed to investigate the neuropharmacological mechanism of this form of information processing, and its relevance to schizophrenic psychopathology, apomorphine (0.125-4.0 mg/kg) and d-amphetamine (0.5-4.0 mg/kg) were administered to rats in an attempt to modify prepulse inhibition of the acoustic startle response. Rats were presented with 40 ms, 118 dB[A] acoustic pulses which were intermittently preceded by a weak 80 dB[A] acoustic prepulse. Both apomorphine and d-amphetamine induced a significant loss of prepulse inhibition, as reflected by increased pulse-preceded-by-prepulse versus pulse-alone startle magnitudes. Haloperidol (0.1 mg/kg), a specific D2 dopamine receptor antagonist, prevented the effects of 2.0 mg/kg apomorphine on prepulse inhibition, while having little effect by itself. An additional study investigated the effects of chronic intermittent administration of 2.5 mg/kg d-amphetamine. Rats given amphetamine for 8 consecutive days also displayed a loss of prepulse inhibition, with no evidence of tolerance. Finally, prepulse inhibition was examined under high- and low-intensity startle stimulus conditions; apomorphine (1.0 mg/kg) induced a loss of prepulse inhibition under both intensity conditions in approximately equal proportion. The results of these studies suggest a connection between sensorimotor gating, as measured by prepulse inhibition, and dopaminergic overactivity, supporting suggestions that information processing deficits in schizophrenia may be responsible for some psychotic symptoms and their effective treatment by antipsychotic D2 dopamine antagonists.
Chapter
DefinitionEtiology and PathophysiologyPathophysiologyAssessment and Differential DiagnosisAlcohol IntoxicationAlcohol WithdrawalAlcohol-induced Persisting Amnestic DisorderAlcohol-induced Persisting DementiaAlcohol-induced Mood DisorderAlcohol-induced Anxiety DisorderAlcohol-induced Psychotic DisorderAlcohol-induced Sleep DisorderAlcohol-induced Sexual DysfunctionAssessment of Alcohol Use DisordersScreeningPsychiatric History and ExaminationRelevant Physical Examination and Laboratory FindingsGender and Developmental PresentationsEpidemiology and ComorbidityPsychiatric Comorbidity in Individuals with an Alcohol Use DisorderCourse and Natural HistoryTreatmentThe Management of Alcohol WithdrawalTherapeutic Modalities: NonpharmacologicalTherapeutic Modalities: PharmacologicalThe Treatment of Psychiatric Comorbidity in AlcoholicsTreatment of Depressive Symptoms/DisordersTreatment of Anxiety Symptoms/DisordersAlcoholics Anonymous (AA) and Mutual Help OrganizationsSpecial Features Influencing TreatmentConclusion Comparison of DSM-IV/ICD-10 Diagnostic CriteriaReferences
Article
Two observations initiated the interest in the role of serotonin in schizophrenia: the structural similarity between LSD and serotonin and the LSD-induced psychosis. This interest was later reinforced by the advent of atypical neuroleptics which, among other mechanisms of action, possess a potent 5-HT2 antagonism. We review in this paper the clinical evidence for a serotonin dysfunction in schizophrenia, including CSF and postmortem studies of serotoninergic markers, results of pharmacological challenge studies, and the use of 5-HT2 antagonists in the treatment of the disease. We attempt to integrate the different observations of abnormal serotonin indices within the context of what is known about the interactions between the serotoninergic and the dopaminergic systems. We propose a model which takes into account the suggestion of a cortical serotoninergic hypofunction and a beneficial effect of 5-HT2 antagonism via modulation of subcortical DA activity.
Article
In this article, we advance a unified hypothesis pertaining to combined dysfunction of dopamine and N-methyl-D-aspartate glutamate receptors that highlights N-methyl-D-aspartate receptor hypofunction as a key mechanism that can help explain major clinical and pathophysiological aspects of schizophrenia. The following fundamental features of schizophrenia are accommodated by this hypothesis: (1) the occurrence of structural brain changes during early development that have the potential for producing subsequent clinical manifestations of schizophrenia, (2) a quiescent period in infancy and adolescence before clinical manifestations are expressed, (3) onset in early adulthood of psychotic symptoms, (4) involvement of dopamine (D2) receptors in some cases but not others that would explain why some but not all patients are responsive to typical neuroleptic therapy, and (5) ongoing neurodegenerative changes and cognitive deterioration in some patients. We propose that since N-methyl-D-aspartate receptor hypofunction can cause psychosis in humans and corticolimbic neurodegenerative changes in the rat brain, and since these changes are prevented by certain antipsychotic drugs, including atypical neuroleptic agents (clozapine, olanzapine, fluperlapine), a better understanding of the N-methyl-D-aspartate receptor hypofunction mechanism and ways of preventing its neurodegenerative consequences in the rat brain may lead to improved pharmacotherapy in schizophrenia.