Faculty of pharmacy department of human pharmacology and toxicology

5. Psychotropic medication and the risk of metabolic abnormalities

There is a great concern focused, throughout the years, on the metabolic complications caused by psychotropic medications including antipsychotics, antidepressants and mood stabilizers agents (Chokka, Tancer & Yeragani, 2006, Correll, Lencz & Malhotra, 2011). During psychopharmacological therapy metabolic side effects are observed, such as changes in body weight especially increased body mass index leading to overweight and obesity, increased risk of development of diabetes mellitus and alterations on the lipid profile. All these factors may increase health risks of several medical problems including cardiovascular complications like coronary heart disease, ischemic stroke, osteoarthritis, respiratory problems, hypertension and also cancer (Ruetsch et al.,2005; Himmerich et al., 2015). As it has been studied in the present review, the weight gain is linked to insulin resistance development and results in metabolic syndrome while it seems that psychotropic medications affect neuronal circuits that regulate appetite and the systems that regulate energy homeostasis (Wysokinski & Knoszewska, 2014).

Bradshaw & Mairs in 2014, represented 4 studies which are focused on patients with schizophrenia, bipolar disorder and depression, investigating the BMI and the existence of metabolic risk factors and the prevalence of metabolic syndrome. The findings suggest that there is a higher prevalence of metabolic risk factors in patients with mood disorders and abnormally high prevalence of metabolic syndrome.

Antipsychotics

Revolution in medical care to people suffering from mental disorders, including schizophrenia and other psychotics disorders, was noted when psychopharmacotherapy was developed in the 1950s. In the beginning, first generation antipsychotics (FGAs), called also typical, were introduced with the synthesis of chlorpromazine by Delay & Deniker in 1952. The first obstacle reffering their use, was the side effect concerning extrapyramidal symptoms including parkinsonian symptoms due to blockade on D2 receptor. This finding caused great difficulties to treatment adherence and tolerance. In 1990s, the introduction of second generation antipsychotics drugs, called also atypical, came to diminish this side effect. These drugs became increasingly popular due to their low potency to produce extrapyramidal symptoms. Although this class seems to be preferable due to this advantage and higher efficacy, metabolic effects came to add a disadvantage, raised as a villain consequence (Teixeira et al., 2006, Reynolds et al., 2010, Potvin et al., 2015, Santini et al., 2016).

Metabolic syndrome is present 2 times higher in adults taking antipsychotics comparing to general population (Wysokinski, Kowman & Knoszewska, 2012). Allison et al (2009) have found that metabolic side effects of antipsychotic medications contribute to the high levels of obesity in schizophrenics. Weight gain including dyslipidemia has been proved as a metabolic side effect of antipsychotic treatment as some antipsychotic agents are related to increased blood lipids, mainly triglycerides (Newcomer, 2005).

Bradshaw and Mairs in 2014 focused on weight gain resulting from taking antipsychotic medication in meta-analysis studies. The evidence shows that all antipsychotic agents could potentially cause weight gain (compared to placebo) while it seems that the first generation antipsychotics cause less weight gain. Olanzapine and clozapine, as second-generation drugs, seem to cause rapid weight gain in the early treatment stages (up to 17 kg at the first year). Furthermore, the meta-analysis of Leucht et al (2009) suggests that olanzapine and clozapine are the most important weight gain-inducing drugs administered to schizophrenia patients. Foley & Morley (2011) have noted that weight gain could be underestimated by up to 50% because of methodological limitations in the studies (like failing to assess for the effects noncompliance with medication). Alvarez-Jimenez et al in 2008 and Allinson et al in 1999 have found that weight gain is more severe and rapid in younger people with first episode psychosis who had limited previous exposure to antipsychotics and those who have a lower BMI pretreatment and more co-medications and antidepressants. These studies blame for weight gain more firmly on the side effects of antipsychotic medication. Allinson et al. suggested that antipsychotic medication has long been associated with weight gain in people with serious mental ill health (SMI) while Foley & Morley (2011) suggested that weight gain is more rapid on second-generation. Also, Kluge et al (2007) have suggested that olanzapine may promote binge eating and Mitchell et al (2013) systematic review found that prevalence of metabolic syndrome in people with SMI were 32.5%.

As it could be observed in figure 10, the extent of weight gain is linked to age and treatment history regarding BMI increase with risperidone in adults and youth. In adults and youth the weight gain-episode patients is greater than in patients with chronic illness (Parsons et al., 2009; Lieberman et al., 2009). Correll et al. (2009) study in 135 children and adolescents showed the heterogeneity of three-month weight gain receiving risperidone (figure 10b). Despite a mean weight gain of 5.3 kg, weight gain outcomes varied considerably: weight loss occurred in 4.4%; weight gain of 0–6.9% of baseline body weight occurred in 31.1%; of 7–13.9% in 39.6%; of 14–20.9% in 18.5%; and of ≥21% in 6.7% of youth.



Figure: a) Effect of prior treatment exposure on BMI increase with risperidone in adult and youth.

b) Heterogeneity of weight gain in antipsychotic-naïve youth treated with risperidone for three months. Figure by Correll, Lencz & Malhotra, 2009.

Among typical antipsychotics, chlorpromazine as dopamine antagonist is associated with significant weight gain comparable to some of the second-generation agents (Adams et al., 2014). Chlorpromazine also affects serotonin (5-HT1 and 5-HT2), histamine (H1), adrenergic (α1 and α2) and muscarinic acetylcholine (M1 and M2) receptors. Phenothiazines represent an elevation of serum triglyceride and total cholesterol levels (Meyer, 2001). An analysis of four studies describing chlorpromazine treatment over 6 weeks in patients suffering from schizophrenia pointed out that about 24%of patients experienced significant weight gain (>7 % above their baseline weight) (Dossenbach et al., 2007).This typical antipsychotic agent is associated with high risk of developing hyperlipidemia and diabetes (Medici et al., 2016). Compared to chlorpromazine, haloperidol seems to be associated with moderate risk of weight gain and diabetes. Saddichha et al, when compared various types of antipsychotics including haloperidol, came to conclusion that the prevalence of metabolic syndrome related to this agent was the lowest among the others.

Regarding to atypical antipsychotics, clozapine and olanzapine, followed by quetiapine and risperidone are connected with greater incidents of diabetes, hyperlipidemia and with the highest weight gain (Santini et al., 2016). Olanzapine and clozapine seem to be linked also with hypertriglyceridemia (Meyer, 2001). Medici et al. reported that the average weight gain associated with clozapine is 2.4 kg with a maximum reported of 10 kg. Olanzapine present a mean of 5.6kg in long term studies. This drug is connected with high risk of diabetes and increase serum lipid levels compared to other atypical antipsychotics. Patients with diabetes should use with caution olanzapine and monitor glycated hemoglobin (HbA1c) for signs of worsening glucose control. Increases in triglycerides, LDL cholesterol and total cholesterol and decreases in HDL cholesterol have been mentioned in the evaluation of studies for olanzapine and monitoring lipid levels during treatment is recommended (Proietto et al., 2004). In contrast to olanzapine and clozapine, the association of risperidone and weight gain is less significant .Sechter et al reported an average of 2.1 kg when risperidone was administered for 6 months to patients with chronic schizophrenia. High inter-individual variability is observed and is clearly demonstrated in published case studies as Fukui et al., which followed two patients treated with combination of risperidone and paroxetine. After 5 months of treatment, the raise of weight gain was up to 14kg.The suggested mechanism by authors was also a possible drug-drug interaction causing inhibition of cytochrome P450 enzyme 2D6. Less risk of developing diabetes is shown by aripiprazole and ziprasidone and that is due to low affinity at histamine receptors and partial antagonism on serotonin receptors (Medici et al., 2016).
Potential mechanisms of antipsychotic drug-induced weight gain

The atypical antipsychotics have an impact on several neurotransmitter systems. These drugs are exerting antagonistic actions at serotonergic, histaminergic, muscarinic, dopaminergic and adrenergic receptor subtypes. The neurotransmitters of the above systems are all implicated, directly or indirectly, in pathways associated with food intake regulation or metabolism (Teff et al., 2011, Panariello et al., 2011, Medici et al., 2016). Body weight gain, adiposity, dyslipidemia, impaired glucose homeostasis, insulin resistance, diabetes mellitus type II and leptin resistance are all factors arising from the use of atypical antipsychotics (Coccurello et al., 2010).

Dopamine plays an important role in feeding behavior. It affects the hypothalamus as well as other regions which determine the food intake. Its effects vary depending on the dose and on the site of administration in the hypothalamus. Atypical antipsychotics show affinity on dopamine binding sites of dopamine receptors (DA). The blockade of hypothalamic D2 can affect the feeding behavior with an increase in food consumption whether by direct action on nervous centers associated with appetite or by secondary hyperprolactinemia (Reynolds et al., 2010, Teff et al., 2011, Volpato et al., 2013, Panariello et al., 2011, Teixeira et al., 2006).

Circulating prolactin could be responsible for increase in food intake or stimulation of lipogenesis and this can be a consequence of blockade of the inhibitory effect of dopamine at the pituitary gland. Hyperprolactinaemia is connected with increased risk of obesity due to the fact that it is associated with insulin resistance and endothelial dysfunction which could improve after achieving normal levels of prolactin (Shibli-Rahhal et al., 2009). Hence, it may contribute to weight gain in patients treated with antipsychotics responsible for raising prolactin (Reynolds et al., 2010).

In contrast, the involvement of other systems particularly of serotonin (5-HT2C), histaminergic (H1), adrenergic (α1, α2 and ß3) and muscarinic (M3) receptors located in central and peripheral pathways could play a stronger and prominent role than that of dopamine receptors (Coccurello et al., 2010).

Another important chemical messenger regulating a great variety of psysiological responses in the brain and peripheral organs including food intake, is monoamine histamine. The histaminergic system is involved in the reduction food intake through the histamine-induced activation of the H1 receptor. Blockade of H1 receptors is involved in increased appetite and consequent weight gain. The histaminergic system also influences the dopaminergic system. Histamine can suppress the mesolimbic dopamine pathway, responsible for controlling food intake, through the H3 autoreceptor and yet activates it through the histamine H1. Clozapine and olanzapine, are frequently used in the clinical setting due to their efficacy in treating the multiple domains of schizophrenia. These two atypical antipsychotics have a high affinity for the H1 receptor and olanzapine treatment has been demonstrated to decrease mRNA expression and H1 receptor binding density in the hypothalamus (Brabant et al., 2010, Haas et al., 2008, Teff et al., 2011, Reynolds et al., 2010 ). The H3 histamine receptor also plays an important role in body weight and food intake. It acts as a heteroreceptor for other neurotransmitter signal pathways, such as noradrenaline, achetylcholine and serotonin (5-HT). Acts, moreover, as presynaptic autoregulator of histamine synthesis and release, which implicates in the regulation of eating behavior. However, whether the effect of weight-inducing antipsychotic drugs at the H3 receptor is unknown, Deng et al., 2010 proposed that the weight gain side effect of atypical antipsychotic drugs could be also a result of their effect on the H3 receptor.

Among neurotransmitters that contribute in food intake regulation, the serotonin system has been referred to as an important factor. That is why it is not surprising that it has been also under critical observation in the research for mechanism that is responsible for weight gain caused by antipsychotics. The 5-HT is a potent satiety signal. The 5-HT2C receptor is the most studied because this subtype is involved in the increase of weight gain through its physiological characteristics. Antagonism of this receptor is leading to induction of weight gain and also attenuates the decrease in food intake which is produced by 5-HT2C agonists (Himmerich et al., 2015, Hayashi et al., 2005, Panariello et al., 2011). However, ziprasidone, which is a strong antagonist of this receptor, has no evidenced association with weight gain and this could be explained by the compensatory anorexigenic action caused by noradrenaline reuptake inhibition (Wirshing, 2004). So the complex properties of a drug regarding the receptor profile play a key role. Murashita et al reported that risperidone blocks the HT2C receptor situated on hypothalamic arcuate nucleus (ARC) neurons, causing an alteration in the action of leptin.
A variation of sympathetic balance has been suggested to be a subject of obesity and diabetes development (Poyurovsky et al., 2003). Certainly, the relationship between sympathetic activity, noradrenaline secretion and role of the α1 receptor in energy metabolism, relating to the way of lipolytic activity, has been established. The role of α1 receptor in atypical antipsychotic induced glucose dysregulation could also be proposed by the hyperglycemic effects of α1 subtype blockade (Coccurello et al., 2010). Furthermore, lipolytic activity by β-adrenergic stimulation was significantly inhibited by the administration of olanzapine. The study of other candidate genes in schizophrenic patients has resulted in the identification of genetic variants β3 adrenergic receptors as a possible risk factor for weight gain induced by olanzapine (Ujike et al., 2008). Association between polymorphism in β3 receptor and adiposity has been described in obese individuals as well as in schizophrenic individuals under clozapine medication (Coccurelo et al., 2010).

Zai et al in 2015, reported that among patients treated with olanzapine and clozapine with predicted weight gain, there is a potential role of genetic mutations involving the GABA alpha 2 receptor subunit variant.

It is widely known that parasympathetic nervous system and cholinergic transmission are involved in glucose-dependent insulin secretion. Additionally, type II diabetes mellitus results from the failure of glucose to stimulate insulin release from pancreatic ß-cells. Muscarinic receptors are distributed in pancreatic ß-cells and cholinergic dependent insulin release is under control of M3 receptors (Himmerich et al., 2015, Coccurelo et al., 2010). These receptors seem to be responsible for the regulation of insulin secretion, glucose homeostasis, and body weight and this can be an explanation for metabolic side effects and the large differences observed between high-to-moderate risk and low-risk antipsychotics. Among second generation antipsychotics, olanzapine, clozapine and quetiapine through its metabolite nor-quetiapine have an essential affinity at M3 receptors (Potvin et al., 2015). M3 receptor blockade from olanzapine in the brain may inhibit the acetylcholine pathway for insulin secretion (Weston-Green et al., 2012). The strong affinity of clozapine and olanzapine for the muscarinic M3 receptor is the mechanism which is suggested to be invloved in the dysregulation of glucose homeostasis and tendency to induce insulin resistance (Teff et al., 2011, Reynolds et al., 2010). Silvestre & Prous, proposed that this affinity is a great predictor to induce diabetes type II. In an in vitro study of isolated islet cells, there was supporting evidence highlighting the strong antagonism of olanzapine and clozapine at M3 sites and their inhibition of cholinergic stimulation of insulin secretion (Johnson et al., 2005).
As an extra factor, hyperleptinemia has been observed in schizophrenic patients. Many antipsychotic drugs could induce leptin resistance resulting to disinhibition of food intake. The disruption of hypothalamic function is provoked by antagonist action of antipsychotics at certain monoamine receptors (Reynolds et al., 2010). Panariello et al, suggested that there is an interaction between leptin and serotonin (specifically 5-HT2C). An important area of the brain, which is connected with food intake and body-weight regulation, is rich in 5-HT2C and the antagonism of these receptors attenuate the reduction in food intake produced by leptin. Furthermore, they suggested that hypothalamic histamine is a modulator of leptin activity. Leptin-induced food intake appears suppresses in H1 knockout mice.

Another one meta-analysis was performed aimed to examine the differential effect of antipsychotics on leptin levels in schizophrenia. Their findings shown an elevation on leptin levels produced by antipsychotics especially from olanzapine, clozapine, and quetiapine. Across their results, body mass index changes were significantly associated with hyperleptinemia. This suggests that leptin acts as a negative feedback signal in the event of fat increase. In addition, alterations in leptin were positively associated with changes in total cholesterol, LDL and triglycerides. These results have a close similarity to the known link between antipsychotic treatment, increased hyperlipidemia and adiposity (Potvin et al., 2015).

In the field of pharmacogenetics of antipsychotic drug-induced metabolic pathology, BDNF (as it was mentioned in the chapter brain substrates) plays a role in the regulation of food intake and one report has found a relationship with the functional Val66Met polymorphism of the BDNF gene of weight gain in male patients treated with antipsychotic drugs (Zhang et al., 2008). More recently, Bonaccorso et al. in 2015 hypothesized that this common functional variant, Val66Met, which has been shown to be linked with increased body mass index (BMI) in schizophrenia, is also associated with antipsychotic-induced weight gain in bipolar disorder. Moreover, this study measured the connection of this variant with other metabolic parameters, such as total cholesterol and triglycerides. It concluded that the expression of Val66Met is connected with a steady, long-term increase in BMI of bipolar patients within a 6-month period treatment with risperidone and olanzapine. Additionally, there was an increase in the triglycerides/high density lipoprotein ratio after a 3-month period treatment with risperidone.

As it could be seen below on table 2 clozapine and olanzapine produce the most weight gain, quetiapine and risperidone produce intermediate weight gain, and ziprasidone and aripiprazole produce the least weight gain. The differences in weight gain are linked to the risk of dyslipidemia, insulin resistance, and glucoregulatory dysfunction (American Diabetes Association et al., 2004).

	Risk of metabolic abnormalities
Antipsychotic agent	Weight	Risk for diabetes	Lipid profile alterations
Clozapine	+++	+	+
Olanzapine	+++	+	+
Risperidone	++	D	D
Quetiapine	++	D	D
Ziprasidone	+/-	-	-
Aripiprazole	+/-	-	-