Faculty of pharmacy department of human pharmacology and toxicology

Table 2: Atypical antipsychotic drugs and metabolic disturbances (adapted from, American Diabetes Association et al., 2004).

D = discrepant results

Antidepressants

Weight gain is an important factor that contributes to patient non-compliance and may lead to medical comorbidity. However, each person separately responds to antidepressants in a different way. Some people seem to gain weight, when treated with a certain antidepressant, while others don't. There is a growing interest in the last two decades, regarding the effect of psychotropic medication on body weight. Despite the fact that the relationship between weight gain and new generation antipsychotics, is verified, the interest on the effect on body weight from antidepressants on the literature is more limited (Uguz et al.,2015). Furthermore, the depression itself could be associated with increased body weight in adults, and this is a parameter that should be taken into account from any study that attends to examine the causal of weight gain from antidepressants (Patten et al., 2011).

Both hyperglycemia and hypoglycemia were observed in patients taking antidepressants. Referring to hyperglycemia, the association with antidepressants is probably due to the high binding affinity on 5-HT2c receptor and norepinephrine reuptake transporter. Additionally, hyperglycemia could be a consequence of the association between disturbances of glucose homeostasis and antihistaminergic antidepressants. Blockade of H1-R might cause such metabolic abnormalities due to counteracting the central anorexigenic effects of histamine or increasing adipose tissue deposition (Derijks et al., 2008a). Hyperglycemia has also been induced by drugs acting as agonists on central serotonin receptors (5-HT2A and 5-HT2B) (Khoza et al., 2011; Chaouloff et al., 1992). The inhibition of insulin signaling cascade by antidepressants, which leads to insulin resistance has also been hypothesized to induce hyperglycemia (Levkovitz et al., 2007). Khoza et al. proposed that antidepressants may provoke the elevation of cortisol through HPA-axis, thus resulting in insulin resistance and hence to hyperglycemia. In contrast, hypoglycemia was observed in diabetic patients taking antidepressants for over 3 years. The possible underlying mechanism is the affinity for the serotonin reuptake transporter (Derijks et al., 2008b).

Salvi et al, the most recent study in 2016, aimed to assess the prevalence of metabolic syndrome in patients with bipolar disorder exposed to different types of antidepressants. More precisely, they investigated whether the prevalence of metabolic syndrome is affected by the H1-R affinity of antidepressants. They classified the antidepressants according to their H1-R affinity in 2 groups. The first one included antidepressants with low affinity on H1 receptors (selective serotonin reuptake inhibitors plus venlafaxine, duloxetine, clomipramine, reboxetine and bupropion) and the second group drugs with high affinity in H1 receptor (amitriptyline, imipramine, nortriptyline, trimipramine, and mirtazapine). Finally, their results are showing that the the prevalence of metabolic syndrome is almost identical reaching the 24 % among patients treated with H1-R low-affinity antidepressants and on the other hand, the prevalence of metabolic syndrome was substantially higher reaching the 53% among patients treated with H1-R high-affinity antidepressants. Throughout the years, this is the first time that this is observed in a clinical setting.

For a long time is known that tricyclic antidepressants and monoamine oxidase inhibitors have shown metabolic side effects related to weight gain and obesity development (Garland, Remick & Zis, 1988). Tricyclic anti-depressants, including nortriptyline, amitryptiline, doxepin, and desipramine, are first-generation anti-depressants acting by inhibiting serotonin and norepinephrine reuptake, with consequent elevation in synaptic concentration of neurotransmitters. High affinity for the H1 receptor, high antimuscarinic action and alphalytic action, are associated with a high incidence weight gain (Harvey et al., 2000). The exact mechanism that leads to weight gain is unknown, but there are probably many contributing factors. Tricyclic antidepressants can increase appetite and carbohydrate cravings. Amitriptyline is associated with short-term (4–8 weeks) and long-term (more than 3 months) weight gain, with a mean gain of about 2 kg. Amitriptyline appears to be the drug associated with the most significant weight gain in its category (Vanina et al., 2002). Moreover, in vitro studies in human culture hepatocytes have demonstrated that amitriptyline upregulates sterol regulatory element-binding protein (SREBP), associated with activation of hepatic lipid deposition (Raeder et al., 2006). These findings are concerning for potential lipotoxicity, even though there is no evidence that amitriptyline is associated with worsening fatty liver.

Monoamine oxidase (MAO) inhibitors, have shown greater potential on weight gain, when compared to selective serotonin reuptake inhibitors (SSRIs). Results from Pande et al. study, on patients with depression showed that the monoamine oxidase inhibitor, phenelzine, over a 6 weeks of treatment was connected with greater likelihood for weight gain than fluoxetine. Fava et al., suggested that from this class, phenelzine seems to be the drug most likely associated with weight gain, because it exerts its effects on mechanisms controlling appetite.

Selective serotonin reuptake inhibitors (SSRIs), including citalopram,
escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, are first-line medicines prescribed for depression and plenty of alternative conditions together with panic attacks, chronic anxiety and post-traumatic stress disorder. Zimmermann et al. (2003) found that SSRIs (selective serotonin reuptake inhibitors) induce weight loss rather than weight gain. Mirtazapine, paroxetine, amitriptyline, citalopram and escitalopram have been associated with weight gain (Dent et al., 2012). The mechanism of action is also based on the binding of post-synaptic 5-HT receptors, resulting in increased serotonin levels and increased stimulus conductivity. SSRIs are related to weight gain less often than other anti-depressants, when used in short-term treatment of 2–3 months in length (Michelson et al., 1999). In contrast, during long term treatment, of 6-30 months, paroxetine has been shown to be associated with the highest risk of weight gain, while fluoxetine has been linked to the lowest risk (Fava et al., 2000). The underlying mechanism which was suggested to be the cause of increased appetite and carbohydrate cravings, is the direct role of SSRIs on 5-HT, that contribute on appetite regulation (Harvey et al., 2000). Lustman et al., in a randomized double-blind placebo-controlled trial, evaluating the increased risk of developing diabetes mellitus from SSRIs, found that fluoxetine showed a great profile on improved glycemic control. In 2013, Andersohn et al., proposed that among SSRIs, paroxetine was associated with increased risk of diabetes. Notwithstanding, clinical studies lack development of visceral obesity and fat distribution, in an in vitro study on murine islet cells incubated with SSRIs, Isaac et al in 2013 suggested that the underlying mechanism that shows approval of the development of diabetes mellitus, is the triggered beta cell death and the inhibition of insulin secretion.

Another drug that shows a greater potential on weight gain in relationship with SSRIs, is mirtazapine, a specific serotonergic and noradrenergic antidepressant (Watanabe et al., 2011). A possible mechanism explaining the correlation between metabolic and psychotropic effects of mirtazapine is the relationship between insulin sensitivity and 5-HT2-antagonism. A direct effect on 5-HT receptors could have a consequence on lipid metabolism. Increase in body weight and hypercholesterolemia were observed when mirtazapine was added to first generation antipsychotics for the treatment of schizophrenia. Similarly to clozapine, mirtazapine inhibits also the histamine H1 receptors and this effect could be an observation of its metabolic changes (Terevnikov et al., 2013). The patient’s weight gain is observed in the beginning stages and during long-term therapy and this is most likely associated with increased appetite. Versiani et al. on 2005, during a double-blind clinical trial, compared mirtazapine and fluoxetine in severely depressed patients for 8 weeks. Mirtazapine-treated patients gained up to 2,7kg, whereas fluoxetine-treated patients lost up to 2,1kg. Studies from 2011 evaluated that the increase in weight from mirtazapine was linked to hyperglycemia and glucose metabolism dysregulation (Khoza et al., 2011). An experimental study found that 4 weeks of treatment with mirtazapine led to an increase in leptin plasma levels and weight gain. Here the leptin resistance could be explained by the antihistaminergic activity of this drug, interfering on hypothalamic nuclei integrating signals relevant for energy balance (Schilling et al., 2013). In one case report, significant elevated levels of plasma glucose were observed by the use of mirtazapine accompanied by a significant weight gain of 15.9 kg in 5 months of treatment (Fisfalen et al.,2003). Duncan et al in 2015 presented a case study of a man 75 years old, suffering from dementia, who was being treated with mirtazapine to improve his mood. High levels of triglycerides were noticed, consequently followed by hyperglycemia. Eventually, after the discontinuation of mirtazapine, hypertriglyceridemia still persisted.

Psychotropic drugs are found to activate the TNFa system and leptin by increasing plasma levels of these cytokines and cytokine receptors. A research study investigated the effect of amitriptyline and paroxetine on weight and on leptin, TNF-α, and TNF receptors and concluded that weight gain induced by psychotropic agents may occur without increased circulating levels of leptin (Himmerich et al., 2015, Hinze-Selch et al., 2000). The increase of leptin concentration could also be present on antidepressants medication as Kraus et al. have observed a small raise of leptin in depressive patients treated with mirtazapine.

Uguz et al. in 2015, investigate the weight gain in 362 patients under antidepressants treatment for 6 to 36 months. The results have shown that 55.2% of patients presented weight gain while 40.6% of them had a weight gain of 7% or more compared to the baseline. Also, citalopram, escitalopram, sertraline, paroxetine, venlafaxine, duloxetine and mirtazapine, but not fluoxetine, were associated with significant weight gain.

Conversely, paroxetine and mirtazapine but not the other newer antidepressants were associated with a greater risk of weight gain in Serretti & Mandelli (2010) research study.

Wise et al (2010) analyzed 10 clinical studies to finding that long-term use of duloxetine and paroxetine is significantly associated with weight gain. Dannon et al (2004) reported an average weight gain of 5.06 kg by paroxetine treatment while Dannon et al (2007) suggested that mean increase in body weight was significant at 6.1 kg. More specifically Dannon et al (2007) reported that fluoxetine, citalopram, paroxetine, and fluvoxamine have respectively weight gain .2, 6.9, 8.2 and 6.3 kg. Patten et al (2009) mentioned that after 12 years the average weight gain is 7.2 to 7.6 kg.

Medication	Effect on Weight
Tricyclics	Most produce weight gain
SSRIs: Citalopram fluoxetine, fluvoxamine and sertraline Paroxetine	Neutral Gain
Bupropion	Loss
Mirtazapine	Gain
Venlafaxine	Neutral

Table 3: Effects of Pharmacotherapy for Depression on

weight (Stunkard, Faith & Allison, 2003)

Mood stabilizers

Drug-induced weight gain has long been associated with antipsychotic medications. Another major class of drugs causing a significant risk in weight gain is mood stabilizers. They are used for the treatment of bipolar disorder and agents included in this class are lithium, valproic acid, carbamazepine and lamotrigine. (Wirshing, 2004; Zimmermann et al.,2003). Among these aforementioned drugs lithium and valproic acid cause the greatest increase in weight, carbamazepine to a lesser degree and lamotrigine does not seem to be associated (Teixeira et al., 2006).

Medication	Effect on Weight
Lithium	Gain
Valproate	Gain
Carbamazepine	Neutral
Lamotrigine	Neutral
Topiramate	Loss

Table 4: Effects of Pharmacotherapy for Bipolar Disorder on

Weight (Stunkard, Faith & Allison, 2003).

Lithium is one of the most frequently used treatments for bipolar disorder and despite its characterization as a gold standard it seems to have serious effects on thyroid and parathyroid glands, BMI and kidneys (Eker & Eker, 2010). One of the most common adverse effects of lithium is weight gain and how exactly this occurs is not clearly understood. Lithium stimulates in a direct way the appetite at the hypothalamus and the proposed mechanisms involved are: an insulin-like action causing increased fat deposition in the initial stages of treatment resulting in glucose tolerance and an increase in insulin sensitivity, edema caused by sodium retention, subclinical hypothyroidism, reduced adiponectin and increased appetite connected with mood improvement (Garland et al., 1988, Gracious and Meyer, 2005,Teixeira et al., 2006, McKnight et al., 2012, Medici et al. 2016). It has also been noted that weight gain caused by lithium occurs even in the presence of high leptin levels and as a result, it has been proposed that mood stabilizers could reduce hypothalamus sensitivity to the action of leptin (Wirshing, 2004; Holt, Peveler & Byrne, 2004; Zimmermann et al., 2003).
The increase in weight caused by lithium is variable ranging from 4 to 12kg (Chengappa et al., 2002). Garland et al. reported that during chronic treatment, there was an increase of 10kg in 20% of the patients while during a small eight-week study by Atmaca et al. a mean weight gain of 5.9kg was found. Gracious and Meyer suggested that risks for weight gain included female gender, nephrogenic diabetes insipidus, history of obesity and combination with antipsychotic drugs.

Regarding valproic acid-induced weight gain, the mechanism of its effect in the hypothalamus is poorly understood and it is suggested that it could enhance secretion of insulin from pancreatic beta cells and reduce insulin clearance by the liver resulting in hyperinsulinemia which leads to weight gain (Pylvanen et al., 2006, Verrotti et al., 2011). Another mechanism suggested by Qiao et ali, is the down-regulation of adiponectin gene transcript levels in adipocytes. The study of Gracious and Meyer noticed that 57% of adults treated with valproic acid gained more than 4kg while the rest remained in a stable weight. Medici et al. mentioned that the increase in weight by valproic acid is dose-related and the maximum increase is observed at 6 months of therapy.

Antidepressants	Relative incidence	Antipsychotics	Relative incidence	Mood stabilizers	Relative incidence
Amitriptyline	+++	Aripiprazole	+	Carbamazepine	+
Bupropion	+/-	Asenapine	+	Lamotrigine	+
Citalopram	+	Chlorpromazine	++	Lithium	++
Duloxetine	+	Clozapine	+++	Valproate	++
Escitalopram	+	Haloperidol	+
Fluoxetine	+	Olanzapine	+++
Mirtazapine	+++	Risperidone	++
Paroxetine	++	Quetiapine	++
Sertraline	+	Ziprasidone	+
Venlafaxine	+

Table 5: The relative incidence of weight gain with selected psychotropic medication, antidepressants, antipsychotics and mood stabilizers (adapted fromWhite et al., 2013).

Conclusion

The present study aimed to investigate the relationship between metabolic abnormalities and psychiatric disorders analyzing the similarities in their biological pathways. In conclusion, several research data indicates the impact of certain risk factors, such as genetic, psychological, environmental and lifestyle factors in abnormalities which are finally expressed as metabolic syndrome.

As it has been studied, the relation between mood disorders and obesity is indeed bidirectional as obesity could cause mood disorders and mood disorders and its pharmacological treatment could cause weight gain and metabolic syndrome.

Certain abnormalities, such as the stress or the dysregulation of HPA axis, the dyslipidemia, the abnormalities on leptin, insulin and cortisol levels, the insulin resistance, the impaired glucose control and glucose disturbances, the adipokines and the broken mechanism of leptin, the higher levels of pro- inflammatory markers, are involved in the process of obesity and metabolic syndrome development which are present in patients with mood disorders. It is remarkable that these patients have twice higher odds to develop obesity (Stubbs et al., 2015).

Finally, drugs such as antidepressants, antipsychotics, and mood stabilizers are strongly associated with weight gain and metabolic syndrome. The following table summarizes the risk of mood disorders medication regarding weight gain, obesity, and development of metabolic syndrome. As it can be seen, amitriptyline, mirtazapine, clozapine and olanzapine (as depression and schizophrenia treatment) are the most inculpatory for weight gain, while mood stabilizers constitute a moderate risk for obesity

(White et al., 2013; Serretti & Mandelli, 2010; Torrent et al., 2010; Muench & Hamer, 2010).

Dopamine-2 receptor antagonism may be a common factor in antipsychotic-induced weight gain (Balt et al., 2011). The interactions of histamine-1, serotonin-2C and muscarinic cholinergic receptors seem to be related to weight gain at antidepressants use. Paroxetine constitutes the most commonly associated with weight gain agent by the selective serotonin reuptake inhibitors (Serretti & Mandelli, 2010). Finally, as lithium is associated with hypothyroidism it seems to result in obesity development by the slowed metabolic rate (McKnight et al., 2012).

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