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Antipsychotic Drugs

Antipsychotic Drugs
1Amity Institute of Biotechnology, Uttar Pradesh, India
2Jaypee Institute of Information Technology, Uttar Pradesh, India
3Amity Education Group, New York, USA
*Corresponding author. E-mail:;
Neuropsychiatric symptoms are mutual in older
adults and can be associated with a decline in
functional and cognitive status. Among the
currently available atypical antipsychotics,
olanzapine, haloperidol, risperidone, clozapine,
and quetiapine have been the most widely
studied in schizophrenia, bipolar disorder,
and depression. Some controversy surrounds
the use of different antipsychotic mediators in
neuropsychiatric disorders with the submission
that they may increase the occurrence of
death or even stroke. Despite the potential for
increased risk of harm from the use of these
drugs, atypical antipsychotics are often effective
in treating troublesome neuropsychiatric
symptoms refractory to other treatments.
Whenever possible, these atypical antipsychotic
drug treatments should be integrated with
nonpharmacological treatments to limit the dose
and need of antipsychotic drugs and constant
monitoring for potential harms should be
maintained. The choice of atypical antipsychotic
agent can be guided by the nature, severity of
the target symptom, and the medication least
likely to cause harm to the patient. This chapter
highlights various antipsychotic drugs and
their mechanism of action in neuropsychiatric
Psychosis characteristically refers to a mental
state involving a loss of contact with reality.
According to the fifth edition of the article,
“Diagnostic and Statistical Manual of Mental
Disorders,” psychosis is defined by the presence
of delusions, hallucinations, disorganized
thinking (speech), grossly disorganized or
abnormal motor behavior (including catatonia),
or negative symptoms (Seikkula et al., 2011).
Psychosis may occur at any age, but in older
population its etiology, manifestation, and
treatment deserve special consideration.
Psychosis in the older population, may occur in
294 Advances in Neuropharmacology: Drugs and Therapeutics
the framework of early-onset schizophrenia that
persists into later life, late-onset schizophrenia,
delusion disorders, mood disorders with
psychotic features, and various dementias
including Alzheimer’s and Parkinson’s diseases.
Additionally, it occurs as a result of drug use
and withdrawal, both prescription and illicit, and
in context of delirium, autoimmune disorders,
stroke, brain tumors, metabolic disturbances,
central nervous system infections, and various
chronic neurological disorders. Further research
indicates that a combination of genetic and
environmental factors creates a situation where
a person is vulnerable to, or at greater risk of
developing psychosis.
A number of brain chemicals, including
dopamine (DA) and serotonin, may play a role
in psychosis development (Rizvi and Maurya,
2007). There is accumulating evidence that
stress plays a role in the etiopathogenesis of
mental disorders, particularly schizophrenia,
and bipolar disorders (BDs), which commonly
       
psychosis (Kapur, 2003). The conventional
hyperprolactinaemia, neuroleptic malignant
syndrome (NMS) and extrapyramidal symptoms
(EPS), which are associated with high doses.
 
and conventional antipsychotics can be
    
     
antipsychotics possess a high rate of responders,
lower risk of suicides, improved quality of life,
   
     
with refractory disease. Many studies focus on
the interaction of the receptor with the drugs as
observed by their therapeutic actions.
The antipsychotic drugs bind mainly to
DA, precisely dopamine receptor 2 (D2) as
antipsychotic drugs can mediate through the
potential site. The dopamine hypothesis is
led by the association between neuroleptic
drugs and D2, DA receptors for schizophrenia.
Therefore, the development of drugs is focused
to act at central DA receptors (Maurya et al.,
2017). Recently, some atypical antipsychotic
drugs, which are prototypic in nature like
clozapine, focus on central receptors rather DA
receptors. The reason behind the above fact is
that as per the data indicated by in vitro binding
clozapine was made to compare with most
typical antipsychotic drugs and haloperidol
for D2, DA receptors. Apart from D2 receptors
  
hypothesis for schizophrenia. The chapter
focuses on the mechanism of action of various
antipsychotic drugs like clozapine, raclopride,
remoxipride, etc. Further, the comparison
   
second-generation antipsychotic drugs has
been described.
Schizophrenia is a mental disorder, severe
chronic and complex disease that affects the
thinking of a person, how he behaves and feels
(Kota et al., 2015). A touch of reality has been
forgotten by sufferers. However, this disease is
not common as other disorders for the fact that
this disease consists of varying of symptoms
(Harvey et al., 2004). The symptoms are
prevalent at the age of 16–30 (Mansur et al.,
2016). The symptoms are subcategorized into
positive, negative, and cognitive.
Antipsychotic Drugs 295 POSITIVE SYMPTOM
It deals with psychotic behavior that is not
widespread in vigorous person. Sufferers may
establish lose touch with authenticity (Harvey
et al., 2004). The symptoms are delusions,
hallucinations, dysfunctional way of intellectual,
and lack of speaking. NEGATIVE SYMPTOM
It is associated with interruption of normal
behavior plus emotion. The symptoms are
reduced feeling of pleasure in daily routine,
difficulty in commencing and sustaining
activities, lack of speech, and lack of facial
expressions (Erhart et al., 2006). COGNITIVE SYMPTOMS
These symptoms may vary from person to
person. Sufferers might experience subtle to
severe changes in their intellect or any other
aspects of thinking. Symptoms may consist
of difficulty in concentration; problems with
memory, lack of execution facility, that is,
trouble in grasping information and making
judgments (Simpson et al., 2010).
Bipolar disorder (BD) is a mental disorder
recognized by episodes of hypomania or
maniac and depressions. The contribution
of genetic factors to the susceptibility of BD
ranges from 59% to 93%. BD is a complicated
disorder. Symptoms of hypomanic or mania
and depression define this disorder (Perlis et
al., 2006). It is a psychotic disorder with the
occurrence of 2–5%. Genetic factors, individual
genes, contribute to this disorder with the
range of the 59–93%. A T cell activation
marker mainly interleukin-6 receptor (sIL-6R);
sIL-2R which is soluble in nature, acute-phase
proteins and positive proteins like fibrinogen,
haptoglobin, hemopexin, and alpha-1 acid
glycoproteins; complement factors (C3 and
C6) and immunoglobulins (Igs), IgG1. Alike,
the immune-inflammatory profile is depicted
in BD which is a major depression and is
indicated by the escalation of sIL-2R, sIL-6R,
IL-6 (Maurya et al., 2016). Therefore, maniac
and BDs are accompanied due to increment
of T cell activation and IL-6 transsignalling
(Goldberg et al., 2009). Biological
underpinnings of this disorder mainly focuses
on nitrosative (NS) and oxidative stress (OD),
neurotrophins, hypothalamic pituitary adrenal
(HPA), circadian dysregulation, and alterations
occurring in the course of BD (termed as
neuroprogression) (Geddes and Miklowitz,
Disturbances in perception and pathological
effects are considered to be a salient feature
of depression. The characteristics of major
depressions are a negative shift of emotional
recognition and poor recognition of expressions.
For example, judging happy faces as sad and sad
faces as neutral (Van den Eynde et al., 2008). CAUSES
The causes of depression include genetics,
environmental, biological-changes in
neurotransmitter level, psychological and social.
Although the causes of depression may not arise
from single source (Hasler, 2010).
Author: Please check the sentence “A T cell
activation marker…” for completeness.
Author: Please check the sentence
“Although, the causes of depression…” as it
seems incomplete.
296 Advances in Neuropharmacology: Drugs and Therapeutics SYMPTOMS
Depressed moods, lack of interest in activities,
insomnia or hypersomnia, fatigue, feeling of
worthlessness, and lack of concentration are the
various symptoms of depression as shown in
Table 13.1 (Kreutzer et al., 2001). Many studies
support neuroprogressive and dysregulated
redox signals. Reactive nitrogen, and oxygen
species (RNS, ROS) including superoxidase,
peroxynitrite, nitric oxide, and peroxidases
are generated via the interactions with fatty
acids, proteins and DNA during a balanced
physiological process, performing various
roles to regulate cellular function (Mosley
et al., 2006). Increased level of RNS/ROS
can cause functional and structural changes
leading to injury of cell. Due to a mechanism of
intrinsic antioxidant, under optimum condition,
these toxic effects are offset. NS and OD,
can decrease the accessibility of antioxidant
defense or/and elevate production of RNS and
ROS. This result in the induction of dangerous
autoimmune responses, destruction of cellular
components and causes normal cell processes
to fail.
Patients with bipolar and unipolar
depression show impairment of redox signals
(Vieta et al., 2013). According to studies,
using animal and clinical models indicate
that rise in the level of redox products like
8-iso-prostaglandin F2 and malondialdehyde.
A lot of studies have demonstrated that in
postmortem hippocampus oxidative damage
to RNA in depression occurs, shortening of
telomeres, oxidative damage to DNA due
to a high level of 8-OHdG (8-hydroxy-2-
deoxyguanosine) in serum.
    
from depression indicated to have increased
concentration of NS and OD. This leads
to decreased index of OD stress of serum,
      
in the antioxidant-functioning demonstrating
decreased level of vitamin C and E
concentration in plasma, reduced level of
amino acids like tyrosine and tryptophan and
antioxidant like coenzyme Q10, glutathione
(GSH) and reduction in level of albumin.
  
also been reported. Low concentration
of glutathione peroxidase (GPx) and
superoxidase dismutase (SOD) have been
reported in patients. An antioxidant enzyme
paraoxonase (PON1) bound to high-density
lipoprotein (HDL), was considered to be
unipolar, not bipolar (Barim et al., 2009).
The use of antipsychotic drugs (Fig. 13.1)
includes a difficult trade-off amid the benefit
of lessening psychotic symptoms and the risk
of a numerous adverse effects. Antipsychotic
drugs are not curative and do not abolish
chronic thought disorders, but they frequently
decline the power of hallucinations and
delusions and allow the person with
schizophrenia to function in a caring situation
(Harvey et al., 2011).
FIGURE 13.1 Classification of antipsychotic drugs.
Antipsychotic Drugs 297
The conventional antipsychotics produce
undesirable effects like hyperprolactinemia,
NMS and EPS, these are associated with
high doses (Haddad and Sharma, 2007). The
difference between atypical antipsychotic
and conventional antipsychotics can be
characterized by its effectiveness, increased
safety, and influence on behavior (Kapur and
Remington, 2001). Atypical antipsychotics
possess a high rate of responders, lower risk
of suicides, improved quality of life, favorable
pharmacoeconomic profile, better functional
capacity, and efficiency in patients with
refractory disease. Many studies focus on the
interaction of the receptor with the drugs as
observed by their therapeutic actions. The
antipsychotic drugs bind mainly to DA, precisely
D2 as antipsychotic drugs can mediate through
the potential site (Chiodo and Bunney, 1983).
Association leads the dopamine hypothesis
between neuroleptic drugs and D2 receptors for
schizophrenia. Therefore, the development of
drugs is focused to act at central DA receptors.
Recently, some atypical antipsychotic drugs
which are prototypic in nature like clozapine
focus on central receptors rather DA receptors
(Kuroki et al., 2008). The reason behind the
above fact is that, as per the data indicated by
in vitro binding clozapine was made to compare
TABLE 13.1 Outline of the Consequences of Drugs that Are Used As an Antipsychotic Drugs.
Drug Description FDA
Bioavailability Roots of
Effective against References
Reserpine Indole alkaloid,
Yes 50% Oral Schizophrenia, BD,
depression, reduced
blood pressure
Risperidone Antipsychotic
Yes 70% Injection into the
muscle or oral
Schizophrenia, autism,
manic and mixed
episodes of BD
Clozapine Atypical
Yes 60–70% Oral Schizophrenia,
Parkinson’s disease,
depression, BD
Olanzapine Antipsychotic
Yes 87% Oral,
Schizophrenia, BD Olanzapine,
Haloperidol Typical
Yes 60–70% Intravenously,
Tourette syndrome,
mania in BD, nausea,
hallucinations in
alcohol withdrawal,
delirium, acute
Quetiapine Atypical
Yes 100% Oral Schizophrenia, major
depressive disorder,
298 Advances in Neuropharmacology: Drugs and Therapeutics
with most typical antipsychotic drugs and
haloperidol and it was found that clozapine
has low affinity for D2 receptors. Apart from
D2 receptors the affinity of the site of action
for clozapine also led to modification in DA
and dopamine hypothesis for schizophrenia
(Miyamoto et al., 2005).
The elemental target of all antipsychotic
drugs is to attach with receptor names dopamine
D2. By attaching to it, leads to induction of
EPS (Shiloh et al., 2000). They may also bind
to the receptor to increase serum prolactin.
The clinically active range does not bring
       
The disconnection of a distributed network of
pyramidal neurons causes schizophrenia, which
acts as a principal substrate for processing
of information (Shiloh et al., 2000). The
dysfunction in the connectivity of glutamatergic
neurons is the proof of schizophrenia (Coyle,
2004), such as lowering in the density of
prefrontal cortex of dendrites of pyramidal cells,
the expression of mRNA as a synaptic density
marker found in the postmortem in people
of brain and increases density of pyramidal
        
stated by the fact that morphological disorders
      
Nonappearance of gliosis in the intellect of
    
     
     
schizophrenia (Wong and Van Tol, 2003). The
trigger of all antipsychotic drugs is elementary
monoaminergic receptors that are in the
association of G proteins. These drugs have the
ability to change the behavior of pyramidal cells.
      
the glutamatergic system directly as a partial
agonist at the NMDA (N-methyl--aspartate)
receptor which is associated to recognition
site of glycine and indirectly by glutamate
transporters and blockade of glycine at the
synaptic level (Wong and Van Tol, 2003).
The term neuroplastic refers to the ability by
which nervous system gets easily adapted
by environmental changes. It may include
synaptic plasticity and aids in the generation
of new neuronal connection, as well as
neurogenesis. Antipsychotic drugs appear to
induce restructure of the network of neurons
by inducing variation in neuroplastic. Thus, it
subsidizes substantial description of contact
between neurodevelopment variation in
functions and antipsychotics and structure
of brain of schizophrenia patients. It also
helps in explaining the late onset of effect of
antipsychotic drugs (Galletly, 2014).
The following are the drugs required to treat
the disease. The drugs mainly are reserpine,
risperidone, clozapine, haloperidol, quetiapine,
olanzapine. RESERPINE
Reserpine (Fig. 13.2) synonymous names
are (raudixin, serpalan), an indole alkaloid,
antihypertensive, antipsychotic drug, which is
essential for the relief of psychotic symptoms.
Rauvolfia serpentine or Indian snakeroot is
a species of a flower of family Apocynaceae.
Antipsychotic Drugs 299
Reserpine is one of the indole components of
this family only. However, today the use of
the drug is limited because of the development
of better drugs and due to numerous side
effects of reserpine, it is now rarely used
(Wilkins, 1961). These drugs have an ability
to destruct catecholamines from peripheral
sympathetic nerve endings. These drugs are
associated to control the rate of heart, peripheral
vascular resistance, and cardiac contraction.
Furthermore, if a monoamine neurotransmitter
is disrupted in the synapses act as a proof of
depression in humans. Reserpine is associated
to lowering the blood pressure by decreasing
the nervous system which allows the reduction
and widening of blood vessels (Halbreich et al.,
2003). Thus, it helps the heart to beat slowly,
and improving the flow of blood. Reserpine also
contributes with treating a psychotic condition
like schizophrenia.
FIGURE 13.2 Chemical structure of reserpine. Therapeutic Effects
The literature on the behavior of the mental
disorder schizophrenia with drug named
reserpine is now widely acknowledged.
Reserpine is operative in chronic and acute cases
of schizophrenia (Carlsson and Carlsson, 2006).
The ratio of its conduction is narrated from 5%
to 85%. However, the variation is dependent on
factors like:
nature of disease treated,
medication and time period of treatment,
to what extent it constitutes ‘improve’
verdict by investigators.
      
consistency as to how one subtype of
schizophrenia reacts better than any other
subtypes. The reason behind this is due to
variation of criteria patients are sited at
     
Angermeyer, 2003). Hebephrenics is a type
of schizophrenia which is categorized by
disorganized behavior and speech (Ujike et
al., 2002). It is also termed as disorganized
schizophrenia and has the meager diagnosis
if not treated well on time and its paranoids
frequently have increased remission rate. If the
drug acted to bring out the improvement one can
expect the deprived reaction in hebephrenic. It
is our imprint that the type of schizophrenia is
a less important factor in predicting the result
of the drug except that in generalized order
of its response which is due to spontaneity.
Although, the recovery of all classes would
not have been accomplished without the
use of the drug (Maurya et al., 2016). More
the degree of excitement and nervousness
better will be the diagnosis. However, this is
        
is also responsible for other procedures like
lobotomy (it is a neurosurgical procedure, a
form of psychosurgery). The known fact is
not all stressed patients give a good reaction
to the same. Many patients seem to maintain
their therapy and the drug gets inhibited by
the active administration. This holds true in
the case of less stressed patients, therefore the
period of evaluating treatment is generally 6
weeks to 2 months.
300 Advances in Neuropharmacology: Drugs and Therapeutics
 
of consistency with respect to the sex of patients.
The drug in children is found to be meager as
compared to adults but the general impression
lays states that schizophrenic children do not react
as favorably as an adult do. However, patients
under hospitalization during all durations and in
all conditions show a good reaction. It is rightly
stated that the patients should not be denied
for a therapeutic trial because it is said that
the supplies of drug clinically are limited and
therefore, it should be applied to the areas where
  
al., 2006). Schizophrenia cannot be cured but it
contains partial symptoms of remission (Masand
et al., 2009). There are also patients living a
glorious life without even being hospitalized. If
careful examinations are performed in respect
to psychological tests, chances are that the
person might be schizophrenic. However, there
would still be an unwillingness to tag them as
disease-free. RISPERIDONE
It is associated with the chemical class named
benzisoxazole derivatives (Fig. 13.3) it has got
a high affinity for D2 and 5-hydroxytryptamine
(5-HT) receptors (de Leon et al., 2005). It
primarily aims in treating positive and negative
symptoms of schizophrenia. It also triggers
irritability in children suffering from an
autistic disorder, BD, inappropriate behavior
in dementia, and manic episodes related to BD
(Lam et al., 2010). Risperidone can either be
taken orally or injected into muscles. The effect
of injection lasts for about 2 weeks (Strickley,
2004). The common side effects include
sleepiness, increased weight, and movement
problems (Tempaku et al., 2016). Serious side
effects include disorder in potentially permanent
movement (tardive dyskinesia) and NMS,
high blood sugar level. Risperidone is freeing
soluble in methylene chloride, soluble in 0.1 N
HCL and methanol and insoluble in water, it is
off-white to beige powder. Its structural formula
is C23H27FN4O2 and molecular weight is 410.49.
FIGURE 13.3 Chemical structure of risperidone and its
active metabolite. Mode of Action
Risperidone is an antipsychotic drug of second
generation having an affinity for receptors like
       
mechanism of action is not fully agreed, the
recent theories focus mainly on receptors like
5-HT2A and D2 (Butini et al., 2008). From
the perspective of pharmacodynamics, the
antipsychotics share a common characteristic
that is the ability to reduce neurotransmission
of dopaminergic. According to the theory of
dopamine in schizophrenia, overactivity of
mesolimbic pathway explains the positive
symptoms of schizophrenia. Cognitive and
negative symptoms of schizophrenia are
associated with dysfunction of this pathway.
Antipsychotic drugs have an ability to inhibit
dopamine receptors. A significant proportion
of patient reacts poorly towards neuroleptics,
especially sufferers with negative symptoms,
Antipsychotic Drugs 301
which include social withdrawal and apathy.
Some other neurotransmitters which include
5-hydroxytryptamine acts on receptor
5HT2,which aims to block ritanserin (Miyamoto
et al., 2012).
  
D2 adrenoceptors is blocked by risperidone.
Risperidone contains antihistamine (H1)
      
   
(Mishra et al., 2007). According to open
studies, it has been suggested that therapeutic
     
and positive symptoms and it might be
supportive in patients who lack response against
conventional neuroleptics. Less frequent
symptoms like extrapyramidal do not occur
    
negative symptoms but it does cause fewer
Risperidone can also be used as an alternative
for clozapine (Geddes et al., 2000). Therapeutic Effects
Supplementary treatment of schizophrenia
with celecoxib has positive effects when
treated with risperidone (Geddes et al., 2000).
Also, treatment alongside immunomodulatory
drug resulted to be helpful for dealing with
the symptoms of schizophrenia indicating
dysfunction of the immune system. It is
associated to pathomechanism and is not just an
epiphenomenon. The effect of celecoxib which is
a nonimmunological therapeutic is mediated by
the receptor of NMDA. Risperidone is considered
to be well-established and a proven drug for the
treatment of schizophrenia (Müller et al., 2002).
The addition of celecoxib has a high impact in
improvement of patients suffering from both
negative and positive symptoms of schizophrenia
(Miller et al., 2011).
of COX-2 and the brain, this COX-2 articulates.
Cytokines, such as IL-6, IL-2, IL-10 induces
is mediated by cytokine-activated COX-2
expression. In schizophrenic patients CSF level
of sIL-2R and IL-2, soluble IL-6 receptors are a
functional part of IL-10 and IL-6 system which
are seen to be an increased amount.
Expression of adhesion molecules is
regulated by blocking of COX-2. The reduction
of the regulation of adhesion molecules is
observed in schizophrenia, which leads to lack
of communication and imbalance between CNS
and peripheral immune system (Müller et al.,
Clozapine is an atypical antipsychotic
which aims in triggering schizophrenia and
its symptoms. It is a high-dose neuroleptic
(Haddad and Sharma, 2007). The derivative
of this drug is dibenzodiazepine. Chemical
class of clozapine is dibenzoxazepine drug
loxapine (Fig. 13.4). In schizoaffective disorder
and schizophrenia, clozapine decreases the
percentage of suicidal conducts. Clozapine
is considered to be more active than typical
antipsychotics. It is taken orally. Clozapine is
related in lowering the leucocytes which result
in death. So to overcome the problem sufferers
should monitor their blood regularly (Moolman,
2013). It is considered to be the safest and
effective medicine. This drug can also be
used for patients against Parkinson’s disease
although, it differs from loxapine with respect
to pharmacological characteristics. Clozapine
has several blocking activities like: adrenergic
has muscarinic acetylcholine receptor, which
Author: Please
check the
sentence “This
drug can also be
used…” for
correctness as it
has been edited
for clarity.
302 Advances in Neuropharmacology: Drugs and Therapeutics
is an antagonist and is potent. The binding of
this drug is weak with receptors like D2 and
D1. If high amount of doses is given to patient’s
clozapine, then it produces little transient
elevation observed in serum prolactin. The side
effects produced by this drug are very dissimilar
from typical neuroleptics. However, clozapine
is considered to be superior to chlorpromazine
because it produces fewer side effects. Clinically,
clozapine has revealed its antipsychotic
effects to be greater or same to haloperidol,
levomepromazine, and chlorpromazine (Sim
et al., 2004). This drug does not yield EPS like
tardive dyskinesia or akathisia, parkinsonism,
acute dystonia. Hypersalivation, tachycardia,
orthostatic hypotension can be evoked as side
effects of this drug.
FIGURE 13.4 Chemical structure of clozapine. Mechanism of Action
Clozapine produces serotonin (5HT2) and
dopamine (D2) blockade receptor. These
receptors have an ability to inhibit the increased
cortisol secretion and growth hormone which
is produced by MK-212 and apomorphine.
They directly act on agonist like 5-HT2 and
DA. Clozapine neither inhibits deceased level
in plasma prolactin (PRL) concentration due
to induction of prolactin nor does it increase
PRL level, unlike D2 antagonist. Although,
clozapine drug increase DA release, evidenced
by consistent PRL results (Sim et al., 2004).
Clozapine decreases plasma homovanillic
acid (HVA), basal plasma cortisol leaves and
plasma tryptophan. According to rodent studies,
it was suggested that clozapine is associated
to an increase 5-HT release. However, later it
was found that antagonism of 5-HT2 and D-2
receptors and increase of 5-HT and DA release
are vital in minimizing schizophrenia symptoms
both negative and positive without producing
side effects like increase in plasma PRL or
EPS. Dysregulation of D-2 and 5-HT2 mediated
neurotransmission is involved in schizophrenia
and clozapine partially restores the normal
balance of dopaminergic and serotonergic
neurotransmission. Clozapine treatment
accelerates the level of 5-hydroxyindoleacetic
acid (5-HIAA), a significant metabolite of 5-HT.
Clozapine treatment marks level of tryptophan,
which is the precursor of 5-HT (Manchia et al.,
2017). Clozapine as Serotonin
Serotonergic effects of lysergic acid
diethylamide are inhibited by clozapine and it
also blocks the social effect of quipazine which
is a 5-HT agonist (Glennon and Dukat, 2002).
This is the proof that this drug is a serotonin
antagonist (5-HT). It has also been discovered
that clozapine inhibits hormone stimulating
effect which is produced by MK-212 due to
secretion of cortisol, as well as the hyperthermic
effects. The treatment of this drug inhibits
induced MK-212 increased secretion of plasma
cortisol and therefore, its area under the curve
Antipsychotic Drugs 303
in sufferers appeared to be less as compared to
neuroleptic and nonmedicated patients. Thus,
chlorpromazine inhibits induction of MK-212
cortisol like clozapine drug does but it is
expected that clozapine is more effective and
efficient in vivo than chlorpromazine as a 5-HT2
antagonist on the foundation of data for in vitro
affinity (Abidi and Bhaskara, 2003). Otherwise,
a response seen in a man due to induction of
MK-212 cortisol is because of stimulation of
receptor 5-HT of some other type which is not
inhibited by chlorpromazine but is by clozapine. Neuroendocrine Effects
Risperidone is associated to increase serum
prolactin level unlike clozapine in humans
which therefore differentiates it from a classical
neuroleptic drug. The increased level of serum
prolactin interferes with the menstrual cycle
(Raggi, 2002). Therapeutic Effects
Clozapine is efficient against schizophrenic
patients who flop to react to typical neuroleptics
(Marek, 2002). Clozapine minimizes
psychiatric symptoms with high efficacy. It is
medically proven that clozapine is superior
to chlorpromazine. It differs from other
conventional neuroleptics with respect to its
pharmacological characteristics. Blockade
of dopamine type-1 receptors are strong and
blockade of dopamine type-2 receptors as
compared to perphenazine which is a high potent
      
receptor and serotonin receptor antagonist and
has high affinity for dopamine type-4 receptors
and anticholinergic effect.
       
cognitive functions have been discovered in
schizophrenic patients. According to a study, it
was observed that some patients who received
    
patients receiving clozapine (Jones et al.,
2006). However, one such issue is critical in
clarifying this if cognitive impairment is an
epiphenomenon or a primary manifestation.
However, an improvement was seen due to
clozapine but no change was observed in
cognitive functions. Clinically, as clozapine
patients were found to be more cooperative and
they appeared to be much improved, however,
many cognitive functions were observed to
remain impaired.
The cognitive dysfunction in schizophrenia
is because of interference occurred by
epiphenomenon or by positive psychotic
     
 
memory was seen in patients due to clozapine.
The cholinergic and anticholinergic system
plays vital role in memory (Trivedi, 2006). To
summarize, clozapine did reduce symptoms of
chronic schizophrenia but it lagged cognitive
impairments, which appeared to be intrinsic
feature for diseases. Vocational and social
adjustments persisted to be on margin (McEvoy
et al., 2006). OLANZAPINE
It is also an atypical antipsychotic, which aims
to trigger BD and early onset of schizophrenia. It
is also efficient in treating acute exacerbations.
The structure of olanzapine (Fig. 13.5) is
similar to quetiapine and clozapine but
contains slightly different affinity at binding
sites. Olanzapine has comparable structure
relation with benzodiazepine anxiolytics,
304 Advances in Neuropharmacology: Drugs and Therapeutics
it has got minimum affinity for GABAA
receptor and its effect is mediated via 5HT
receptors and on dopamine. It is a derivative
of thienobenzodiazepine and is a dopamine
antagonist. Its treatment results in increased
glucose level, cholesterol level, and weight
gain as compared to other antipsychotics of
second generation except clozapine. This
drug produces minimum sedation induction,
anticholinergic symptoms, prolactin elevation,
no traces of hematotoxicity, and extrapyramidal
effects. Therefore, it is believed that
olanzapine is the first drug for the treatment of
schizophrenia (Leucht et al., 2009).
FIGURE 13.5 Chemical structure of olanzapine. Mechanism of Action
Olanzapine possesses affinity at binding
sites like serotonergic (5HT2, 3, 6), D1-D5,
    
and histaminergic (H1). This receptor is an
alternative mediator in the histaminergic
system, which aims for regulation of weight and
behavior. Patients with less schizophrenia suffer
from less side effects of olanzapine. But if the
disorder is severe then it is to choose between
atypical or typical drug. Olanzapine is efficient
in dropping negative symptoms of this disorder
but its clinical relevance is not clear yet (Geddes
et al., 2000). Therapeutic Effects
Between haloperidol and olanzapine, the latter
showed better results on secondary measure
including depression and overall improvement
(Horacek et al., 2006). This drug is related less
discontinuation of treatment because of lack of
adverse events or deficiency of drug efficacy.
However, it shows wider and greater spectrum
of efficacy in patients and consists of favorable
safety profile than haloperidol. HALOPERIDOL
It is a typical antipsychotic (Fig. 13.6) and is
used to cure tics in Tourette syndrome, mania
in BD, vomiting, nausea, acute psychosis,
hallucinations in alcohol withdrawal, and
schizophrenia. It can either be consumed
orally or intravenously, injecting into muscles.
This drug takes 30–60 min to work (Rifkin et
al., 1991). Tardive dyskinesia is a movement
disorder which is caused by haloperidol and it
might be permanent. This drug is considered to
be the safest and effective. It exerts antiemetic
and sedative activity. The pharmacological
effect of haloperidol is parallel to piperazine-
derivative phenothiazines. The drug acts at all
the phases of central nervous system but majorly
it acts at subcortical level-plus on multiple
organ system. Haloperidol has feeble peripheral
Antipsychotic Drugs 305
anticholinergic and strong antiadrenergic
activity. The blocking action of ganglionic is
slight. Haloperidol possesses little antiserotonin
and antihistaminic activity (Gold, 1967).
FIGURE 13.6 Chemical structure of haloperidol. Mechanism of Action
The mechanism of production of therapeutic
effect is not known yet, but this drug depresses
CNS at mid brain, brainstem reticular formation
and at subcortical level of brain. The ascending
reticular activating system is blocked by this
drug of brainstem via caudate nucleus, thus
the impulse gets interrupted between cortex
and diencephalon. Action of glutamic acid is
antagonized by the drug inside the extrapyramidal
system and blockage of catecholamine receptors
also help in mechanism of haloperidol (Naidu
et al., 2003). Reuptake of neurotransmitters
of mid-brain gets hinder by haloperidol and
appears to have feeble central anticholinergic
and solid central antidopaminergic activity.
The drug inhibits spontaneous motor activity
and produces catalepsy and conditions ignorant
behavior in animals. Although, antiemetic
action of this drug has not been determined
fully yet but the drug blocks dopamine receptor
of chemoreceptor trigger zone (CTZ) and
therefore, it affects directly (Naidu et al., 2003). QUETIAPINE
It is an atypical antipsychotic (Fig. 13.7) and
objectives to shoot BD, major depressive
disorder and schizophrenia. It contributes as a
sleep aid because of the presence of sedative
effect. It can be taken orally only. Elder patients
suffering from dementia are at risk of death
because of quetiapine. If used in during late
pregnancy, it might cause movement disorder in
baby for a time period after the birth. Quetiapine
blocks dopamine and serotonin receptor
(Srisurapanont et al., 2004).
FIGURE 13.7 Chemical structure of quetiapine. Mechanism of Action
It is a second-generation drug and has got
and 5-HT1A. Its mechanism has not been fully
known. But antipsychotic effects are associated
to lower dopaminergic neurotransmission in
mesolimbic pathway (Seeman, 2002). Therapeutic Effects
Quetiapine is effective for the treatment against
positive symptoms of subchronic and chronic
symptoms of schizophrenia. As measured by
306 Advances in Neuropharmacology: Drugs and Therapeutics
positive and negative syndrome scale (PANSS),
this drug has enhanced negative symptoms of
schizophrenia (Vardigan et al., 2010). Quetiapine
was statistically related to minimize the level of
akathisia. According to the study of population,
this drug was well tolerated. The major worst
events were either moderate or mild like insomnia
or agitation (Van den Eynde et al., 2008). As
compared to chlorpromazine, quetiapine was
related with less clinically vital signs and low
postural hypotension. This drug is not related to
increase serum prolactin level.
Bipolar disorder (BD) is a mental disorder
recognized by episodes of hypomania or maniac
and depressions. It is a psychotic disorder.
The following are the drugs required to treat
the disease. The drugs mainly are: reserpine,
risperidone, clozapine, haloperidol, quetiapine,
and olanzapine (Maurya et al., 2016). RISPERIDONE
Atypical antipsychotic drugs are used for curing
BDs. Specifically, for bipolar mania, these drugs
posses’ good tolerability and high efficacy.
Nowadays, atypical antipsychotics medications
for bipolar mania are used as polytherapy or
monotherapy. Usage of antipsychotic drugs is
widespread in clinical settings (Benazzi, 2007).
A lot of BDs are centralized as antimaniac agents
(Purcell et al., 2009). The first antipsychotic
drug, that is, olanzapine received Food and
Drug Administration (FDA) indication for
bipolar mania, in 2000. Subsequently, in 2003
and 2004 FDA approvals were received for
risperidone and for compounds like ziprasidone,
aripiprazole, quetiapine for indication of bipolar
Risperidone is considered to be second
generation antipsychotic and is an atypical
antipsychotic drug (McEvoy et al., 2006).
      
receptor and serotonin. Bipolar indications
approved by FDA include:
Combined therapy with valproate or
lithium for treating mixed episodes or
acute mania with disorder of bipolar I.
Short-term treatment accompanied by
monotherapy of mixed episodes or acute
mania with disorder bipolar I. Pharmacokinetics and
Risperidone possess high affinity for receptor
      
receptor and 5-HT2 therefore, this drug is
considered to be selective monoaminergic
antagonist. This drug has low affinity for
5-HT1d, 5-HT1a, 5-HT1c receptors and feeble
affinity for haloperidol sensitive site, D1 and
no affinity for B2 adrenergic or cholinergic
muscarinic receptor (Hirschfeld et al., 2003).
This drug is absorbed easily, and food does not
affect extent and rate of absorption. The oral
bioavailability of this drug is 70% (Marder and
Meibach, 1994).
    
acid and albumin. The plasma protein binding
is 90% and 77% is the 9-hydroxyrisperidone
bound. Metabolism of risperidone takes place
in liver (Mauri et al., 2014). The hydroxylation
through CYP2D6 enzyme of risperidone to
9-hydroxyrisperidone is the major metabolic
pathway. Genetic polymorphism determines
the rate of metabolism through the enzyme
CYP2D6 (Kang et al., 2009).
Antipsychotic Drugs 307
It is an atypical antipsychotic drug used for
treating not only schizophrenia but also for
curing psychotic, mania, and nonpsychotic
depression. This drug is effective against
these three syndromes for long period of time.
Although the mechanism of action of this drug
is not same for all the syndromes (Kane et al.,
1988). Clozapine is known to have high affinity
for neurotransmitters like 5-HT2A, 5-HT6,
     
and H1. It has weak affinity for 5-HT1A, D1,
D4, D2, 5-HT3. The efficacy of the drug in
case of refractory depression in psychosis has
proven the nonvital for D2 receptor. The reason
behind is that clozapine produces low blockade
than any other neuroleptics. For downregulating
receptor 5-HT2 clozapine possesses rapid and
potent effect. Also, this drug is highly effective
for treating schizophrenia and other major
disorders (Rollema et al., 1997). RESERPINE
Reserpine, when complexed with diuretic,
helps to lower arterial pressure. To increase the
response of thiazide diuretic it is mixed with
regimen. The uptake of this drug is 0.1 mg/
day, the reason being its long half life. This
drug is contraindicated in history of depression,
renal failure, BD. During asthma, pregnancy,
ulcerative colitis this drug is avoided. It may
cause complications if used during hypothermia
and pregnancy. As a precaution, less quantity
of this drug is recommended. Thus, this drug is
not measured as a drug of choice because of its
numerous side effects. This drug is associated
in causing harmful amendments in fetal brain
(Dawson et al., 1958). RISPERIDONE
Risperidone is an antipsychotic drug of second
generation having affinity for receptors like
       
mechanism of action is not fully agreed, the
recent theories focus mainly on receptors
like 5-HT2A and D2 (Edwards, 1994). From
the perspective of pharmacodynamics, the
antipsychotics share a common characteristic
that is the ability to reduce neurotransmission
of dopaminergic. According to the theory
of dopamine in depression, overactivity of
mesolimbic pathway explains the positive
symptoms of schizophrenia. Cognitive and
negative symptoms of schizophrenia are
associated to dysfunction of this pathway
(Swerdlow and Koob, 1987).
Antipsychotic drugs have an ability to inhibit
   
of patient reacts poorly towards neuroleptics,
    
which include social withdrawal and apathy.
Some other neurotransmitters which include
5-hydroxytryptamine acts on receptor 5HT2
which aims to block ritanserin (de Leeuw and
Westenberg, 2008). HALOPERIDOL
This drug is used for delirium as a medication
in an intensive care unit. In comparison with
placebo this drug shows better result in reducing
the duration of delirium. It is a widely used
drug for neuroleptic patients. Due to its adverse
effects (like NMS, dystonias, and extrapyramidal
effects) its uptake is in low amount. This drug
should be avoided to patients suffering with
electrocardiographic. The class of this drug is
butyrophenone of neuroleptics. Recently, this
drug has gained favor due to acute treatment in
delirium and psychosis (Rifkin et al., 1991).
308 Advances in Neuropharmacology: Drugs and Therapeutics QUETIAPINE
This drug binds strongly with 5-HT2A and
weakly 5-HT2C or 5-HT1 receptors better
than D2 receptor. This drug occupies 30%
of D2 receptors. Dibenzothiazepine is a
derivative of this drug. This drug is used for
sedating patients as it has strong affinity for
H1-histamine receptor. The active compound of
this drug is norquetiapine, it possesses greater
or similar potency toward receptors like its
parent compound. The side effects of this drug
are dyslipidemia, diabetogenesis, orthostatic
hypotension, weight gain; the side effects are
not adverse in comparison to olanzapine and
clozapine. This is an antipsychotic drug which
aids in treating psychosis (Srisurapanont et al.,
This drug is FDA approved and is used to treat
BD. The major side effects of this drug are
weight gain and sedation. The initial dose of this
drug is 2.5–5 mg and can exceed to 20 mg. This
drug is oxidized by CYP 1A2 and metabolized
by glucuronidation. It’s a monoaminergic
antagonist. It can bind to multiple receptors like
5-HT6, 5-HT2/2C, D1-4, adrenergic receptors
and H1 (Duggan et al., 2005).
Extensive availability of antipsychotic drugs is
observed. Psychotic diseases can be treated in the
upcoming years, with the help of drugs, aiming in
causing minimal side effects and drugs that cause
less harm to the body of patient (Schiavone and
Trabace, 2018). The new area of investigation is
the translational research that encompasses the
mutual application of innovative technologies
that involve multiple disciplines of science
including pathophysiology, genetics, physiology
natural history of disease, and proof-of-concept
studies of devices and drugs. Recent research
breakthroughs, most importantly, completion
of the human genome project, offer a pool of
nonending opportunities for basic investigators
to work and make further advancements in the
areas of neuroscience. Other accomplishments
like advances in biocomputing, information
technology, high-throughput technologies for
screening, identifying, and studying compounds
of interest, and novel imaging capabilities also
tend to provide immediate and direct payment
for individual investigators and the institutions
that support their work (Haefner and Maurer,
This chapter covers the use of common
antipsychotic drugs (clozapine, reserpine,
risperidone, olanzapine, haloperidol,
quetiapine) in neuropsychiatric disorders.
Authors also discussed various mechanism of
action of aforementioned drugs. Despite the
controversy that surrounds the use of atypical
antipsychotic drugs in neuropsychiatric
disorders, these medications are frequently
being prescribed for the treatment of
neuropsychiatric diseases. The final choice of
atypical antipsychotic drugs should be guided
by the nature and severity of the target symptom
being treated, and the medication least likely to
cause harm to the patient. Whenever possible,
these atypical antipsychotic drug treatments
should be combined with non-pharmacological
treatments to limit the need and dose of
antipsychotic drugs.
Antipsychotic Drugs 309
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Aging is associated with an increase in the prevalence of obstructive sleep apnea syndrome (OSAS) as well as the shortening of telomeres. It is known that OSAS-related factors are stimuli that can contribute to the acceleration of cellular senescence. Thus, the present study aimed to compare the leukocyte telomere length (LTL) between OSAS patients and controls, as well as to verify the correlation between LTL and sleep parameters. We used DNA extracted of 928 individuals from EPISONO to measure the LTL by the quantitative real-time polymerase chain reaction. All individuals were subjected to one full-night polysomnography. LTL was significantly shorter in OSAS patients compared to controls. The results showed negative correlations between LTL and the following variables: apnea-hypopnea index, respiratory disturbance index, desaturation index and wake after sleep onset. LTL was positively correlated with sleep efficiency, total sleep time, basal, minimum and maximum oxygen saturation. Lastly, it was observed that OSAS severity was associated with shorter LTL even after adjusting for sex, age, years of schooling, body mass index, diabetes, stroke and heart attack. In conclusion, our study indicates the presence of an association between LTL and OSAS and a significant impact of severity of OSAS in telomeres shortening.
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Objective: To develop an evidence base for recommendations on the use of atypical antipsychotics for patients with schizophrenia. Design: Systematic overview and meta-regression analyses of randomised controlled trials, as a basis for formal development of guidelines. Subjects: 12 649 patients in 52 randomised trials comparing atypical antipsychotics (amisulpride, clozapine, olanzapine, quetiapine, risperidone, and sertindole) with conventional antipsychotics (usually haloperidol or chlorpromazine) or alternative atypical antipsychotics. Main outcome measures: Overall symptom scores. Rate of drop out (as a proxy for tolerability) and of side effects, notably extrapyramidal side effects. Results: For both symptom reduction and drop out, there was substantial heterogeneity between the results of trials, including those evaluating the same atypical antipsychotic and comparator drugs. Meta-regression suggested that dose of conventional antipsychotic explained the heterogeneity. When the dose was </=12 mg/day of haloperidol (or equivalent), atypical antipsychotics had no benefits in terms of efficacy or overall tolerability, but they still caused fewer extrapyramidal side effects. Conclusions: There is no clear evidence that atypical antipsychotics are more effective or are better tolerated than conventional antipsychotics. Conventional antipsychotics should usually be used in the initial treatment of an episode of schizophrenia unless the patient has previously not responded to these drugs or has unacceptable extrapyramidal side effects.
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Background Socioeconomic disadvantage (SED) has been consistently associated with early life mental health problems. SED has been shown to impact multiple biological systems, including the regulation of neurotrophic proteins, immune-inflammatory and oxidative stress markers, which, conversely, have been reported to be relevant to physiological and pathological neurodevelopment This study investigated the relationship between SED, different domains of psychopathology, serum levels of interleukin-6 (IL6), thiobarbituric acid-reactive substance (TBARS) and brain-derived neurotrophic factor (BDNF). We hypothesized that a composite of socioeconomic risk would be associated with psychopathology and altered levels of peripheral biomarkers. In addition, we hypothesized that SED would moderate the associations between mental health problems, IL6, TBARS and BDNF. Methods and Findings Using a cross-sectional design, we measured the serum levels of IL6, TBARS and BDNF in 495 children aged 6 to 12. We also investigated socio-demographic characteristics and mental health problems using the Child Behaviour Checklist (CBCL) DSM-oriented scales. SED was evaluated using a cumulative risk model. Generalized linear models were used to assess associations between SED, biomarkers levels and psychopathology. SED was significantly associated with serum levels of IL6 (RR = 1.026, 95% CI 1.004; 1.049, p = 0.020) and TBARS (RR = 1.077, 95% CI 1.028; 1.127, p = 0.002). The association between SED and BDNF was not statistically significant (RR = 1.031, 95% CI 0.997; 1.066, p = 0.077). SED was also significantly associated with all CBCL DSM-oriented scales (all p < 0.05), whereas serum biomarkers (i.e. IL6, TBARS, BDNF) were associated with specific subscales. Moreover, the associations between serum biomarkers and domains of psychopathology were moderated by SED, with stronger correlations between mental health problems, IL6, TBARS, and BDNF being observed in children with high SED. Conclusions In children, SED is highly associated with mental health problems. Our findings suggest that this association may be moderated via effects on multiple interacting neurobiological systems.
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Background: Although the principal brain target that all antipsychotic drugs attach to is the dopamine D2 receptor, traditional or typical antipsychotics, by attaching to it, induce extrapyramidal signs and symptoms (EPS). They also, by binding to the D2 receptor, elevate serum prolactin. Atypical antipsychotics given in dosages within the clinically effective range do not bring about these adverse clinical effects. To understand how these drugs work, it is important to examine the atypical antipsychotics' mechanism of action and how it differs from that of the more typical drugs. Method: This review analyzes the affinities, the occupancies, and the dissociation time-course of various antipsychotics at dopamine D2 receptors and at serotonin (5-HT) receptors, both in the test tube and in live patients. Results: Of the 31 antipsychotics examined, the older traditional antipsychotics such as trifluperazine, pimozide, chlorpromazine, fluphenazine, haloperidol, and flupenthixol bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. The newer, atypical antipsychotics such as quetiapine, remoxipride, clozapine, olanzapine, sertindole, ziprasidone, and amisulpride all bind more loosely than dopamine to the dopamine D2 receptor and have dissociation constants higher than that for dopamine. These tight and loose binding data agree with the rates of antipsychotic dissociation from the human-cloned D2 receptor. For instance, radioactive haloperidol, chlorpromazine, and raclopride all dissociate very slowly over a 30-minute time span, while radioactive quetiapine, clozapine, remoxipride, and amisulpride dissociate rapidly, in less than 60 seconds. These data also match clinical brain-imaging findings that show haloperidol remaining constantly bound to D2 in humans undergoing 2 positron emission tomography (PET) scans 24 hours apart. Conversely, the occupation of D2 by clozapine or quetiapine has mostly disappeared after 24 hours. Conclusion: Atypicals clinically help patients by transiently occupying D2 receptors and then rapidly dissociating to allow normal dopamine neurotransmission. This keeps prolactin levels normal, spares cognition, and obviates EPS. One theory of atypicality is that the newer drugs block 5-HT2A receptors at the same time as they block dopamine receptors and that, somehow, this serotonin-dopamine balance confers atypicality. This, however, is not borne out by the results. While 5-HT2A receptors are readily blocked at low dosages of most atypical antipsychotic drugs (with the important exceptions of remoxipride and amisulpride, neither of which is available for use in Canada) the dosages at which this happens are below those needed to alleviate psychosis. In fact, the antipsychotic threshold occupancy of D2 for antipsychotic action remains at about 65% for both typical and atypical antipsychotic drugs, regardless of whether 5-HT2A receptors are blocked or not. At the same time, the antipsychotic threshold occupancy of D2 for eliciting EPS remains at about 80% for both typical and atypical antipsychotics, regardless of the occupancy of 5-HT2A receptors. Relevance: The "fast-off-D2" theory, on the other hand, predicts which antipsychotic compounds will or will not produce EPS and hyperprolactinemia and which compounds present a relatively low risk for tardive dyskinesia. This theory also explains why L-dopa psychosis responds to low atypical antipsychotic dosages, and it suggests various individualized treatment strategies.
Objective: When a schizophrenia patient has an inadequate response to treatment with an antipsychotic drug, it is unclear what other antipsychotic to switch to and when to use clozapine. In this study, the authors compared switching to clozapine with switching to another atypical antipsychotic in patients who had discontinued treatment with a newer atypical antipsychotic in the context of the Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) investigation. Method: Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone in phase 1 or 1B of the trials, primarily because of inadequate efficacy, were randomly assigned to open-label treatment with clozapine (N=49) or blinded treatment with another newer atypical antipsychotic not previously received in the trial (olanzapine [N=19], quetiapine [N= 15], or risperidone [N=16]). Results: Time until treatment discontinuation for any reason was significantly longer for clozapine (median=10.5 months) than for quetiapine (median= 3.3), or risperidone (median=2.8), but not for olanzapine (median=2.7). Time to discontinuation because of inadequate therapeutic effect was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone. At 3-month assessments, Positive and Negative Syndrome Scale total scores had decreased more in patients treated with clozapine than in patients treated with quetiapine or risperidone but not olanzapine. One patient treated with clozapine developed agranulocytosis, and another developed eosinophilia; both required treatment discontinuation. Conclusions: For these patients with schizophrenia who prospectively failed to improve with an atypical antipsychotic, clozapine was more effective than switching to another newer atypical antipsychotic. Safety monitoring is necessary to detect and manage clozapine's serious side effects.
Aggressive individuals have higher rates of mental illness compared to non-aggressive individuals. Multiple factors, including psychosocial, genetic, and neurobiological determinants modulate the liability to both aggressive behavior and mental illness. Concerning the latter factors, multiple lines of evidence have shown a dysfunction in the serotonin (5-HT) system occurring in aggressive and in mentally ill individuals. In particular, a reduced 5-HT activity has been associated with depression as well as with aggressive behavior, especially with impulsive aggression. Consistently, psychopharmacological interventions aimed at boosting the 5-HT system (e.g. with selective serotonin reuptake inhibitors) have demonstrated therapeutic efficacy in a high percentage of patients with either or both pathological conditions. Current knowledge does not yet allow to clearly disentangle whether 5-HT dysfunction, most often a 5-HT deficiency, is the consequence of the aggressive/violent behavior, of the underlying mental disease/s, or the expression of the comorbidity. Future studies are thus needed to clarify the association between changes in 5-HT levels, altered activity of 5-HT receptors and their intracellular signaling cascades, and modifications of 5-HT genes, and in particular the neurobiological link between the altered 5-HT machinery and aggressive behavior in the context or in the absence of mental illness. In this review, we employ a dimensional approach to discuss the trivariate relationship among the 5-HT system, aggressive behaviour, and mental illness, focusing our attention on 5-HT levels, 5-HT receptors, metabolic enzymes and their genes. Emphasis is given to controversial findings, still unanswered questions, and future perspectives.
Telomere length attrition has been demonstrated in schizophrenia but not in individuals in ultra high risk (UHR) for psychosis. The present study aimed to compare the leukocyte telomere length (TL) between patients at UHR for psychosis and healthy controls (HC). Twenty-two participants with UHR and 88 HC were enrolled in this study. Telomere lengths were determined using a multiplex qPCR assay. After adjustment for age, sex, ethnicity, and education, patients in UHR, compared with HC groups, had shorter telomere length (RR: 0.929, p=0.031). Shorter leukocyte telomere length in UHR could represent early signs of accelerated aging in this population.