Weight gain is a major problem that contributes to patient noncompliance with psychotropic regimens, may lead to symptomatic relapse, and contributes to medical comorbidity, and currently prescribed psychotropics may cause 2–17 kg of weight gain over the course of clinical treatment [1,2]. The antipsychotics, mood stabilizers [3–5], and antidepressants  are all known to cause weight gain. Comparatively, there are only a very few psychotropics associated with weight loss [7–9]. This article is not intended to be an exhaustive review, but a brief introduction and overview in regard to the prevalence, etiology, and treatment of psychotropic-induced, iatrogenic weight gain and obesity. This manuscript should give the reader a sense of the agents involved and provide clinical application for use in psychopharmacological practice.
Cause of Weight Gain
This section will attempt to briefly review the possible causes of iatrogenic weight gain.
Gothelf et al.  studied weight gain mechanisms and energy balance in olanzapine-treated patients and found that an increase in body mass index (BMI) was due to an increase in calorie intake, but also revealed effects on the resting energy expenditure or slowing of metabolism. The simplest explanation for this antipsychotic-induced weight gain is that olanzapine increased appetite and caloric intake while slowing the basal metabolic rate.
Psychotropics have broad pharmacodynamic profiles, and it is likely that multiple neurotransmitters, receptors, and neurocircuits are responsible for drug-induced weight gain. Olanzapine has activity at several different receptor sites . Others, like clozapine, may act at even different receptors (i.e., sigma-opiod receptors) effecting weight gain . Research suggests that serotonin 5-hydroxytryptamine 2C (5-HT2C) receptors play a role in regulating appetite. In rats, activating these receptors decreases eating behavior and mice lacking in 5-HT2C (deactivated) receptors become obese . Atypical antipsychotics often block this receptor functionally, which may cause an increase in eating and caloric intake. Many of the antipsychotics (olanzapine, quetiapine, clozapine) and some antidepressants (mirtazapine) have this 5-HT2C blocking property. Beta-3 adrenergic receptors found in adipose tissues play an active role in weight control by converting fat into energy especially in response to norepinepherine . Clinically there are no data to suggest effects on weight gain with alpha-adrenoceptor antagonists but it is noted that psychotropics with higher affinities (i.e., TCA) for these are associated with weight gain whereas those with low affinities for these receptors(e.g., SSRI) are not . The exact role of histamine-1 receptors in appetite control is not known. However, psychotropics with greater ability to block H-1 receptors often show greater weight gain potential  possibly through deactivating brain satiety centers and increasing hunger. Another mechanism may be related to blockage of anticholinergic sites, all of which are related to appetite stimulation.
Treatment Weight Gain
Early intervention is the key to preventing significant drug-related weight gain. Patients should be told about weight gain as a potential adverse effect before they begin treatment and their weight should be monitored routinely as a standard of care, as long as they continue taking drugs that may increase weight. Informed consent about this risk should be the standard of care. Routine blood monitoring for hyperlipidemia, hyperglucosemia, hypertension, and abdominal girth should occur. Metabolic syndrome is now a well-documented effect of second-generation antipsychotic use. Ideally, a diet and exercise plan should be initiated to prevent or treat weight gain before medically significant weight gain occurs . A successful weight loss program is one which can produce a loss of 0.5–1% of the patient's initial body weight per week, a rate of loss considered safe and acceptable . Diet and exercise produces maximal benefit, but require considerable commitment and motivation on the part of the patient. This is often difficult or impossible in the mentally ill.
Besides diet and exercise, formal behavior modification techniques involve changing eating habits and reinforcing desired dieting behavior. It is the gradual but consistent change in behavior that leads to healthier eating habits and weight loss. Simple use of “portion control” behaviors can teach patients to eat less at every meal without the complexity of counting fat versus carbohydrate calories and does not require the willpower to follow a bland low-salt, low-fat, and low-sugar diet . Behavior modification alone can generate a weight loss of 0.5–0.7 kg per week . Through formal cognitive therapy patients can achieve satisfaction with body image and acceptance of modest weight loss. In one study, the effects of cognitive-behavioral therapy on weight gain due to psychotropics were studied in six schizophrenics (mean age 37.3 years). The mean BMI (kg/m2) decreased from 29.6 kg to 25.1 kg in the post-treatment group .
Generally, drug therapy informed consent, active monitoring of weight and early intervention or even prophlyaxis with diet and exercise are the first treatment options. If this fails, or the patient is too ill to comply, then clinical practice suggests that antiobesity drugs may be appropriate. Risks and benefits should be evaluated for each antiobesity agent. Sometimes, prior to trying an antiobesity medication, one may choose to switch the current psychotropic medication to one with same indication but less weight gain potential.
Drugs that reduce caloric intake, suppress hunger, are commonly known as anorectic agents or appetite suppressants. They act centrally by decreasing appetite or increasing satiety. Sympathomimetic agents include phendimetrazine, phentermine, mazindol, diethylpropion (many are controlled substances), amphetamine-related compounds, and phenylpropanolamine. The amphetamine products are used on label for the treatment of sleep apnea, narcolepsy, and attention deficit/hyperactivity disorders. When these conditions are comorbid with other primary psychiatric disorders a weight loss advantage is often clinically noted. Serotonergic agents, fenfluramine and dexfenfluramine, were withdrawn from the US market in September 1997 over concerns about valvular heart disease .
The three most currently prescribed drugs that are FDA approved to treat obesity likely are phentermine, sibutramine, and orlistat. Drugs approved for treating obesity usually result in an additional weight loss of approximately 2–5 kg over placebo. At least four other types of single-agent weight loss drugs are in possible late-stage development:  selective central cannabinoid-1 receptor blockers,  selective central 5-HT2C serotonin receptor agonists,  an intestinal lipase blocker, and  central-acting incretin mimetic drugs . Furthermore, other agents under development that may produce beneficial changes in appetite expression in the obese include glucagon-like peptide-1 analogs such as liraglutide, an amylin analog davalintide, the 5-HT2C receptor agonist lorcaserin, the monoamine reuptake inhibitor tesofensine, and a number of combination therapies such as pramlintide and metreleptin, bupropion and naltrexone, phentermine and topiramate, and bupropion and zonisamide . Psychiatrists will recognize some of the above agents as they are FDA approved for other indications but are well known to cause weight loss as an adverse effect.
As an example, in one study, following a 1-week placebo lead-in, 244 obese or overweight, nondiabetic subjects received placebo subcutaneously (sc) t.i.d., pramlintide sc (120 microg t.i.d.), pramlintide sc (120 microg t.i.d.) + oral sibutramine (10 mg q.a.m.), or pramlintide sc (120 microg t.i.d.) + oral phentermine (37.5 mg q.a.m.) for 24 weeks. Weight loss achieved at week 24 with either combination treatment was greater than with pramlintide alone or placebo . As weight gain is often substantial with psychotropics, combined antiobesity therapy in clinical practice is frequently needed. Psychiatrists are often clinically savvy using rational polypharmacy to achieve remission of the psychiatric disorder at hand, and perhaps may consider polypharmacy in severe cases of psychotropic drug-induced obesity.
Single sympathomimetic amphetamine agents because of their high potential for abuse, cardiac and psychiatric side effects, are generally not often recommended for treating obesity . Sibutramine is a nonaddictive, mixed serotonergic, and noradrenergic reuptake inhibitor, which recently is being evaluated by the FDA due to cardiac safety concerns. It helps patients achieve a 10–15% loss of body weight [87–90]. The safety and effectiveness beyond 1 year of use have not been determined. The mechanism by which sibutramine acts is increased satiety. It decreases the levels of triglycerides, total cholesterol and LDL cholesterol, while also increasing the levels of HDL cholesterol (seen in people who lose > 5% of body weight). Sibutramine can increase blood pressure and heart rate. Other common adverse effects of sibutramine are dry mouth, anorexia, insomnia, irritability, and constipation. These studies were conducted in obese individuals who were not taking psychotropics, so outcome may not be generalizable to the mentally ill. This agent when combined with other antidepressants may lead to serotonin syndrome and is often avoided or contraindicated.
Orlistat, a fat or lipase blocker, shows safety and efficacy for up to 2 years. Orlistat may be a better option than sibutramine for patients already taking other drugs because it does not act systemically, so there is less risk of interaction with centrally acting medications. Specifically, it inhibits gastric and pancreatic lipases by binding covalently to the serine residue at the active site of these enzymes . This allows fat not to be absorbed by the GI system when taken with meals [92–94]. It decreases triglycerides, total cholesterol, and low-density lipoprotein cholesterol while increasing high-density lipoprotein cholesterol . The drug also improves glycemic control . The most common adverse effects are gastrointestinal: including increased defecation, soft stools, fatty or oily stools, and vitamin A and E deficiency [93,94]. Patients take orlistat 120 mg three times daily and must take a multivitamin to avoid deficiencies.
Two large placebo-controlled trials [95,96] document the efficacy of orlistat use for up to 2 years. After 1 year, the orlistat group lost 10.2% of body weight in one study and 8.8% in the second study. After 2 years, twice as many patients taking orlistat maintained a weight loss of more than 10%. Patients must take other medications 1 h pre- or postorlistat to avoid change in absorption of these medications . One study in the mentally ill reported that 13 consecutive patients with psychotropic induced weight gain lost 34.6% of side effect weight gained . Nine of the 13 subjects suffered from major depressive disorder and were taking serotonergic antidepressants. Patients were deemed obese with a BMI of > 30 kg/m2. The average weight gained from psychotropics prior to orlistat initiation was 16.4 kg. The average weight loss within this relatively short time period was 5.6 kg, or 34.6% of the weight gained as a result of psychotropic drug use.
Amantadine has also been studied  in 12 patients who had already gained a mean of 7.3 kg during olanzapine treatment. Subjects were started on amantadine at 300 mg per day. Results of the study showed an average weight loss of 3.5 kg over 3–6 months. No adverse effects were reported. Nizatidine, a histamine-2 receptor antagonist was studied in a 16-week, randomized, double-blind, placebo-controlled study. Dosed at 300 mg twice per day, it allowed patients to gain an average of 2.5 kg compared with the 5.5 kg gained by patients treated without nizatidine . Naltrexone, an opioid antagonist, at a dosage of 50 mg/day, has been shown to decrease weight by reversing the observed hunger and craving for sweet, fatty foods caused by TCAs and lithium. Subjects reported decreased enjoyment ratings of food and also diminished subjective feelings of hunger. No adverse effects of opioid antagonism were seen regarding depressive symptoms. In another study, naltrexone was coadministered with antidepressants to eight female patients who had already gained greater than 6 kg. After 8 weeks, the results of the study showed that weight gain reversed in five patients, stopped in two patients and attenuated in one patient. However, weight increased again by 1.5+/−2.7 kg within 14 weeks after the drug was stopped. Of note, the mean weight loss was small compared to previous drug-induced weight gain .
Preliminary findings suggest that topiramate may serve as a dual purpose agent in the treatment of obese patients with affective disorders. In one case report , topiramate was administered to a 29-year-old male schizophrenic who had gained weight due to clozapine. Results showed a sustained weight loss for the first time with an improvement of psychotic symptoms. Additionally, topiramate add-on studies for bipolar disorder have shown 33–55% of patients losing weight ([10–15] lbs) [103,104]. Side effects of fatigue, cognitive dulling, ataxia, glaucoma, oligohydrosis, and acidosis are reported at doses of 100–400 mg/day.
Metformin holds promise as a treatment for weight gain in patients taking psychotropic medications. In a 12-week open-label study  conducted on 19 patients (aged 10–18 years) who had gained over 10% of their baseline weight on antipsychotics, 500 mg three times a day of metformin was given for 12 weeks in addition to psychotropic drugs. The results of the study showed 15 patients lost weight, 3 gained weight, and for 1 weight remained unchanged. Sporadic diarrhea was noted in some patients that resolved with time. The results of the safety tests for lactic acidosis were unremarkable. A recent controlled study by the same group confirmed this open label finding . In a recent review, among 15 different pharmacologic strategies (N = 35, n = 1629), only metformin, fenfluramine, sibutramine, topiramate, and reboxetine were more effective than placebo, with the most evidence being available for metformin, and no head-to-head trials comparing individual pharmacologic interventions .