European Journal of Pharmacology 844 (2019) 231–240

Contents lists available at ScienceDirect

European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar

Review

Antipsychotics-induced metabolic alterations: Recounting the mechanistic T

insights, therapeutic targets and pharmacological alternatives
⁎
Raghunath Singha, Yashika Bansala, Bikash Medhib, Anurag Kuhada,
a
Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh
160014, India
b
Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India

A R T I C LE I N FO A B S T R A C T

Keywords: Atypical antipsychotics (AAPs) are the drug of choice in the management of mental illnesses by virtue of their
Antipsychotics advantage over typical antipsychotics i.e. least tendency of producing extrapyramidal motor symptoms (EPS) or
Weight gain pseudoparkinsonism. Despite the clinical efficacy, AAPs produces troublesome adverse effects, particularly
Hyperphagia hyperphagia, hyperglycemia, dyslipidemia weight gain, diabetes mellitus, insulin resistance and QT prolonga-
Diabetes mellitus
tion which further develops metabolic and cardiac complications with subsequent reduction in life expectancy,
Neuropeptides
poor patient compliance, and sudden death. AAPs-induced weight gain and metabolic alterations are increasing
Uncoupling proteins
Gut-microbiota at an alarming rate and became an utmost matter of concern for psychopharmacotherapy. Diverse underlying
mechanisms have been explored such as the interaction of AAPs with neurotransmitter receptors, alteration in
food reward anticipation behavior, altered expressions of hypothalamic orexigenic and anorexigenic neuro-
peptides, histamine H1 receptor-mediated hypothalamic AMP-activated protein kinase (AMPK) activation, in-
creased blood leptin, ghrelin, pro-inflammatory cytokines. Antipsychotics induced imbalance in energy home-
ostasis, reduction in energy expenditure which is linked to altered expression of uncoupling proteins (UCP-1) in
brown adipose tissue and reduced hypothalamic orexin expressions are emerging insights. In addition, alteration
in gut-microbiota and subsequent inflammation, dyslipidemia, obesity, and diabetes after AAPs treatment are
also associated with weight gain and metabolic alterations. Oral hypoglycemics and lipid-lowering drugs are
mainly prescribed in the clinical management of weight gain associated with AAPs while many other phar-
macological and nonpharmacological interventions also have been explored in different clinical and preclinical
studies. In this review, we critically discuss the current scenario, mechanistic insights, biomarkers, and ther-
apeutic alternatives for metabolic alterations associated with antipsychotics.

1. Introduction antipsychotics (AAPs) or second-generation antipsychotics (SGA) were

The exponential surge in antipsychotic prescription is attributed to a
drastic increase in the prevalence of neuropsychiatric disorders
worldwide (Gonçalves et al., 2015). Chlorpromazine was introduced as
the first antipsychotic drug in 1950s which has effectively cured the
positive symptoms of schizophrenia. With the span of time, more potent
antipsychotics were added in this category and termed as ‘typical’ or
first-generation antipsychotics (Farde et al., 1992). Typical anti-
psychotics pronouncedly produced extrapyramidal side-effects (EPSs,
which includes tardive dyskinesia, akathisia, and pseudoparkinsonism)
and hyperprolactinemia. These adverse events are consequences of ni-
grostriatal dopaminergic (D2) receptor blockade (Klawans et al., 1980).
In order to overcome those severe adverse effects, development of
‘atypical’ antipsychotics took place in 1990s. However, atypical
originally defined as the drugs effective against positive symptoms of
schizophrenia without inducing EPS. AAPs have least or no tendency of
producing EPS and also didn’t provoke catalepsy (Hippius, 1989). Hy-
perprolactinemia which is result of D2 receptor blockade in anterior
pituitary, was absent with AAPs except risperidone and its active me-
tabolite paliperidone (Bostwick et al., 2009; Kusumi et al., 2015). Ad-
ditionally, AAPs are effective in treatment of negative symptoms as well
as cognitive impairment associated with schizophrenia (Leucht et al.,
2009; Woodward et al., 2005). By virtue of their clinical efficacy, AAPs
are drug of choice in the management of mental illnesses like schizo-
phrenia, bipolar disorder, psychotic depression, schizoaffective dis-
orders and autism spectrum disorder, etc. (Lian et al., 2016a). Despite
their strong clinical efficacy in controlling symptoms of the psychiatric
disorders, AAPs having a propensity of producing severe metabolic

⁎
Correspondence to: University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh 160014, India.
E-mail address: anurag_pu@yahoo.com (A. Kuhad).

https://doi.org/10.1016/j.ejphar.2018.12.003
Received 13 October 2018; Received in revised form 2 December 2018; Accepted 5 December 2018
Available online 07 December 2018
0014-2999/ © 2018 Published by Elsevier B.V.
R. Singh et al.
alterations like increased BMI, central obesity, hyperphagia, hypergly-
cemia, dyslipidemia, insulin resistance, and diabetes mellitus, which
are collectively termed as metabolic syndrome (MetS) (Cuerda et al.,
2014; Reynolds and Kirk, 2010). Among all, olanzapine and clozapine
has highest likelihood of inducing weight gain which may be due to
their higher affinity to 5-HT2C and H1 receptors (Reynolds and Kirk,
2010).
Antipsychotic-induced weight gain (AIWG) and metabolic altera-
tions lead to cardiovascular complications, socio-occupational in-
abilities, decreased life expectancy and poor patient compliances.
Weight gain and MetS are observed as a severe side effect observed
in > 40% of patients receiving AAPs (Lett et al., 2011; Mittal et al.,
2017). Patients with the first episode of psychosis (FEP) are more sus-
ceptible to getting obese as compared to those who had previous ex-
posure to AAPs (Almandil et al., 2013). Recently, a study suggested that
monitoring of weight change (1 kg or more of baseline weight) with
olanzapine treatment at week 2 can be useful in predicting weight gain
at week 6 (Lin et al., 2018). The underlying mechanism of AIWG is not
understood clearly as it is multifactorial. Several mechanistic insights
underlying AIWG have been extensively investigated like interaction of
AAPs with neurotransmitters and their receptors, altered reward cir-
cuitry and food reward anticipation behaviors, alterations in expression
of hypothalamic orexigenic/anorexigenic neuropeptides, gut and adi-
pose tissues driven peptides and hormones, pituitary hormones,
proinflammatory cytokines, energy balance, thermoregulation, and al-
teration in gut microbiota. In different sections of this review, we have
discussed the updated mechanistic insights, biomarkers and pharma-
cotherapeutic alternatives for antipsychotic-induced metabolic altera-
tions.
2. AAPs: neurotransmitter-receptor interactions
AAPs have heterogeneous receptor interaction which makes it dif-
ficult to understand the mechanism behind metabolic alterations.
Mesolimbic and mesocortical dopaminergic hyperactivity is a major
pathophysiological aspect of schizophrenia. Based on pharmacody-
namics profiling of ‘typical’ antipsychotics, dopamine (D2) receptor is a
major target of antipsychotic action and extrapyramidal motor symp-
toms (EPS) (Kapur and Remington, 2001). Projections of dopaminergic
neurons from ventral tegmental area (VTA) to the striatum are crucial
players in brain reward modulation and appetite regulation. CNS sti-
mulants are found to decrease appetite leading to weight loss by de-
creasing dopamine (DA) turnover in striatal neurons. Conversely, pre-
clinical studies show that antipsychotics (amisulpride) with high D2
receptor antagonism in the striatum lead to increased appetite, hyper-
phagia and weight gain (Nielsen et al., 2016). DA antagonists impair
the reward circuitry leading to altered feeding, hyperphagia, and
weight gain. Functional magnetic resonance imaging (fMRI) studies in
the brain of obese individuals showed reduced reward response in
dorsal striatum which corroborated in the schizophrenic patients re-
ceiving acute or no antipsychotic treatment (Nielsen et al., 2012). Other
DAergic projections involved are dorsal striatal, cortical, limbic and
hypothalamic (Volkow et al., 2011). Hypothalamic DAergic neurons
express D1 and D2, which may be linked to metabolic conditions. Hy-
pothalamic D1 are highly expressed in the ventromedial nucleus hy-
pothalamus (VMN) of obese rats whereas D2 found in lesser amount in
VMN of lean rats (Fetissov et al., 2002). Second to the dopamine, 5HT
receptors (mainly 5-HT2A and 5-HT2C) are major sites for the anti-
psychotic effect of AAPs and also for ‘atypicality’ (Kusumi et al., 2015;
Meltzer, 2004). 5-HT2C antagonism is particularly related to hyper-
phagia and weight gain (as shown in Fig. 1). 5-HT2C antagonism by
olanzapine has been reported to induce hyperphagia, glucose intoler-
ance and altered energy homeostasis which were reversed by selective
5-HT2C agonist (lorcaserin) (Lord et al., 2017). Polymorphism in the 5-
HT2C receptor promoter gene (-759C/T) has been associated with
weight gain and elevated leptin levels after antipsychotics treatment
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European Journal of Pharmacology 844 (2019) 231–240
(Panariello et al., 2011). Unlike other AAPs, ziprasidone and ar-
ipiprazole have less tendency to produce weight gain and metabolic
syndrome due to their partial agonistic property on 5-HT2C receptors.
Olanzapine is an inverse agonist of 5-HT2C receptors and exhibits the
highest tendency to induce weight gain (Leucht et al., 2009) therefore,
it is widely used to induce metabolic syndrome in the experimental
animal.
The adrenergic system plays a very important role in metabolism
and energy balance. Adrenergic system stimulates glycogenolysis, glu-
coneogenesis, and lipolysis which ultimately leads to hyperglycemia
(Peterson et al., 1988). α-2 adrenoceptor present at pre-synaptic nerve
endings are antagonized by several atypical antipsychotics (risperidone,
clozapine, aripiprazole) may plausible role in weight gain. α-2R also
present on pancreatic β-cell inhibits insulin release once activated
(Starrenburg and Bogers, 2009). Postural hypotension is another major
side effect of risperidone and quetiapine which is because of α-1 re-
ceptor antagonism (Haddad and Sharma, 2007). A higher incidence
(> 8%) of QTc prolongation in patients receiving AAPs is a major in-
sight for cardiovascular complications like arrhythmia and coronary
artery diseases (Alvarez and Pahissa, 2010). Additionally, AAPs an-
tagonizes β-3 adrenoceptor (ADRB3), present mainly on adipocyte,
pancreatic beta-cells and disrupt energy homeostasis. Physiologically,
ADRB3 activated by norepinephrine leads to lipolysis thus useful in
weight control, maintaining energy homeostasis (Basile et al., 2001;
Starrenburg and Bogers, 2009). β-3 activation also reduces insulin-
mediated leptin release (Gettys et al., 1996) so their antagonism can be
correlated with hyperleptinemia associated with AAPs. Alongside the
sympathetic nervous system, interaction of AAPs with parasympathetic
nervous system has been correlated with metabolic side effects.
Blockade of muscarinic cholinergic (mACh) receptors by antipsychotics
lead to weight gain through anticholinergic effect (as shown in Fig. 2).
Clozapine has a variable effect on subtypes of muscarinic receptors. It
acts as a partial agonist (M1, M2, and M4) and antagonist (M3, M5) to
muscarinic receptors whereas N-desmethylclozapine (an active meta-
bolite of clozapine) acts as a full agonist (M1), partial agonist (M5), and
also as an antagonist (M3) (Davies et al., 2005). Olanzapine and clo-
zapine in low concentrations impair cholinergic-mediated insulin se-
cretion by M3 receptors blockade in isolated rat islet cells (Coccurello
and Moles, 2010). Atropine attenuated the acute insulin release after
olanzapine treatment which confirms the involvement of muscarinic
receptor augmentation in olanzapine-induced hyperinsulinemia as a
result of glucose intolerance (Rickels et al., 2017). Olanzapine and
clozapine increase feed intake and weight gain which is associated with
H1 antagonism mediated by activation of hypothalamic AMPK whereas,
clozapine did not increase pAMPK in H1 knockout mice (Kim et al.,
2007). An H1 receptor agonist, 2-(3-trifluoromethylphenyl) has been
shown to inhibit hyperphagia-AMPK activation induced by olanzapine
in a dose-dependent manner (He et al., 2014). There are several clinical
and preclinical studies on betahistine (a H1 agonist, and H3 antagonist)
showing its protective effects in AAPs-induced weight gain and meta-
bolic alterations. Betahistine co-treatment has been reported to de-
crease feeding and increase thermogenesis in BAT by altering H1 re-
ceptor mediated neuropeptide-Y (NPY) and AMPKα pathways in the
hypothalamus and protects against olanzapine-induced dyslipidemia
through modulation of AMPKα-SREBP-1 (Sterol regulatory element
binding protein-1)-PPARα-dependent pathways (Lian et al., 2016b,
2014a, 2014b).
Furthermore, cannabinoid neurotransmission is also associated with
appetite regulation which is mainly due to the abundance of the re-
ceptors in the brainstem. Cannabinoid receptor (CB1) downregulates
anorexigenic neuropeptides like cocaine and amphetamine-regulated
transcript (CART) in the Arc, corticotropin-releasing hormone (CRH) in
PVN, while upregulates orexigenic neuropeptide Y (NPY) and melanin-
concentrating hormone (MCH) in the lateral hypothalamus (LH) (Cota
et al., 2003; Osei-Hyiaman et al., 2005). A gene polymorphism study
showed that weight gain in individuals with chronic schizophrenia
R. Singh et al.
Fig. 1. Schematic representation of interaction of AAPs with major neurotransmitter-receptors and association with metabolic alterations. 5-HT-serotonin,
GABA-γ-aminobutyric acid, Glut- glutamate, CB- cannabinoids, ECs-endocannabinoids, NMDA- n-methyl D-aspartic acid, VGLUT- vesicular glutamate transporter,
CB1R- cannabinoid receptor 1, α-1& α-2- α-adrenergic receptor 1 & 2, M1, M2 & M3,- muscarinic receptor 1, 2 & 3, H1, H3-histamine 1 and 3 receptor, CVD-
cardiovascular diseases, MetS- Metabolic syndrome.
receiving AAPs has been associated with a polymorphism in CB1R gene
(Tiwari et al., 2010). Chronic treatment in male rats with high-dose
risperidone increases cannabinoid binding density of CB1 receptor
agonist [3H]CP-55940 in Arc while olanzapine-treated female rats
showed decreased binding in DVC (Weston-Green et al., 2012, 2008).
CB1R antagonist (AVE1625) has shown to be useful in treating cogni-
tive impairments associated with schizophrenia additionally reduced
olanzapine-induced weight gain in mice (Black et al., 2011). Hence,
targeting CB receptors could be another therapeutic approach in the
management of weight gain associated with antipsychotics.
3. AAPs: altered lipid and carbohydrate homeostasis
Schizophrenia patients are at increased risk of developing dyslipi-
demia due to genetic inclination (Gough and O’Donovan, 2005) along
with dietary habits and AAPs treatment. Clinical studies have reported
dyslipidemia following AAPs treatment in patients with schizophrenia
(Mackin et al., 2007). Olanzapine has been reported to have the highest
likelihood of producing dyslipidemia (Takeuchi et al., 2015). AAPs
treatment leads to insulin resistance followed by increased synthesis of
fatty acids and triglycerides from liver and causes hypertriglyceridemia.
AAPs treatment increases the synthesis of free fatty acids, phospholipid,
triacylglycerides in rodents and human hepatocytes (Canfrán-Duque
et al., 2013). Further, schizophrenic patients are susceptible to diabetes
mellitus and AAPs play a synergistic role in this context (Lindenmayer
et al., 2001). AAPs increases fasting glucose in patients which leads to
glucose intolerance (Fernandez-Egea et al., 2009) and ultimately im-
pairs glucose homeostasis. Altered glucose homeostasis developed after
certain hours-days of AAPs treatment which is independent of weight
gain in both rodents and human (Albaugh et al., 2011). Olanzapine
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European Journal of Pharmacology 844 (2019) 231–240
found to increase hepatic glucose production by activation of hy-
pothalamic AMP-activated protein kinase (Ikegami et al., 2013). In-
creased BMI following AAPs treatment is positively correlated with
increased levels of insulin, leptin, and HOMA-IR (Baeza et al., 2017).
Hypoadiponectinemia associated with insulin resistance and increased
leptin levels have been reported in schizophrenia patients receiving
AAPs treatment (Sapra et al., 2016). Additionally, chronic olanzapine
treatment has been found to increase serum glucagon levels in human
(Teff et al., 2013) as well as in rats (Smith et al., 2011). A single in-
jection of olanzapine in rats failed to increase glucagon levels (Nagata
et al., 2016) while clozapine did (Jassim et al., 2012). Recently, glu-
cagon receptor knockout mice (Gcgr(-/-)) were found to be protected
against hyperglycemia induced by acute olanzapine treatment which
was associated with reduced liver glucose production (Castellani et al.,
2017). GLP-1 (Glucagon-like peptide-1) agonist (exenatide) given in
adjunctive with AAPs reduced weight gain and delayed development of
diabetes (Ishøy et al., 2014). Glucose homeostasis alterations need to be
monitored with ongoing AAPs treatment, early monitoring of glucose
levels can prevent or reduce chances of developing T2DM, insulin re-
sistance, cardiovascular complications and development of MetS. A
possible correlation between altered glucose homeostasis and AAPs has
been depicted in Fig. 2.
4. AAPs: folate and one carbon metabolism
Folate, a cofactor for enzymes involved in DNA and RNA bio-
synthesis and donor of methyl groups to the methylation cycle for the
synthesis of homocysteine (Hcy) using methionine. N5-methyltetrahy-
drofolate (MTHF) donates its methyl group to vitamin B12-dependent
enzyme (methionine synthase) which recycles Hcy back to methionine
R. Singh et al. European Journal of Pharmacology 844 (2019) 231–240

Fig. 2. Schematic representation of antipsychotic drugs-induced metabolic alteration. Effects of AAPs on major organ/systems, alteration in biomarkers
(Peptides, hormones, adipokines, cytokines) and corresponding metabolic alterations leading to weight gain and MetS associated with AAPs treatment. GH-growth
hormone, TSH-thyroid stimulating hormone, MSH-melanocyte-stimulating hormone, T3-triiodothyronine, T4-thyroxine, UCP-uncoupling proteins, BAT-brown
adipose tissue, WAT-white adipose tissue, NPY-neuropeptide-Y, AgRP-agouty related peptide, POMC- pro-opiomelanocortin, CART-cocaine-and amphetamine-
regulated transcript, MCH-melanin-concentrating hormone, GLP-1-glucagon like peptide, MetS-metabolic syndrome.

(Scott et al., 1994). Hyperhomocysteinemia has been associated with
risk of schizophrenia (del Rosario García-Miss et al., 2010). Many re-
ports suggest disrupted one-carbon metabolism (OCM) and hyperho-
mocysteinemia together with depleted levels of folate and vitamin B12
levels among FEP patients (Ayesa-Arriola et al., 2012). Mechanisms
depicting associations between OCM alterations and schizophrenia may
be due to the interaction of Hcy with NMDA receptors. OCM alterations
may lead to anomalous DNA methylation of genes responsible for
neurodevelopment and neurotransmission has been associated with
schizophrenia pathophysiology (Misiak et al., 2013). Association of
MetS and AAPs with MTHFR gene polymorphisms have been frequently
studied (Roffeei et al., 2014). MTHFR C677T polymorphism found to be
associated with AIWG in patients with schizophrenia (Srisawat et al.,
2014). Hcy is known in advancing of schizophrenia following several
mechanisms especially for negative symptoms and cognitive impair-
ment with schizophrenia (CIAS). A study reported that elevated serum
Hcy and triglyceride and lower folate and HDL levels in FES patients
than in healthy controls. Higher Hcy and lower B12 in patients with
metabolic syndrome were found to be associated with negative symp-
toms and CIAS (Baeza et al., 2017; Misiak et al., 2016). Folate sup-
plementation has been stated to reduce AAP-associated metabolic risks
and also to reduce the risk of endothelial dysfunction (Ellingrod et al.,
2015). Moreover, hyperhomocysteinemia and disrupted folate meta-
bolism could be a biomarker for severity of negative symptoms and
cognitive impairment associated with schizophrenia and further de-
velopment of metabolic alterations.
5. AAPs: adipokines and cytokines
Adiponectin is an adipocyte-derived hormone that is secreted by
mature adipocytes. It controls the physiological pathways of carbohy-
drate and lipid metabolism and has anti-inflammatory, insulin sensi-
tizer and anti-atherogenic properties to mediate various vascular pro-
cesses (Trujillo and Scherer, 2005). Adiponectin inhibits local pro-
inflammatory cytokines production regulated via activation of toll-like
receptors (TLRs) (Neumeier et al., 2006) and inhibition of nuclear
factor-κB (NF-κB) (Lira et al., 2012; Robinson et al., 2011). Reduced
adiponectin levels have been reported in obese patients and also in
high-fat diet fed rats which subsequently associated with the develop-
ment of insulin resistance (Yamauchi et al., 2001). Reduced adipokines
and metabolic anomalies are found to be associated with AAPs treat-
ment (Gonçalves et al., 2015). Meta-analyses clearly conclude the
correlation of hypoadiponectinemia and AAPs, particularly olanzapine
and clozapine, but not with quetiapine and risperidone (Bartoli et al.,
2015a, 2015b). Further, leptin is another adipokine, synthesized in
white adipose tissue (WAT), possesses cytokine-like properties and
anorexigenic in nature. Elevated leptin levels have been observed in
schizophrenic patients treated with AAPs and its associated with BMI
might be a result of a negative feedback mechanism to compensate
increased fat mass (Potvin et al., 2015). Hyperleptinemia associated
with adipogenecity is often complemented by hypoadiponectinemia.
These alterations are believed to be a predisposing factor for metabolic
anomalies and an elevated inflammatory state. Risperidone treatment
in children with autism has been found to increase blood levels of
glucose, insulin, prolactin, leptin, and HOMA-IR significantly

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R. Singh et al.
(Srisawasdi et al., 2017). Recently, a study suggested that leptin/adi-
ponectin ratio could be a preferential indicator of AIWG and MetS
(Chen et al., 2018).
Altered levels of pro-inflammatory cytokines are associated with
schizophrenia (Martínez-Gras et al., 2012). Earlier, Miller et al. have
carried out a meta-analysis reporting the correlation of altered cyto-
kines levels and antipsychotic treatment. They have reported that first
episode of schizophrenia (FEP) and acutely relapsed inpatients showed
an increase in interleukin (IL-1 and IL-6), and transforming growth
factor-β (TGF-β) levels which were normalized with antipsychotic
treatment. Conversely, IL-12, interferon-γ (IFN-γ), tumor necrosis
factor-α (TNF-α) and IL-2 receptor appeared as trait markers because
their levels were not normalized with antipsychotic treatment whereas
unaffected IL-6 level and decreased the level of IL-1β were found in
schizophrenia patients (Miller et al., 2011). Further, in another meta-
analysis, Capuzzi et al. have shown a decrease in IL-2 and IL-6 levels
after four weeks of APD treatment. IL-2, IL-6, and IL-1β were suggested
as state markers whilst TNF-α, IFN-γ and IL-17 were considered as trait
markers (Capuzzi et al., 2017). Haloperidol and risperidone increased
interleukin (IL-10, which is an anti-inflammatory cytokine) levels while
no significant change was seen in levels of tumor necrosis factor-α
(TNF-α) and IL-1β (Obuchowicz et al., 2017). A seven-month follow-up
study showed increased levels of C-peptide, leptin and decreased levels
of adiponectin which were found to be associated with increased BMI
and APD treatment (Balõtšev et al., 2017). AAPs induces activation of
NF-κB and it's target genes which transcripts for TNF-α, IL-1β, IL-8 and
MCP-1 in human and rodent's adipocytes (Sárvári et al., 2014). In a
nutshell, it could be said that APD treatment alters the levels if adipo-
kines and cytokines which further involve in development of metabolic
alteration. The possible interaction between adipokines-cytokines and
AAPs have been illustrated in Fig. 2.
6. AAPs: appetite-regulating neuropeptides and hormones
Central neuroendocrine system is the controller of appetite, energy
intake, and expenditure. Arc controls feeding by two interconnected
groups of orexigenic (NPY/AgRP) and anorexigenic (POMC/CART)
neuronal circuits. These neuronal circuits control secretion, metabo-
lism, and action of hormones which regulate metabolism in the body
(Palou et al., 2009; Trayhurn and Bing, 2006). The orexigenic, NPY/
AgRP neurons group corresponds to the feeling of hunger along with
some co-expressed orexins receptors (OX1R and OX2R). OXR are co-
expressed in GABAergic neurons which makes them inhibitory factors
for a network of hypothalamic neurons (Abizaid and Horvath, 2008).
On another hand, the anorexigenic group of neurons, consist of the
CART, POMC, α-MSH, which are satitation factors and inhibits food
intake (Kohno and Yada, 2012). Histamine receptor (H1 and H2) are
expressed in PVN and VMH and produce the anorexic effect. Olanza-
pine and clozapine are a blocker of histaminergic receptors and pro-
duces hyperphagia. Histaminergic transmission can be enhanced by
blocking of presynaptic H3 receptor and H3 antagonists could be tar-
geted for anorexigenic their potential (Deng et al., 2010; Rojczyk et al.,
2015). Further, ghrelin is an orexigenic hormone mainly secreted in the
stomach (Nakazato et al., 2001) binds to the ghrelin receptor (GHS-
R1a) which is highly expressed in the Arc and regulates food intake and
energy expenditure (Andrews, 2011). In the hypothalamic networks
(Arc), ghrelin found to upregulate orexigenic neuropeptide (NPY and
AgRP) whereas downregulate anorexigenic peptides (POMC and CART)
expressions, which can directly contribute to the orexigenic effect.
Olanzapine and clozapine increases ghrelin release as well it's receptors
expression which clearly indicate hyperphagia and weight gain
(Albaugh et al., 2006; Murashita et al., 2007; Van Der Zwaal et al.,
2012; Zhang et al., 2014). Hence, AAPs-induced upregulates expression
of ghrelin and its receptors upregulate hypothalamic orexigenic neu-
ropeptides and down-regulates anorexigenic neuropeptides.
In addition to these neuropeptides and ghrelin, hypothalamic
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European Journal of Pharmacology 844 (2019) 231–240
feeding area (lateral and dorsomedial hypothalamus and perifornical
area) have abundance of orexins (hypocretins) and their receptors
(orexin 1 and 2, OX1R and OX2R). The orexins are regulators of
feeding, arousal, reward and implicated extensively for alcohol and
opioid-seeking (Baimel et al., 2015). Orexin fibers co-expressed with
dopaminergic neurons medial pre-frontal cortex (mPFC) and the medial
shell of the NAc, which suggests its link with dopamine and reward.
AAPs found to activate hypothalamic orexin neurons, which activate
dopamine neurons in VTA leading to increase dopamine levels in PFC
and striatum, which was found to be associated with weight gain (Fadel
et al., 2002). Activation of dopaminergic neurons by activated orexins
neurons in PFC by AAPs has been implicated for antipsychotic action
(Chien et al., 2015). Rats treated with olanzapine showed activated
orexins positive neurons in the PFC and perifornical region of LH which
is associated with weight gain (Stefanidis et al., 2009). Quetiapine,
haloperidol, and clozapine lowers sympathetic hyperthermic reactions
in rats treated with a cerebral injection of orexin A. Risperidone in-
creases the hyperthermic sympathetic reaction in rats, this explains the
effect of AAPs on thermoregulation and weight gain (Monda et al.,
2006). Hence, modulators of these neuropeptides, hormones and their
receptors could be of great interest in management of obesity and
metabolic alterations associated with AAPs treatment. Association of
these neuropeptides- hormones with AIWG has been illustrated in
Figs. 1 and 2).
7. AAPs: altered gut-microbiota
Altered gut-brain axis has been implicated in neuropsychiatric dis-
orders like schizophrenia and depression and also with weight gain
associated with AAPs. Microbial colonization has been found to reverse
altered behavior and synaptic plasticity in mice. Gut microbiome has a
direct correlation with adaptive immune response and inflammation
which are closely associated with the pathogenesis of schizophrenia.
Gut-dysbiosis leads to obesity and metabolic alterations which are
common with schizophrenia (Nemani et al., 2015). The negative impact
of AAPs on gut microbiota has been correlated with weight gain (Kanji
et al., 2018). Olanzapine-induced weight gain in germ-free mouse
suggests a plausible role of gut microbiota in weight gain which is
possible because of its antimicrobial potential to residential enteric
bacteria (Morgan et al., 2014). Chronic olanzapine treatment has shown
significant weight gain in female rats and also showed elevated plasma
proinflammatory cytokines (IL-8, and IL-1β) and gut-dysbiosis was
found to be positively association (Davey et al., 2012). Children re-
ceiving risperidone for 12 months showed an increase in BMI and a
reduced ratio of Bacteroidetes: Firmicutes as compared with AAPs naïve
patients (Bahr et al., 2015). Olanzapine-induced increased body weight,
fat deposition, and increased plasma free fatty acids have been reversed
by co-administration of antibiotic cocktail (neomycin, metronidazole,
polymyxin B) in rats, which affirms the role of gut microbiota in AIWG
(Davey et al., 2013). A recent study reported that adjunction of the
prebiotic formulation (BGOS) with olanzapine has reduced the risk of
metabolic alteration and improve cognitive function in rats (Kao et al.,
2018). Along with other novel insights, altered gut microbiota with
AAPs treatment could be of ample interest. Maintaining the gut-mi-
crobiota with probiotics and probiotics could be of great advantage in
order to enhance the safety of psychophramacotherapy.
8. AAPs: energy homeostasis
Energy (calorie) intake, expenditure, and storage are major com-
ponents of energy balance. Body weight changes only when there is an
imbalance in energy consumption and expenditure i.e. higher intake
and lesser expenditure. Obesity could be considered as consequences of
high intake and less expenditure of energy (Hill et al., 2012). There are
several factors that regulate food intake and energy expenditure are
discussed well in neuropeptide section. Melanocortin, leptin, orexin,
R. Singh et al.
NPY/AgRP, ghrelin, endocannabinoids, sympathetic nervous system,
histamine, dopamine, acetylcholine, pituitary hormones, and many
others, regulates food intake and energy balance in either way. Central
control of food intake also involved in reward circuitry and cognition
which gives a neuronal basis for food intake regulation. Palatable food,
spices, triggers reward signals and stimulates the mesolimbic system
(Liu et al., 2014). Rats treated with risperidone showed a reduction in
body temperature without weight gain (Ota et al., 2005). In humans,
risperidone has conflicting results on body temperature, in some cases
extremely high fever and muscle rigidity was observed. Mice treated
with risperidone shows weight gain associated with reduced locomo-
tion and hyperphagia along with higher levels of uncoupling protein
(UCP-1) in the BAT (Li et al., 2013). UCP1 and UCP2 regulates adaptive
thermogenesis and have been investigated for their possible roles in
body temperature regulation and energy balance and associated with
AIWG (Cope et al., 2009; Stefanidis et al., 2009). Mice treated with
risperidone shows weight gain as a consequence of energy imbalance,
while hyperthermia is due to elevated UCP1 in BAT, UCP3 in gastro-
cnemius, depleted orexin expression in the hypothalamus (Cope et al.,
2009). Additionally, reduced BDNF levels in hypothalamus and serum
are associated with AIWG. Polymorphism in the BDNF Val66Met gene
has been positively correlated with AIWG (Fonseka et al., 2015). BDNF
after sympathetic stimulation increases mRNA expression of UCP1
(Tsuchida et al., 2001). Hence, the role of AAPs in thermoregulation,
energy expenditure, altered BDNF levels can be assimilated hyper-
phagia and weight gain.
9. AAPs: reward system modulation
The DAergic neurons projecting from VTA to striatum are crucial
players in the brain reward system which controls appetite. Drugs in-
creasing DAergic turnover in the striatum, reduces body weight by
decreasing appetite whereas animal studies show amisulpride with high
D2 receptor affinity in the striatum lead to increased appetite, hyper-
phagia and weight gain (Nielsen et al., 2016). Obesity and weight
dysregulations are most likely comorbidities with psychopathology and
are persistent with the severity of the psychiatric illnesses and showed
considerable overlapping substance abuse and reward system. Altered
reward anticipation in psychiatric illnesses has been implicated in in-
creased food intake, weight gain, and susceptibility towards substance
abuse and addiction. Striatal DAergic neurotransmission is a major site
for regulation of eating behavior, motivation, reinforcement, and re-
ward anticipation (Grimm et al., 2017). The reward deficiency hy-
pothesis suggested reduced DA activity impairs reward circuitry and
lead to abnormal craving/eating behavior, and obesity (Blum et al.,
2014). Volkow et al. unveiled the role of dopamine in food reward,
reinforcement, and obesity and also reported associations of striatal D2
receptors with prefrontal metabolism and overeating in obese patients.
Reduction in striatal D2 receptors could contribute to overeating via
their modulation of striatal prefrontal pathways (Volkow et al., 2011).
PET studies in human proved the role of DA in obesity. A reduced
striatal D2 density was found in obese patients (Wang et al., 2001). This
indicates, overlapping in the neurobiology of obesity and addiction
disorders. Additionally, chronic consumption of high-fat (HFD) and
high-sugar diet found to down-regulate DA receptors which shows
phenotype like of chronic drugs abuse related increased dopaminergic
signaling (Val-Laillet et al., 2015).
Almost all antipsychotics produce weight gain which is because of
their D2 receptors blockade and inhibition of phasic dopaminergic ef-
fect in the striatum and other areas (Bak et al., 2014). AAPs leads to the
reduced motivation for physical activity and increased motivation for
feeding rich in calories. A longitudinal study highlighted the correlation
between AAPs treatment, weight gain, and striatal activity. Patient re-
ceiving amisulpride for more than six weeks showed an association of
weight gain with increased putamen activity and reward anticipatory
response in monetary incentive delay task (Nielsen et al., 2016).
236
European Journal of Pharmacology 844 (2019) 231–240
Additional to all other mechanistic insights discussed in this review,
alteration in reward anticipation could be an alternative mechanism in
weight gain associated with AAPs.
10. Management of AIWG
Many non-pharmacological approaches have been implicated in
management of AIWG. Behavioral interventions have found to be ef-
fective in psychiatric patients on APDs and development of metabolic
syndrome. Caregivers need to take care of patients, record their daily
food intake, exercise and medication intake. Controlled dietary intake
(dietary intervention), regular psychoeducational sessions and regular
exercise could prevent and/or reduce the incidences of weight gain,
diabetes, and CVDs (Amiaz et al., 2016). A recent study reported that
lifestyle modification along with metformin treatment can significantly
reduce the risk of weight gain and metabolic risk associated with AAPs
(Zheng et al., 2018).
Pharmacological interventions used clinically in management of
antipsychotics-induced metabolic alterations are mainly oral hypogly-
cemic and antihyperlipidemic drugs. Metformin, a safest oral hy-
poglycemic drug, which has been extensively studied and is used
clinically for this purpose. It increases peripheral utilization of glucose,
inhibits hepatic glucose production and prevents the development of
insulin resistance. It can reduce prevent and reduces weight gain in
psychiatric patients receiving AAPs (Arman et al., 2008; Klein et al.,
2006; Lee and Jeong, 2011). However, a study showed no improvement
in olanzapine-induced weight gain but some lipid parameters were re-
versed (Baptista et al., 2006). Early metformin prescribing with AAPs
has been found preventive against AIWG (Goltz and Rice, 2017;
Hendrick et al., 2017). Antidiabetic and antihyperlipidemics are the
drug of choice in the management of AIWG (Varghese et al., 2016).
Statins prescribed in patients with severe mental illness has been found
to control lipid profile but failed to protect against cardiovascular
complications (Blackburn et al., 2017). H1 agonist (betahistine) is the
most explored drug against AIWG in clinical trials, and many studies
are reported its clinical efficacy in the management of the problem
(Poyurovsky et al., 2013, 2005). Along with the above, following
pharmacological interventions have also been tested clinically for
AIWG (Mizuno et al., 2014), amantadine (Deberdt et al., 2005; Graham
et al., 2005), aripiprazole (Fan et al., 2013), atomoxetine (Ball et al.,
2011), D-fenfluramine (Goodall et al., 1988), famotidine (Poyurovsky
et al., 2004), fluoxetine (Bustillo et al., 2003), sibutramine (Biedermann
et al., 2014), metformin-sibutramine combination (Baptista et al.,
2008), modafinil (Sudhakar et al., 2008), nizatidine (Assunção et al.,
2006), orlistat (Joffe et al., 2008), phenylpropanolamine (White et al.,
2002), reboxetine (Poyurovsky et al., 2007), betahistine-reboxetine
combination (Poyurovsky et al., 2013), rosiglitazone (Baptista et al.,
2009), topiramate (Afshar et al., 2009), zonisamide (Ghanizadeh et al.,
2013), exenatide (Ishøy et al., 2014), naltrexone (Tek et al., 2014) and
α-lipoic acid (Kim et al., 2016). Most recently, melatonin found to re-
duce AIWG in adolescent patients with bipolar disorder (Mostafavi
et al., 2017), bergamot-derived polyphenolic fraction in low dose im-
proved metabolic parameters after use of AAPs (Bruno et al., 2017). The
focus of current pharmacotherapy of neuropsychiatric disorders should
be on maximizing the efficacy and minimizing the development of
adverse effects especially metabolic alterations.
11. Conclusion
The dramatic surge in neuropsychiatric illness has significantly in-
creased antipsychotic prescription. With higher clinical efficacy as
compared to typical antipsychotics and less tendency to induce EPS
makes them first-line drugs in the management of schizophrenia, bi-
polar, psychotic depression, autism, and other neuropsychiatric dis-
orders. Besides the advantages, AAPs induce metabolic abnormalities
which are of utmost concern for current psychopharamcotherapy.
R. Singh et al.
Mechanistic insight includes alterations in hypothalamic neuropep-
tides, striatal and mesolimbic dopamine reward pathways, gut hor-
mones, peptides, pituitary hormones, elevated proinflammatory cyto-
kine, altered energy homeostasis, and gut-dysbiosis are involve in
AAPs-induced MetS. The focus should be given to the development of
antipsychotics with partial agonistic effect on the 5-HT2C receptor or
unlike existing AAPs, the newer one should have minimal effect on
other neurotransmitter systems. Pre/probiotics need to be incorporated
into the diet of the patient while taking AAPs, which can prevent the
gut dysbiosis and could prevent the progression of MetS. Monitoring of
biomarkers discussed here need to be given more emphasis while an-
tipsychotic therapy is ongoing. Early diagnosis could be preventive and
can delay or restrict the development of MetS in a patient receiving
AAPs.
Acknowledgments
Financial support from Indian Council of medical research (ICMR)/
Department of health research (DHR), New Delhi, India is gratefully
acknowledged for research grant awarded to Dr Anurag Kuhad under
the grant number GIA/59/2014-DHR. We gratefully acknowledge re-
search grant sanctioned by SERB, DST, and UGC New Delhi. Council of
Scientific and Industrial Research (CSIR), New Delhi, India is gratefully
acknowledged for awarding senior research fellowship to Mr
Raghunath Singh.
Conflict of interest
Authors have none to declare.
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