Effects of Ketamine in Normal and Schizophrenic Volunteers

Article (PDF Available)inNeuropsychopharmacology 25(4):455-67 · October 2001with26 Reads
DOI: 10.1016/S0893-133X(01)00243-3 · Source: PubMed
Abstract
This study evaluates the effects of ketamine on healthy and schizophrenic volunteers (SVs) in an effort to define the detailed behavioral effects of the drug in a psychosis model. We compared the effects of ketamine on normal and SVs to establish the comparability of their responses and the extent to which normal subjects might be used experimentally as a model. Eighteen normal volunteers (NVs) and 17 SVs participated in ketamine interviews. Some (n = 7 NVs; n = 9 SVs) had four sessions with a 0.1-0.5 mg/kg of ketamine and a placebo; others (n = 11 NVs; n = 8 SVs) had two sessions with one dose of ketamine (0.3 mg/kg) and a placebo. Experienced research clinicians used the BPRS to assess any change in mental status over time and documented the specifics in a timely way. In both volunteer groups, ketamine induced a dose-related, short (<30 min) increase in psychotic symptoms. The scores of NVs increased on both the Brief Psychiatric Rating Scale (BPRS) psychosis subscale (p =.0001) and the BPRS withdrawal subscale (p =.0001), whereas SVs experienced an increase only in positive symptoms (p =.0001). Seventy percent of the patients reported an increase (i.e., exacerbation) of previously experienced positive symptoms. Normal and schizophrenic groups differed only on the BPRS withdrawal score. The magnitude of ketamine-induced changes in positive symptoms was similar, although the psychosis baseline differed, and the dose-response profiles over time were superimposable across the two populations. The similarity between ketamine-induced symptoms in SVs and their own positive symptoms suggests that ketamine provides a unique model of psychosis in human volunteers. The data suggest that the phencyclidine (PCP) model of schizophrenia maybe a more valid human psychosis/schizophrenia drug model than the amphetamine model, with a broader range of psychotic symptoms. This study indicates that NVs could be used for many informative experimental psychosis studies involving ketamine interviews.
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© 2001 American College of Neuropsychopharmacology
Published by Elsevier Science Inc. 0893-133X/01/$–see front matter
655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(01)00243-3
Effects of Ketamine in Normal and
Schizophrenic Volunteers
Adrienne C. Lahti, M.D., Martin A. Weiler, M.D., Tamara Michaelidis B.A., Arti Parwani, M.D., and
Carol A. Tamminga, M.D.
This study evaluates the effects of ketamine on healthy and
schizophrenic volunteers (SVs) in an effort to define the
detailed behavioral effects of the drug in a psychosis model. We
compared the effects of ketamine on normal and SVs to
establish the comparability of their responses and the extent to
which normal subjects might be used experimentally as a
model. Eighteen normal volunteers (NVs) and 17 SVs
participated in ketamine interviews. Some (
n
7 NVs;
n
9
SVs) had four sessions with a 0.1–0.5 mg/kg of ketamine and a
placebo; others (
n
11 NVs;
n
8 SVs) had two sessions
with one dose of ketamine (0.3 mg/kg) and a placebo.
Experienced research clinicians used the BPRS to assess any
change in mental status over time and documented the
specifics in a timely way. In both volunteer groups, ketamine
induced a dose-related, short (
30 min) increase in psychotic
symptoms. The scores of NVs increased on both the Brief
Psychiatric Rating Scale (BPRS) psychosis subscale (
p
.0001) and the BPRS withdrawal subscale (
p
.0001),
whereas SVs experienced an increase only in positive
symptoms (
p
.0001). Seventy percent of the patients
reported an increase (i.e., exacerbation) of previously
experienced positive symptoms. Normal and schizophrenic
groups differed only on the BPRS withdrawal score. The
magnitude of ketamine-induced changes in positive symptoms
was similar, although the psychosis baseline differed, and the
dose-response profiles over time were superimposable across
the two populations. The similarity between ketamine-induced
symptoms in SVs and their own positive symptoms suggests
that ketamine provides a unique model of psychosis in human
volunteers. The data suggest that the phencyclidine (PCP)
model of schizophrenia maybe a more valid human psychosis/
schizophrenia drug model than the amphetamine model, with
a broader range of psychotic symptoms. This study indicates
that NVs could be used for many informative experimental
psychosis studies involving ketamine interviews.
[Neuropsychopharmacology 25:455–467, 2001]
© 2001 American College of Neuropsychopharmacology.
Published by Elsevier Science Inc.
KEY
WORDS
:
Schizophrenia; Ketamine; Psychosis;
N-methyl-D-aspartate; Glutamate; Drug model
Ketamine is an anesthetic drug and a noncompetitive
NMDA antagonist, with mild psychotomimetic proper-
ties. It is one of the only pharmacologic probes of the
NMDA-sensitive glutamate system available for hu-
man study. The proposal that human studies with ket-
amine will inform the study of schizophrenia is based
on preclinical evidence (Carlsson and Carlsson 1990;
Javitt and Zukin 1991; Coyle and Puttfarcken 1993; Ol-
ney and Farber 1995) and clinical evidence (Krystal et al.
1994; Lahti et al. 1995a; Malhotra et al. 1997a) of the po-
tential involvement of glutamate in schizophrenia.
Both normal and schizophrenic volunteers (SVs) re-
ceived ketamine under controlled experimental condi-
tions to explore the hypothesis that the drug provides a
valid drug model for schizophrenia with a broad range
From the Maryland Psychiatric Research Center, University of
Maryland School of Medicine, Baltimore, MD.
Address correspondence to: Adrienne C. Lahti, M.D., Maryland
Psychiatric Research Center, University of Maryland School of Med-
icine, P.O. Box 21247, Baltimore, MD 21228.
Received May 25, 2000; revised January 24, 2001; accepted Febru-
ary 12, 2001.
Online publication: 2/20/01 at www.acnp.org/citations/
Npp02200182.
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of induced symptoms. This study critically evaluates
the effects of ketamine on mental status in normal vol-
unteers (NVs) and SVs and defines the detailed behav-
ioral effects of the drug in a psychosis model.
Several other psychotomimetic compounds have
been examined as a potential drug model for schizo-
phrenia. Indirect-acting dopamine agonists, such as
amphetamine or methylphenidate, have provided a
widely accepted model of paranoid schizophrenia. Both
drugs have been studied in NVs and SVs in controlled
research conditions. A single acute challenge with low-
dose psychostimulant in schizophrenic patients induces
a heterogeneous response, either improving or worsen-
ing mental status (vanKammen et al. 1982). High-dose
repeated administration of amphetamine to NVs can
produce paranoid symptoms that resemble paranoid
schizophrenia in normal persons (Connell 1958; Griffith
et al. 1968; Angrist and Gershon 1970; Bell 1973).
The psychotomimetic indoleamines: d-lysergic acid
diethylamide (LSD) and psilocybin, both structural ana-
logues of serotonin—have been studied in humans.
Both drugs act as agonists at serotonin receptors, most
potently at the 5HT2 receptor (Aghajanian and Marek
1999). The state induced by these drugs in normal sub-
jects is commonly described as a “psychedelic experi-
ence,” with vivid hallucinatory experience, fusion of vi-
sual and other sensory experiences, and emotional
alterations (Langs and Barr 1968; Giannini 1994; Vollen-
weider et al. 1998).
Interest in the role of excitatory neurotransmitter
systems in the pathophysiology of schizophrenia devel-
oped from two observations. First, phencyclidine (PCP)
produces schizophrenia-like symptoms in humans
(Luby et al. 1959). Second, PCP noncompetitively
blocks ion flow through the NMDA-sensitive glutamate
receptor ionophore (Anis et al. 1983). Ketamine is a
structural analogue of PCP, which binds to the PCP site
of the NMDA receptor with about one tenth the po-
tency of PCP (Kornhuber and Weller 1995). At higher
doses ketamine, like PCP, has broader neurochemical
actions (Tonge and Leonard 1969; Raja and Guyenet
1980; Castellani and Adams 1981; Nabeshima et al.
1981; Malare et al. 1982). Ketamine is made of a racemic
mixture with the S-enantioner displaying a 3–4 higher
affinity for the NMDA receptor than the R-ketamine
(Oye et al. 1991).
Challenge and symptom provocation studies are
currently held to stricter ethical standards than other
human research. They must include a clinically signifi-
cant theoretical rationale, involve a careful risk-benefit
discussion with the volunteer resulting in informed
consent, and use persons with a brain disease only if
healthy volunteers cannot be substituted. Therefore,
this study compares the effect of ketamine on NVs and
SVs to establish whether control subjects could be used
informatively in future studies.
METHODS
Participants
Normal Volunteers.
To recruit healthy volunteers, we
used newspaper advertising. A social worker screened
them in a structured telephone interview, and then a
trained research assistant interviewed them face to face
using the Structural Clinical Interview Diagnosis
(SCID) (Spitzer et al. 1990), the Structural Clinical Inter-
view for Personality Diagnosis (SCID-P) (Stangl et al.
1985), and the Wisconsin Scales of Psychosis Proneness
(Chapman et al. 1994). These Psychosis Proneness
scales were developed to rate features of schizotypal
personality disorder. Of the seven scales, we chose five
for this study: Perceptual Aberration, Social Anhe-
donia, Physical Anhedonia, Magical Ideation, and Non-
conformity. A psychiatrist interviewed the NVs to re-
view any questions raised during screening and to
verify diagnosis. All participants received a physical ex-
amination and EKG. Laboratory plasma and urine sam-
ples were also obtained, including HIV testing and a
drug screen.
The exclusion criteria included any history of an axis
I or II psychiatric disorder (including substance abuse),
any first-degree relatives with a diagnosis of schizo-
phrenia, any major medical diagnosis, any abnormal
chemical screen, or high blood pressure. We informed
volunteers that they may have random toxicologic
urine screens. Participants were paid $10/h for partici-
pating in this study.
Eighteen healthy volunteers received ketamine inter-
views, 14 males and four females, 14 Caucasians and
four African Americans. The mean age of the volun-
teers was 29.4 (
5.5) years and their mean weight was
175.2 (
32.1) pounds.
Schizophrenic Volunteers.
We recruited SVs from the
group of voluntary inpatients on the Residential Re-
search Unit (RRU) of the MPRC. Patients on the RRU
are recruited from Maryland to participate in on-going
research protocols. Before hospitalization, we informed
candidates about the research nature of the program
and encouraged them to visit and examine the facilities.
Patient volunteers have active but stable symptoms re-
quiring hospitalization and/or have experienced sev-
eral reoccurrences of the illness and require supervised
residential care.
Two experienced clinicians gave SVs a psychiatric
diagnosis of schizophrenia using DSM-III-R criteria
based on all of the historical and direct assessment in-
formation available. We evaluated each participant us-
ing the Structured Clinical Interview Diagnosis (SCID),
the Schedule for the Deficit Syndrome (SDS) (Kirk-
patrick et al. 1989), the MPRC Involuntary Movement
Scale (IMS) (Cassady et al. 1997), the Cannon-Spoor
Premorbid Adjustment Scale (PAS) (Cannon-Spoor et al.
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Effects of Ketamine in Normal and SVs
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1982), and the Prognostic Scale (PRO) (Strauss and Car-
penter 1974). Moreover, each participant had a detailed
clinical psychiatric history and family history of mental
illness and had extensive contact with past treatment
facilities and family members, when available. Each
subject was medically healthy by history and free of
current significant disease by physical exam, EKG, and
laboratory examination. None of these volunteers had a
recent history of drug or alcohol abuse. We used these
exclusion criteria: any major medical diagnoses, an ab-
normal plasma chemical screen, or high blood pressure.
All SVs were on a fixed dose of haloperidol (HAL) (0.3
mg/kg/day) for four weeks before the first ketamine
interview. SVs were not paid for their participation in
this study. Seventeen SVs received ketamine inter-
views. For their demographic characteristics, see Table 1.
Informed Consent.
We fully informed all of the NVs
and SVs about the nature of the protocol and the poten-
tial side effects of ketamine, including psychosis exacer-
bation. Afterward, each gave informed consent. Obtain-
ing consent with SVs was a more lengthy process than
with the NVs, who signed consent after the research
team [including the Principal Investigator (P.I.)] in-
formed them and answered their questions. Only pa-
tients who were judged to be competent and clinically
capable of understanding and appreciating the risks in-
volved in these studies were selected to participate.
This selection was made by a clinician; an indepen-
dently designated State of Maryland Mental Health Ad-
ministration (MHA) employee confirmed the ability of
the volunteer to understand the nature of the research.
For patient volunteers, several people presented the
nature of the protocol, including the P.I. We involved
family members or care-givers in the information pro-
cess when they were available. We gave patients de-
tailed verbal descriptions of the procedures and risks
described in the protocol. After being informed, they
were required to document their understanding by list-
ing key features and risks of the protocol. A designated
RRU ombudsperson was responsible for monitoring
the quality of the consent procedures and working
closely with patients throughout the research project,
reinforcing the requirements and risks of the protocol.
The roles of the independent MHA representative and
the MPRC ombudsperson were instituted in 1998.
The University of Maryland Internal Review Board
(IRB) approved the protocol and consent form. The IRB
initially approved the research and gave detailed and
ongoing review of this project, especially when the
mental status consequences of ketamine in schizophre-
nia became apparent.
Ketamine Administration Procedure
We conducted the ketamine interviews in the same way
for NVs and SVs—either four sessions with a dose
range of ketamine (0.1–0.5 mg/kg) and a placebo, or
Table 1.
Demographics: Schizophrenic Volunteers
Patient # Sex Race Age
Length of
Illness (years) Diagnosis
BPRS
a
Total
Score
BPRS
a
Psychosis
Score
Deficit
b
Symptoms PAS
c
PRO
d
Weight
e
1 F A 28 9 Schizo./paranoid 38 3 X 0.2 2 132
2 F AA 28 4 Paranoid 24 3 X 0.01 1 165
3 M C 28 8 Paranoid 32 6 0.27 5 154
4 M C 23 7 Disorg. 36 8 0.26 1 142
5 M C 22 3 Paranoid 41 6 0.48 6 166
6 M AA 25 8 Paranoid 36 5 0.03 5 162
7 M AA 29 8 Paranoid 42 6 0.15 5 209
8 F A 53 24 Undiff. 35 10 X 0.22 0 143
9 F C 34 13 Undiff. 33 12 0.56 0 118
10 M C 35 19 Undiff. 27 5 0.12 5 166
11 M AA 30 14 Paranoid 44 10 0.46 1 184
12 M C 36 17 Undiff. 43 7 X 0.31 3 152
13 F C 39 8 Paranoid 25 8 0.15 5 132
14 M C 37 26 Undiff. 36 9 0.7 4 184
15 M C 26 9 Disorg. 42 13 0.42 4 158
16 F AA 25 10 Undiff. 21 5 0.44 3 228
17 M C 39 22 Undiff. 27 8 0.54 8 232
Mean
SD 31.6 12.3 34.2 7.3 0.3 3.4 166.3
7.8
7.0
7.2
2.9
0.2
2.3
32.4
Abbreviations: AA, African American; A, Asian; C, Caucasian; schizo., schizophrenia; disorg., disorganized; undiff., undifferentiated.
a
BPRS Total and Psychosis Scores at baseline.
b
Primary negative symptoms.
c
Premorbid Adjustment Scale: Age Scales Total Score (lower score is better).
d
Prognostic Scale: General Items Total Score (higher score is better).
e
in pounds.
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two sessions with one dose of ketamine (0.3 mg/kg)
and a placebo. Each dose or placebo was administered
as a bolus over 60 s in a double-blind fashion. One dose
was given on each of two or four different days over
two weeks. Typically, subjects were never studied on
two consecutive days. One physician (CT) and one re-
search nurse were not blind to drugs but were not in-
volved in clinical assessments. The order of the drugs
was random, except that the highest dose was not rou-
tinely given first.
On the day of the experiment and 1 h before injec-
tion, an indwelling catheter was placed in the forearm
while the patient was comfortably positioned in a quiet
room with familiar staff members. We used an EKG
monitor to monitor cardiac status continuously for 30
min after ketamine; we closely monitored pulse, blood
pressure, and blood oxygen saturation. We rated men-
tal status at baseline and 20, 90, and 180 min after drug
administration.
Mental Status Evaluation
We evaluated mental status using the Brief Psychiatric
Rating Scale (BPRS) (Overall and Gorham 1962). The
BPRS was used to evaluate subjects on the day of the in-
fusion before administering ketamine/placebo and af-
ter drug injection at 20, 90, and 180 min. We evaluated
the BPRS total score as well as its subscale scores (Hed-
lund and Vieweg 1980): psychosis (items: conceptual
disorganization, hallucinatory behavioral, and unusual
thought content); withdrawal (emotional withdrawal,
motor retardation, and blunted affect); activation (items:
tension, mannerisms and posturing, and excitement);
anxiety (items: somatic concern, anxiety, guilt feelings,
and depressive mood); hostility (items: hostility, suspi-
ciousness, and uncooperativeness).
Experienced research clinicians blind to dose or drug
status conducted the mental status; each volunteer’s
ketamine series was rated by the same clinician. Raters
are trained and re-trained periodically on the BPRS to
maintain adequate reliability. These are the representa-
tive intraclass correlation coefficients for RRU raters for
the BPRS total and subscale scores: 0.86 for the BPRS
thought subscale and 0.73 for the BPRS total score. To
produce a timely written record of the responses, the
blinded clinician took detailed clinical notes. The same
clinician conducted a follow-up clinical interview while
still blind to the drug or dose at 8 h and 24 h after
injection.
Plasma Assays
We obtained blood samples for ketamine levels at the
0.3 mg/kg challenge at baseline, 10, 20, 30, and 60 min
after ketamine bolus infusion. We rapidly processed the
blood samples in a refrigerated centrifuge and stored
the plasma samples at
80
C. Plasma ketamine and
norketamine were assayed in the laboratory of Thomas
Cooper (Nathan Klein Institute, Orangeburg, NY), us-
ing a validated liquid chromatographic (LC) procedure
with UV detection. Following the addition of 500 ng of
internal standard (2-phenylmorphoinol, BW 306U), ket-
amine, and the metabolite norketamine were extracted
from 1 ml of plasma, made alkaline with 0.5 M NaOH,
with 5.0ml of 1.5% isoamyl alcohol in n-heptane.
The organic extract was back-extracted with 0.25ml of
0.01M HCI and transferred to inserts for injection on the
LC. Chromatography was carried out using a trimeth-
ylsilyl bonded silica column (LC-1, Supelco) with a mo-
bile phase of 85% phosphate buffer, 15% acetonitrile,
adjusted to pH of 2.4 with phosphoric acid, triethylamine,
and heptane sulfonate. At a flow rate of 2.0 ml/min,
ketamine, norketamine, and the internal standard were
separated and detected at a UV wavelength of 210 nm
in less than 12 min.
Statistical Analysis
To test the effects of ketamine on mental status, we ana-
lyzed BPRS total and subscale scores. For the single
dose dataset (NVs
18, SVs
17), we performed a
univariate repeated measures analysis of variance to
test for a main effect of group (NVs, SVs) and two re-
peated measures: dose (placebo, 0.3 mg/kg) and time
(baseline, 20”, 90”, 180”). We used a Greenhouse-Geis-
ser correction following significant dose-by-time inter-
actions, and we used post-hoc contrasts to contrast each
time point to baseline. All repeated measures effects are
reported with the original degrees of freedom and
Greenhouse-Geisser corrected
p
-values. Subsequently,
we analyzed both groups separately, using the same
dose and time repeated measures. Changes in BPRS to-
tal, psychosis, and withdrawal scores were predicted
a-priori. Therefore, the analyses of these variables were
treated as planned comparisons with an
value of 0.05.
The analyses of other BPRS subscales were subjected to
a Bonferroni correction (
0.017).
A subset of volunteers in the single-dose dataset re-
ceived two additional ketamine doses (NVs
7, SVs
9). These data were analyzed by a corrected univariate
repeated measures analysis of variance, as described
above, with four repeated doses (placebo, 0.l mg/kg,
0.3 mg/kg, 0.5 mg/kg).
For SVs, we correlated demographic descriptors:
age, baseline symptomology, age of onset of symptoms,
and length of illness, against BPRS total and subscale
scores at 0.3 mg/kg and 20 min, using Pearson’s Prod-
uct Moment correlations. We analyzed the effects of
sex, race, diagnosis, and deficit symptomology on BPRS
scores individually by a univariate analysis of variance.
Ten schizophrenic patients had a period of antipsy-
chotic medication withdrawal lasting at least four
weeks as part of another approved research protocol.
There were no links between the withdrawal and ket-
amine studies; thus various time intervals elapsed be-
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tween them. During the medication withdrawal period,
we obtained weekly ratings from blind clinicians using
the BPRS. We correlated the changes in BPRS ratings
over four weeks of medication withdrawal with each
subject’s ketamine behavioral change scores at 20 min
(from baseline) at 0.3 mg/kg, using Pearson’s Product
Moment Correlations.
For NVs, we correlated the demographic descriptor
of age with BPRS total and subscale scores at 0.3 mg/kg
and 20 min, using Pearson’s Product Moment Correla-
tions. We analyzed the effects of sex and race on BPRS
scores individually by a univariate analysis of variance.
We correlated the Wisconsin scale scores with BPRS to-
tal and subscale scores at 0.3 mg/kg and 20 min, using
Pearson’s Product Moment Correlations.
RESULTS
Eighteen NVs and 17 SVs received an interview with
0.3 mg/kg ketamine and a placebo. Of those, seven
NVs and nine SVs received the complete dose curve
and a placebo. We did the full dose curve first to estab-
lish the optimal dose for the interview. After that, only
one drug dose (0.3 mg/kg) was used with placebo. This
was the lowest dose, which most consistently produced
a ratable psychotomimetic effect.
Single Dose vs. Placebo
Normal Volunteers.
In NVs, there was a significant
time-by-dose interaction for: the BPRS total score
(F[3,51]
68.10;
p
.0001); the BPRS psychosis score
(F[3,51]
59.64;
p
.0001); the BPRS withdrawal score
(F[3,51]
59.12;
p
.0001).
Post-hoc analyses showed that compared to placebo
the increase from baseline was significant at 20 min for
the BPRS total and several subscales: the BPRS total
(F[1,17]
62.71;
p
.0001), the BPRS psychosis (F[1,17]
72.15;
p
.0001), and the BPRS withdrawal (F[1,17]
56.67;
p
.0001). See Table 2a for means (mean change
score) and standard deviations (SD).
In summary, in NVs the BPRS total, psychosis, and
withdrawal scores increased significantly at 20 min, but
not at 90 or 180 min after ketamine. Placebo did not
produce this pattern (Figure 1).
Schizophrenic Volunteers.
In SVs, there was a signifi-
cant time-by-dose interaction for the BPRS total (F[3,48]
7.75;
p
.0037) and the BPRS psychosis (F[3,48]
21.94;
p
.0001) scores. Post-hoc analyses revealed an
increase at the 20-min rating for ketamine for the BPRS
total (F[1,16]
10.45;
p
.0052) and the BPRS psychosis
(F[1,16]
24.84; p .0001). Ketamine did not signifi-
cantly effect the withdrawal score. See Table 2a for
means and SD.
In summary, in SVs the BPRS total and psychosis
scores, but not the withdrawal score, significantly in-
creased at 20 min, but not 90 or 180 min after ketamine.
Placebo did not produce this pattern (Figure 1).
Multiple Dose vs. Placebo
Normal Volunteers. Among NVs, there was a signifi-
cant time-by-dose interaction for: the BPRS total (F[9,54]
43.58; p .0001); the BPRS psychosis (F[9,54] 12.20; p
.0001); the BPRS withdrawal (F[9,54] 12.45; p .001);
and the BPRS anxiety score (F[9, 54] 4.39; p .0026).
Post-hoc analyses showed that compared to placebo
an increase occurred at 20 min for all three ketamine
Table 2a. BPRS Change Scores after Ketamine (0.3 mg/kg) and Placebo
Dose Time
BPRS
Total
BPRS
Psychosis
BPRS
Withdrawal
SV SD NV sd SV sd NV sd SV sd NV sd
PBO 200.9 3 0.1 1.3 0.1 0.8 0.1 0.2 0.2 0.8 0.1 0.2
0.3 mg 20 6.8 9 8.7 4.1 3.3 2.4 3.5 1.8 1 3.1 3.4 1.9
PBO 901.9 3.3 0.8 1.1 0.1 0.2 0 0 0.1 0.6 0.1 0.2
0.3 mg 901.1 3.5 0.4 1.7 0.4 0.9 0.2 0.6 0.8 1.8 0.1 0.2
PBO 1802.6 4.1 0.7 1.1 0.1 0.3 0 0 0.4 0.9 0.1 0.2
0.3 mg 1801.1 2.7 0.8 1.4 0.4 0.7 0.1 0.5 0.8 1.9 0.1 0.2
BPRS
Anxiety
BPRS
Activation
BPRS
Hostility
PBO 200.7 1.9 0.2 1.1 0.3 0.5 0 0.3 0.1 0.6 0 0
0.3 mg 20 0.1 3.9 0.7 1.5 1.4 3.2 0.1 0.6 0.6 2.1 0.2 0.4
PBO 901.5 2 0.8 0.9 0.2 0.8 0.1 0.2 0.1 0.7 0 0
0.3 mg 900.9 2.1 0.7 1 0 0.9 0.1 0.5 0.1 1.3 0 0
PBO 1801.4 2.2 0.7 0.9 0.4 0.9 0.1 0.2 0.2 0.6 0 0
0.3 mg 1800.8
1.5
0.8 1 0.1 0.7 0.1 0.2 0.1 0.9 0 0
SV N 17.
NV N 18.
460 A.C. Lahti et al. NEUROPSYCHOPHARMACOLOGY 2001VOL. 25, NO. 4
doses in the BPRS total score (0.1mg/kg: F[1,6] 10.8;
p .0167) (0.3 mg/kg: F[1,6] 51.69; p .0004) (0.5
mg/kg: F[1,6] 122; p .0001) and the BPRS psychosis
score (0.1 mg/kg: F[1,6] 22.74; p .0031) (0.3 mg/kg:
F[1,6] 18.18; p .0053) (0.5 mg/kg: F[1,6] 26.03; p
.0022). On the BPRS withdrawal score, an increase was
evident at 20 min only for the 0.3 and 0.5 mg/kg doses
(0.3 mg/kg: F[1,6] 13.56; p .0103) (0.5 mg/kg: F[1,6]
12.79; p .0117). For the BPRS anxiety score, an in-
crease at a trend level occurred only at 20 min for the
0.5 mg/kg dose (0.5 mg/kg: F[1,6] 8.24; p .0284).
See Table 2b for means and SD.
In summary, in NVs the BPRS total and psychosis
scores increased significantly at 20 min, but not at 90 or
180 min after ketamine, for all three ketamine doses. The
BPRS withdrawal score increased significantly at 0.3 and
0.5 mg/kg at 20 min, but not at 90 or 180 min and not at
0.1 mg/kg. There was a trend for the BPRS anxiety score
to be elevated at 0.5 mg/kg at 20 min (Figure 2).
Schizophrenic Volunteers. There was a significant time-
by-dose interaction for the BPRS total score (F[9,72]
4.21; p .0012) and the BPRS psychosis score (F[9,72]
6.10; p .0006).
For the BPRS total score (0.1 mg/kg: F[1,8] 5.33; p
.0497; 0.3 mg/kg: F[1,8] 7.24; p .0275; 0.5 mg/kg:
F[1,8] 13.75; p .006), and the BPRS psychosis score
(0.1 mg/kg: F[1,8] 33.11; p .0004; 0.3 mg /kg: F[1,8]
13.96; p .0057; 0.5 mg/kg: F[1,8] 17.31; p .0032),
the increase was apparent at 20 min for all three ket-
amine doses. No drug effects on the withdrawal score
was apparent. See Table 2b for means and SD.
In summary, in SVs the BPRS total and psychosis scores
significantly increased at 20 min, but not at 90 or 180 min
after ketamine, for all three ketamine doses. See Figure 2.
Comparing Normal and Schizophrenic Volunteers Sin-
gle Dose. There was a main effect for group on all
BPRS subscales: (BPRS total F[1,33] 88.17; p .0001;
Figure 1. Time course of mental status after acute injection of ketamine 0.3 mg/kg (closed symbols) and placebo (ope
n
symbols) in normal (n 18) and SVs (n 17). Mean BPRS total and subscales scores are shown. Asterisk indicates a signifi-
cant increase in mean change score at a given time point. The BPRS total and psychosis change scores were significantl
y
increased at 20 min after ketamine in both volunteer populations. The BPRS withdrawal change scores were significantl
y
increased at 20 min only in NVs. For both populations, there were no significant increases in the BPRS anxiety change scores
at any time after ketamine.
NEUROPSYCHOPHARMACOLOGY 2001VOL. 25, NO. 4 Effects of Ketamine in Normal and SVs 461
BPRS psychosis F[1,33] 51.70; p .0001; BPRS with-
drawal F[1,33] 11.48; p .0018; BPRS anxiety F[1,3]
15.10; p .0005; BPRS hostility F[1,33] 19.74; p
.0001; BPRS activation F[1,33] 8.83; p .0055). But,
there were no significant interactions between group
and dose, group and time, or group and dose and time
for the BPRS total, the BPRS thought, anxiety, hostility,
or activation scores.
On the BPRS withdrawal score, the analysis revealed
a dose-by-group interaction (F[1,33] 4.44; p .0428)
and a trend for a dose-by-time-by-group interaction
(F[3,31] 2.58; p .07). To further contrast SV and
NV’s positive symptoms in response to ketamine, the
BPRS psychosis subscale was split into two compo-
nents: A thought disorganization score (item 4) and a
hallucinations and delusions score (items 12 and 15).
There was a main effect for group on both scores (item
4: F[1,33] 11.41; p .019; items 12 and 15 F[1,33]
53.95; p .0001). But there were no significant interac-
tions for neither of the two scores.
In summary, normal and schizophrenic groups re-
sponded similarly on BPRS total, psychosis, and anxi-
ety measures. But on the BPRS withdrawal score, NVs
experienced a more marked increase in the withdrawal
score than SVs. We identified a trend for the groups to
differ on the BPRS withdrawal score over time.
Multiple Dose. There was a significant group effect
for the BPRS total score and all its subscales, except for
the BPRS activation subscale (BPRS total F[1,14]
37.66; p .0001; BPRS psychosis F[1,14] 21.83; p
.0004; BPRS withdrawal F[1,14] 8.58; p .0110; BPRS
hostility F[1,14] 15.47; p .0015; BPRS anxiety F[1,14]
8.93; p .0098). There were no significant interactions
between group and dose, group and time, and group
and dose and time for the BPRS total, psychosis, with-
Figure 2. Time course of mental status after a dose range of ketamine doses (0, 1, 0.3 and 0.5 mg/kg) and placebo in NVs (n
7) (open symbols) and SVs (n 9) (closed symbols). Mean BPRS total and subscales scores are reported. Asterisk indicates a
significant increase in mean change score at a given time point. For the BPRS total and psychosis scores, there was a dose-
related significant increase at 20 min after ketamine in normal and SVs. The BPRS withdrawal significantly increased at 20
min for the higher doses in NVs only. The BPRS anxiety was elevated at a trend level at 20 min for the highest dose in NVs.
462 A.C. Lahti et al. NEUROPSYCHOPHARMACOLOGY 2001VOL. 25, NO. 4
drawal, and hostility. For the BPRS anxiety there was a
trend for a significant time-by-group interaction
(F[3,42] 3.02; p .06).
In summary, patterns of ketamine response in nor-
mal and schizophrenic groups did not differ signifi-
cantly on any of the BPRS scores. Regardless of dose,
the NVs had an increase in anxiety at 20 min whereas
SV showed a decrease or little change in anxiety across
time and doses (Figure 2d). Although not significant,
this pattern also with the 0.3mg/kg vs. placebo compar-
ison. (Figure 1).
Ketamine Plasma Level. Ketamine plasma levels
were analyzed from samples taken during challenge
with 0.3 mg/kg ketamine in 12 SVs and 12 NVs. There
were no significant differences in ketamine level be-
tween schizophrenic and normal controls at any time
point sampled (Figure 3).
Correlations between Mental Status Changes and
Baseline Symptomology/Demographics. There were
no significant associations between any aspect of the
symptom changes induced by ketamine and age, sex, or
race for all volunteers (normal or schizophrenic). There
were no significant correlations between ketamine-
induced symptom changes and plasma ketamine levels
in either normal or schizophrenic populations.
In SVs, we found no significant correlations between
diagnosis, deficit symptoms, age of illness onset, length
of illness, baseline symptoms, or change in symptoms
during medication withdrawal, and any symptom
change with ketamine.
For NVs, we identified a significant correlation be-
tween change in BPRS psychosis score at 20 min and
two of the Wisconsin subscales [PER (r 0.53; p .04)
and PERMAG (r .53; p .04)]. These two Wisconsin
subscales measure perceptual distortions alone (PER)
or combined with wrong attribution of causation (PER-
MAG) in normal persons.
Clinical Observations
Positive Symptoms. Figure 2b demonstrates a similar
dose-response pattern in all BPRS subscales in both nor-
mal and SVs, except for baseline values. Obviously, the
SVs have higher baseline BPRS values. Although some
aspects of the ketamine response of these two groups
were similar (symptom type, for example), some as-
Table 2b. BPRS Change Scores after Ketamine (0.1, 0.3, 0.5 mg/kg) and Placebo
Dose ime
BPRS
Total
BPRS
Psychosis
BPRS
Withdrawal
SV sd NV sd SV sd NV sd SV sd NV sd
PBO 202 2.9 0.4 1 0.3 0.5 0.1 0.4 0 0.7 0 0
0.1 mg 5.3 8 3 2.2 3.6 1.8 1.9 1.2 0.7 2.8 0.3 0.5
0.3 mg 4 5.3 8.4 3.1 2.9 2.4 3 2 1.2 4 3.3 2.4
0.5 mg 7.6 8.4 14.6 4.2 4.7 3.7 4.7 2.4 1.9 4 3.9 2.9
PBO 902.3 4.3 0.1 0.4 0.1 0.3 0 0 0.2 0.7 0 0
0.1 mg 2.6 4.5 1 1.3 0.2 1.1 0.1 0.4 1.3 2.2 0.1 0.4
0.3 mg 1.1 4.7 0.1 0.7 0.4 1.2 0.6 0.8 1.3 2.3 0 0
0.5 mg 3.8 6.6 0.6 1 0.2 1.6 0.3 0.5 1 3.1 0.1 0.4
PBO 1803.4 5.2 0.1 0.4 0.2 0.4 0 0 0.6 1.1 0 0
0.1 mg 3.3 4.1 1.1 1.1 0.3 1.9 0 0 1.6 2.6 0.1 0.4
0.3 mg 1.7 3.6 0 0.8 0.4 0.9 0.3 0.8 1.4 2.4 0 0
0.5 mg 3.9 4 0 0.6 0.1 1.4 0 0 1.6 2.1 0 0
BPRS
Anxiety
BPRS
Activation
BPRS
Hostility
PBO 201 2.2 0.3 1 0.3 0.5 0 0 0.1 0.1 0 0
0.1 mg 0.6 2.5 0.7 1.8 1 2.8 0 0.6 0.6 0.6 0.1 0.4
0.3 mg 1.2 1.1 1.4 1.5 0.4 1.9 0 0 0.4 0.4 0.1 0.4
0.5 mg 0.4 4 2.9 2 0.9 2.3 1 1.73 0.4 0.4 0.7 1.1
PBO 901.9 2.6 0.1 0.4 0.2 1.1 0 0 0.2 0.2 0 0
0.1 mg 0.4 1.1 0.9 0.9 0 0.5 0.1 0.4 1.1 1.1 0 0
0.3 mg 0.7 2.6 0.4 0.5 0.1 1.3 0 0 0 0 0 0
0.5 mg 1.7 3 0.1 0.7 0.2 1.1 0 0 0.4 0.4 0 0
PBO 1801.8 2.8 0.1 0.4 0.4 1 0 0 0.3 0.3 0 0
0.1 mg 1 1.2 0.9 0.9 0 0.5 0.1 0.4 0.8 0.8 0 0
0.3 mg 0.7 1.7 0.3 0.8 0 0.9 0 0 0.2 0.2 0 0
0.5 mg 1.8 3.2 0 0.6 0.1 1.1 0 0 0.1 0.1 0 0
SV N 9.
NV N 7.
NEUROPSYCHOPHARMACOLOGY 2001VOL. 25, NO. 4 Effects of Ketamine in Normal and SVs 463
pects of ketamine-induced behavioral changes between
the two groups were different in several ways (Table 3).
SVs experienced visual and auditory illusions, distor-
tions, and somaesthetic sensations at the 0.1 mg/kg
doses and unformed (e.g., buzzing, popping sounds)
and formed (e.g., articulated voice) hallucinations at the
0.3 mg/kg and 0.5 mg/kg doses. On the other hand,
throughout the ketamine dose range, NVs experienced
illusions and perceptual distortions and less frequently
perception without external stimuli (e.g., popping
sounds) or unusual, odd thought (idea of reference,
participating in a study for aliens). These kinds of
symptoms can be seen in schizophrenic persons with
very low levels of positive symptoms and have been
typically seen as the start of a “psychosis” spectrum
(Astrachan et al. 1972). Formed hallucinations were
rarely reported by NVs at the doses used here. How-
ever, both subject groups experienced thought disorga-
nization (looseness of association, concreteness, bizarre
reasoning) at all doses.
Schizophrenics experienced two kinds of symptoms.
First, they had delusions whose theme and content re-
minded them of delusions they had previously experi-
enced during an acute psychotic state (particularly
grandiose and paranoid delusions). Second, they expe-
rienced unformed psychotic symptoms similar to those
experienced by NVs. Approximately 70% of the pa-
tients experienced some ketamine-induced symptoms
reminiscent of their usual psychotic symptoms during
an illness exacerbation.
NVs experienced formed mental images, which they
described as a dream, movie, or cartoon. Their themes
were occasionally paranoid. Occasionally, NVs evi-
denced a “true” schizophrenic-like psychotic symptom,
such as an idea of reference (two NVs). Sometimes,
schizophrenics reported their experience without in-
sight as though they were reporting their usual illness-
associated symptoms. One patient spontaneously made
the parallel between the current ketamine interview
and his acute symptoms; another connected this experi-
ence with a need to take further anti-psychotic medica-
tion. NVs always commented on how the experience
was unusual, bizarre.
Negative Symptoms. Only NVs showed an increase in
withdrawal scores with ketamine, increases that were
significant for the 0.3 and 0.5 mg/kg dose level. None
of the changes were significant for the patient volun-
teers. NVs displayed negative symptoms based on their
blunted facial expression; often they remained silent
during the first minutes of the experiment. However,
after the session, they always reported their mental ex-
periences with ketamine in an involved and animated
fashion lacking the typical curbing of interest and di-
minished social drive that are intrinsic to the negative
symptoms spectrum. Thus, ketamine induced only
some of the dimensions of negative symptoms.
DISCUSSION
These data show that subanesthetic doses of ketamine
in healthy and SVs induce a mild, dose-related, short-
lasting increase in psychotic symptoms. The design car-
ried out in this experiment contrasts responses of the
two populations: some responses were similar (e.g., on
positive symptoms), and some were also different (e.g.,
on negative symptoms). To enable the comparison, we
have compared adequate groups of patients and NVs
across a subanesthetic dose range, analyzing the pat-
tern of changes produced.
All of the normal and patient volunteers who re-
ceived ketamine experienced psychotic symptoms. Al-
though the normal and patient individuals had differ-
ent levels of baseline psychosis, the magnitude and
time course of ketamine-induced changes were similar,
and the dose-response profile in BPRS-rated positive
symptoms changes was parallel across the two popula-
tions. This behavioral result is consistent with the func-
tional regional cerebral blood flow studies of ketamine
in normal and SVs, which have shown similar activa-
tion patterns and dynamics between the two groups
(Lahti et al. 1995b, 1999) (Holcomb et al. in press).
Both groups experienced thought disorganization, such
Figure 3. Time course of plasma ketamine concentrations
for the 0.3 mg/kg challenge in normal and SVs. There were
no significant differences between schizophrenic and nor-
mal controls.
464 A.C. Lahti et al. NEUROPSYCHOPHARMACOLOGY 2001VOL. 25, NO. 4
as concreteness and loose association. With respect to
hallucinations, the NVs experienced mostly perceptual
changes, but in more than 70% of patients the positive
symptoms included previously experienced symptoms
such as hallucinations and delusions. Others have also
reported the similarity between normal and SVs in pos-
itive symptoms with ketamine (Adler et al. 1999). Thus,
ketamine appears to induce hallucinatory and delu-
sional symptoms along a gradient of intensity. NVs ex-
perience symptoms at the putative low end of the spec-
trum (simple illusion, perceptual distortion, formed
mental images), and already-psychotic schizophrenic
patients experience symptoms at the high end of the
spectrum (formed hallucination, reactivation of delu-
sional beliefs).
Only the NVs had a significant increase in the with-
drawal subscale of the BPRS. And in that volunteer
population, only some of the dimensions of negative
symptoms, such as blunted affect and emotional with-
drawal, were induced by ketamine. SVs had higher
negative symptoms ratings at baseline and showed a
nonsignificant rise in response to ketamine, possibly in-
dicating a ceiling effect. Ketamine may increase only
secondary negative symptoms in the NVs (secondary to
experiencing altered perceptual experience for exam-
ple). Reports of acute PCP intoxication in humans ac-
count primarily productive states (Pearlson 1981)
whereas descriptions of chronic PCP abuse include
characteristics of dulled thinking and lethargy (Cos-
grove and Newell 1991). Others have reported ket-
amine-induced changes in negative symptoms, both in
patient and NVs (Malhotra et al. 1997a). A difference in
drug administration (acute bolus vs. slow infusion)
could account for this, by inducing only a brief ket-
Table 3.
NV Acute Drug Effect SV Acute Drug Effect
1 False beliefs (participating in study for aliens), anxiety,
perceptual distortion, confusion, thought
disorganization
1 A typical visual hallucinations, reduced emotional
withdrawal and blunted affect
2 False beliefs (like being in the movie 2001), thought
disorganization, confusion (time), perceptual
distortion (somaesthetic & visual)
2 Suspiciousness, visual hallucinations, increased
withdrawal and blunted affect
3 Ideas of reference, perceptual distortions (visual),
anxiety, confusion (time), “tunnel vision”
3 Perceptual distortions-illusions, increased suspiciousness,
delusions of control, auditory hallucinations, atypical
visual hallucinations
4 Anxiety, perceptual distortion (somaesthetic & visual),
out-of-body experience, auditory buzzing, idea of
reference (people could hear her thoughts)
4 Increased thought disorder, paranoid ideation,
visual hallucinations
5 Perceptual distortions (somaesthetic, auditory) 5 Perceptual distortions-illusions, atypical visual
hallucinations
6 Visual hallucination, perceptual distortions (auditory,
visual), olfactory hallucination
6 Grandiose delusions
7 Perceptual distortion (visual) 7 Disorganized thought (word salad), grandiose
delusions
8 Overinclusiveness, perceptual distortion (visual,
auditory, somaesthetic), illusions
8 No reported change
9 Perceptual distortions (visual, auditory, somaesthetic),
synesthesia, auditory hallucinations
9 Auditory hallucinations
10 Emotional withdrawal, perceptual distortion (visual,
auditory), conceptual disorganization
10 Excitement, conceptual disorganization, suspiciousness,
paranoid delusion
11 Perceptual distortions (auditory, visual, somaesthetic),
euphoria, thought disorganization
11 Excitement, conceptual disorganization, perceptual
distortion (auditory), paranoid delusion
12 Perceptual distortion (visual, auditory, somaesthetic),
emotional withdrawal
12 Perceptual distortion, increase auditory hallucinations
13 Delusional perception, perceptual distortion (visual,
auditory, somaesthetic), excitement
13 Increased auditory hallucinations, delusions of control,
somaesthetic distortion, disorganization
14 Disorientation, perceptual distortion (auditory,
visual, somaesthetic)
14 Somaesthetic distortions
15 Emotional withdrawal, perceptual distortion (auditory,
visual, somaesthetic), thought disorganization
15 Increased disorganization, increased auditory
hallucinations, increased delusions, increased anxiety
16 Emotional withdrawal, auditory hallucinations,
somaesthetic distortion
16 Anxiety, visual distortion, out of body experience
17 Emotional withdrawal, auditory hallucinations 17 Increased disorganization, increased religious delusions
18 Auditory hallucinations, disorientation, suspiciousness,
perceptual distortion (visual), anxiety, thought
disorganization
NEUROPSYCHOPHARMACOLOGY 2001VOL. 25, NO. 4 Effects of Ketamine in Normal and SVs 465
amine period with the bolus technique. Such differ-
ences between acute bolus and chronic/subchronic in-
fusion administration would be predicted by animal
studies with PCP where neurochemical and behavioral
differences between those two states can be found
(Jentsch et al. 1998; Jentsch and Roth 1999).
The finding of close similarity between ketamine-
induced symptoms and the SV’s own symptoms and their
exacerbation with ketamine suggest that glutamatergic
hypofunction may be close to the pathophysiology of
positive psychotic symptoms in schizophrenia. The lack
of blockade in patient volunteers with the traditional an-
tipsychotic haloperidol (Lahti et al. 1995a), but the re-
ported blunting of response with clozapine (Malhotra et
al. 1997b) is intriguing. Thus the ketamine model may
represent a useful human model of psychosis with hal-
lucinations, delusions, and thought disturbances, and an
opportunity for novel pharmacology.
Several studies have reported changes in measures
of cognition, eye-tracking, and event-related brain po-
tentials with ketamine in normal (Harborne et al. 1996;
Radant et al. 1998; vanBerckel et al. 1998; Oranje et al.
2000; Weiler et al. 2000) and SVs (LaPorte et al. 1996;
Malhotra et al. 1997a). These results suggest that ket-
amine, when further studied, may induce additional
symptoms of schizophrenia, particularly the cognitive.
Among models of schizophrenic psychosis, dopa-
mine has been the most widely studied based on sev-
eral observations: that repeated administrations of
amphetamine can induce paranoid symptoms (see In-
troduction for review), that all effective antipsychotic
drugs block D
2
dopamine receptor, and that their affin-
ity for this receptor correlates positively with drug po-
tency (Creese 1976; Seeman et al. 1976). Recently evi-
dence of augmented dopamine release in schizophrenia
has been reported (Laruelle et al. 1996). However, ad-
ministration of a dopamine agonist to persons with
schizophrenia can induce a heterogeneous symptom re-
sponse. When worsening occurs, it is mostly limited to
paranoid symptoms. Dopamine agonists increase psy-
chotic symptoms in subacute patients and the response
may be predictive of relapse (Lieberman et al. 1987).
These characteristics have been interpreted as indicat-
ing that dopamine agonist-induced psychosis in schizo-
phrenia is a state-dependent phenomenon produced by
increased DA neuronal activity (Janowsky et al. 1973).
These characteristics stand in contrast to what is seen
with ketamine. Ketamine increases symptoms in all SVs
and in a way that is strikingly reminiscent of subjects’
symptoms during active episodes of illness. Traditional
antipsychotics, such as haloperidol, do not reverse
these symptoms (Lahti et al. 1995a). There is no correla-
tion between ketamine psychosis and baseline sympto-
mology, and the change in psychosis is not predictive of
symptom worsening during medication withdrawal.
Thus, ketamine exacerbates symptoms of the illness un-
related to the current clinical state. Putatively, ketamine
may induce a neurochemical abnormality related to the
core of the illness.
Ketamine is an anesthetic drug with a strong record
of safety. Ketamine is commonly used at doses 20–60
times higher than doses administered here. The in-
crease in psychosis with ketamine in this paradigm is
short (20–30 min), and our ratings show that the mental
status of all volunteers’ returns to baseline by 90 min.
Distress is minimal, especially in patients, as shown by
a lack of any change in the BPRS anxiety score. Out-
come studies in patients who received ketamine have
shown that ketamine administration does not compli-
cate the course of schizophrenic illness for the next
eight months after challenge beyond the immediate
post-ketamine 30-min time period (Carpenter 1999;
Lahti et al. 2001).
These data show that the putative antagonism of
NMDA-sensitive glutamatergic transmission with ket-
amine provokes schizophrenia-like psychotic symp-
toms in normal controls and exacerbates specific symp-
toms of schizophrenia in the patient group. Therefore,
the ketamine administration may provide a valid hu-
man model of psychosis. Because ketamine-induced
psychosis is not blocked by haloperidol, and only
blunted by clozapine, it also provides a surrogate
marker of enhanced antipsychotic activity and should
be evaluated further for its usefulness in new drug de-
velopment (Lahti et al. 1999). New compounds with
new modes of action could be screened in this model.
Our study indicates that NVs can be used along side of
the SVs because the symptom profile and time course
with ketamine is parallel across groups. Where possi-
ble, healthy volunteers can validly be used; where nec-
essary, patient volunteers can participate.
ACKNOWLEDGMENTS
This ketamine research was supported in part by grant
DA09483 and for subject characteristic by MH40279. The au-
thors thank all of the schizophrenic and normal volunteers who
took part in these research studies, the staff of the Residential
Research Unit of the Maryland Psychiatric Research Center,
Kristin Frey Deb Medoff and Bob McMahon for statistical ex-
pertise, Thomas Cooper for plasma ketamine assays determina-
tion, and Kristin Ricasa for her administrative assistance.
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    • "These changes are accompanied by concurrent changes in electrophysiological properties, such as increasing excitatory postsynaptic current (EPSC) amplitude and decreasing decay time [15, 17] , and reflect the healthy, activity-dependent maturation of the brain [19][20][21]. NMDA receptor signaling dysregulation has been implicated in schizophrenia, autism spectrum disorder (ASD), epilepsy, and intellectual disability, which are considered disorders of brain development [22][23][24][25][26]. NMDA receptor antagonists ketamine and PCP can induce psychosis symptoms in healthy individuals and worsen such symptoms in individuals with schizophrenia [27][28][29] . Altered NMDA receptor signaling in the prefrontal cortex of individuals with schizophrenia has been identified using a paradigm in which intracellular signaling downstream to receptor activation was moni- tored [30, 31]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Neurodevelopmental disorders such as autism spectrum disorders and schizophrenia differentially impact males and females and are highly heritable. The ways in which sex and genetic vulnerability influence the pathogenesis of these disorders are not clearly understood. The n-methyl-d-aspartate (NMDA) receptor pathway has been implicated in schizophrenia and autism spectrum disorders and changes dramatically across postnatal development at the level of the GluN2B-GluN2A subunit "switch" (a shift from reliance on GluN2B-containing receptors to reliance on GluN2A-containing receptors). We investigated whether sex and genetic vulnerability (specifically, null mutation of DTNBP1 [dysbindin; a possible susceptibility gene for schizophrenia]) influence the developmental GluN2B-GluN2A switch. Methods: Subcellular fractionation to enrich for postsynaptic density (PSD), together with Western blotting and kinase assay, were used to investigate the GluN2B-GluN2A switch in the cortex and hippocampus of male and female DTNBP1 null mutant mice and their wild-type littermates. Main effects of sex and DTNBP1 genotype, and interactions with age, were assessed using factorial ANOVA. Results: Sex differences in the GluN2B-GluN2A switch emerged across development at the frontal cortical synapse, in parameters related to GluN2B. Males across genotypes displayed higher GluN2B:GluN2A and GluN2B:GluN1 ratios (p < 0.05 and p < 0.01, respectively), higher GluN2B phosphorylation at Y1472 (p < 0.01), and greater abundance of PLCγ (p < 0.01) and Fyn (p = 0.055) relative to females. In contrast, effects of DTNBP1 were evident exclusively in the hippocampus. The developmental trajectory of GluN2B was disrupted in DTNBP1 null mice (genotype × age interaction p < 0.05), which also displayed an increased synaptic GluN2A:GluN1 ratio (p < 0.05) and decreased PLCγ (p < 0.05) and Fyn (only in females; p < 0.0005) compared to wild-types. Conclusions: Sex and DTNBP1 mutation influence the GluN2B-GluN2A switch at the synapse in a brain-region-specific fashion involving pY1472-GluN2B, Fyn, and PLCγ. This highlights the possible mechanisms through which risk factors may mediate their effects on vulnerability to disorders of NMDA receptor dysfunction.
    Full-text · Article · Dec 2016
    • "The dopamine hypothesis has tried to explain positive, negative, and cognitive symptoms of the schizophrenia suggesting different alterations of the dopamine activity in different brain regions [3][4][5]. The glutamate hypothesis suggested that phencyclidine and ketamine block of the N-methyl-D-aspartate receptor induced positive, negative, and cognitive symptoms [6][7][8][9][10][11][12]. The cytokine alterations in schizophrenics are consistent with the glutamate hypothesis of schizophrenia [13][14][15][16][17]. "
    [Show abstract] [Hide abstract] ABSTRACT: Schizophrenia is a severe, chronic and debilitating mental disorder. Past literature has reported various hypotheses about the psychopathology of schizophrenia. Recently, a growing literature has been trying to explain the role of inflammation in the etiopathogenesis of schizophrenia. In the past, numerous immune modulation and anti-inflammatory treatment options have been proposed for schizophrenia, but sometimes the results were inconsistent. Electronic search was carried out in November 2015. PubMed and Scopus databases have been used to find studies to introduce in this review. Only randomized-placebo-controlled add-on trials were taken into account. In this way, six articles were obtained for the discussion. Celecoxib showed beneficial effects mostly in early stages of schizophrenia. In chronic schizophrenia, the data are controversial, possibly in part for methodological reasons.
    Full-text · Article · Jul 2016
    • "Glutamate with diverse population of its receptors—e.g., NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)—is involved in the pathogenesis of schizophrenia [1,2]. Antagonists of NMDA receptor such as phencyclidine (commonly known as " angel dust " ) or ketamine cause symptoms mimicking schizophrenia [3] and exacerbate psychosis in schizophrenic patients including also negative and cognitive symptomatology [4]. Glycine is natural co-agonist of NMDA receptor and along with glutamate is required to activate ion flows through the receptor. "
    [Show abstract] [Hide abstract] ABSTRACT: Aim: Find changes in matrix metallopeptidase-9 (MMP-9) levels during augmentation of antipsychotic treatment with sarcosine and a relationship between schizophrenia symptoms severity and initial level of MMP-9. Method: Fifty-eight patients with diagnosis of schizophrenia with predominant negative symptoms participated in a six-month prospective RCT (randomized controlled trial). The patients received two grams of sarcosine (n = 28) or placebo (n = 30) daily. At the beginning, after six weeks and after six months MMP-9 levels were measured. Severity of symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS). Results: MMP-9 serum levels were stable after six weeks and six months in both groups. We noted improvement in negative symptoms, general psychopathology and total PANSS score in sarcosine group compared to placebo; however, there was no correlations between serum MMP-9 concentrations and PANSS scores in all assessments. Initial serum MMP-9 concentrations cannot be used as an improvement predictor acquired during sarcosine augmentation. Conclusions: Our results indicate that either MMP-9 is not involved in the N-methyl-d-aspartate (NMDA)-dependent mechanism of sarcosine action in terms of clinical parameters or sarcosine induced changes in peripheral MMP-9 concentrations cannot be detected in blood assessments.
    Full-text · Article · Jul 2016
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