Potential weight loss strategies are outlined in . Early intervention is the key to preventing significant drug-related weight gain. Patients should be educated 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 and vital sign monitoring for detection of increases in blood sugars, serum lipids, blood pressure, and abdominal girth would be helpful and clinically warranted [72
Weight gain treatment options.
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 [73
]. A successful weight loss program is one which can produce a loss of 0.5 to 1
lb of the patient's initial body weight per week, a rate of loss considered safe and acceptable [74
]. Diet and exercise produces maximal benefit, but requires considerable commitment and motivation on the part of the patient. This is often difficult or impossible in the mentally ill.
Case 1: Part 2
HA had been given informed consent prior to starting her serotonergic antidepressants about the potential for weight gain and was advised to consider prophylactically increasing her current low level exercise regimen, to watch caloric intake, and to weigh herself with directions to notify the clinician if she experienced a consistent gain of 2.5 or more kilograms. After mild initial weight gain, dieting by portion control methods was discussed. After a more remarkable weight gain was noted with the second generation antipsychotic, she was offered off-label use of chromium picolinate, or metformin, or approved use of orlistat. The patient felt chromium picolinate had the most favorable risk profile and tried 1000
mcg daily without weight improvement. At a subsequent visit she was placed on metformin. (These interventions are discussed later in this paper).
AB is a 30-year-old female with depression, anxiety, and substance use disorder. Despite gaining sobriety, she still suffered depressive symptoms and failed to respond to initial SSRI (fluoxetine) and SNRI (duloxetine) therapy. She was placed on the second generation antipsychotic, quetiapine, with moderate symptom reduction but began to gain weight (3–5
kg) and asked for other treatment options. She was cross-titrated onto aripiprazole with an acceptable weight loss as a result and continued symptom reduction.
Besides diet and exercise, formal behavior modification techniques involve changing eating habits and reinforcing desired weight controlling behavior. It is the gradual but consistent change in behavior that leads to healthier eating habits. 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, low-sugar diet [75
]. Behavior modification alone can generate a weight loss of 0.5
kg to 0.7
kg per week [76
]. Through formal, manualized cognitive-behavioral 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 was studied in 6 schizophrenia patients (mean age 37.3 years). The mean BMI (kg/m2
) decreased from 29.6
kg to 25.1
kg in the posttreatment group [77
]. Cognitive therapy has been helpful in reducing weight for children and adolescents [78
]. Furthermore, the addition of cognitive therapy to a diet-controlled method produces better results [79
Generally, drug therapy with specific metabolic 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 the same indication but less weight gain potential as noted in the case above. The risks and benefits of changing an effective medication should be adequately considered before making changes.
Chromium compounds were utilized in a case above and have been used over the counter to facilitate weight loss, although the evidence for its efficacy is lacking so far [80
]. However, chromium picolinate has reasonable data in regards to improving insulin sensitivity in diabetics and has been shown to help curb carbohydrate cravings in depressed patients despite continued depressive symptoms when dosed 600
Drugs that reduce caloric intake or 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 and 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. Of note, however, the serotonergic agents, fenfluramine and dexfenfluramine were withdrawn from the US market in September 1997 over concerns about valvular heart disease [84
The three most currently prescribed drugs that are FDA approved to treat obesity 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: (1) selective central cannabinoid-1 receptor blockers, (2) selective central 5-hydroxytryptamine 2C serotonin receptor agonists, (3) an intestinal lipase blocker, and (4) central-acting incretin mimetic drugs [85
]. 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-HT(2C)
receptor agonist lorcaserin, the monoamine re-uptake inhibitor tesofensine, and a number of combination therapies such as pramlintide and metreleptin, bupropion and naltrexone, phentermine and topiramate, and bupropion and zonisamide [86
]. For example, lorcaserin is a selective agonist of the 5-HT2C
serotonin receptor. Its shared mechanism of action with fenfluramine suggests that a lorcaserin-phentermine combination therapy may be particularly effective for treatment of obesity. The combination of naltrexone and bupropion has recently been examined in a large phase 3 trial for the treatment of obesity. This study demonstrated that one year of treatment with this two-drug combination produced an approximate 4% weight loss beyond that seen with placebo therapy, similar to that seen with other pharmacologic therapies. Because of the distinct mechanism of action of these two medications, naltrexone-bupropion may prove to be an attractive option for patients who are resistant to other agents. Several clinicians have noted that the combination of phentermine and topiramate can generate substantial weight loss in at least a subset of patients who exhibit little weight loss when treated with phentermine alone. These observations led to the development of fixed dose combinations of phentermine and topiramate. A large, phase 3 clinical trial has shown that one year of treatment with this combination led to weight loss of up to 9% beyond that seen with placebo therapy. There have been no head-to-head comparisons, however, and further studies will be needed to determine the relative effectiveness of these various treatments. It is noteworthy that the doses of each agent used in the phentermine topiramate combination studied were lower than the typical doses used for monotherapy with each drug [87
]. 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 (120μ
g t.i.d.), pramlintide sc (120μ
g t.i.d.) + oral sibutramine (10
mg q.a.m.), or pramlintide sc (120μ
g 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 [88
]. 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. Although risk benefits ratio for the use of single or multiple antiobesity agents needs to be determined on a case by case basis before the initiation of these therapies. Sometimes clinicians can “chase their tails” by adding anti-side-effect medications to a patient's regimen. Sometimes the anti-side-effect medications have side effects themselves that must be treated, and so on. Clinicians must make critical, Hippocratic decisions when it comes to this complex clinical polypharmacy decision.
Single sympathomimetic amphetamine agents, because of their high potential for abuse, cardiac, and psychiatric side effects (anxiety induction, insomnia), are generally not often recommended for treating obesity [84
]. Sibutramine is however relatively safer, as it is a mixed serotonergic and noradrenergic reuptake inhibitor. It helps patients achieve a 10% to 15% loss of body weight [89
]. 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 the 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.
Case 2: Part 2
SK had only a partial improvement on the MAOI treatment, and subsequently, it was stopped but her weight gain was not alleviated. She was ultimately treated with a complex polypharmacy antidepressant regimen with near remission of her symptoms. Similar to Case 1, she was given metformin and orlistat with gradual, but not complete weight loss. To gain final remission of depression symptoms she was placed on a stimulant (methylphenidate) medication which was titrated to a moderate dose. Her depression resolved and she continued to lose weight to her baseline level.
Orlistat, a fat or lipase blocker, has safety and efficacy data for use, up to two 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 [89
]. This allows fat not to be absorbed by the GI system when taken with meals [90
]. It decreases triglycerides, total cholesterol, and low-density lipoprotein cholesterol while increasing high-density lipoprotein cholesterol [93
]. The drug also improves glycemic control [94
]. The most common adverse effects are gastrointestinal, including increased defecation, soft stools, anal leakage, fatty or oily stools, and vitamin A and E deficiencies [95
]. Patients take orlistat 120
mg three times daily and must take a multivitamin to avoid deficiencies and eat a low-fat diet.
Two large placebo-controlled trials [97
] document the efficacy of orlistat use for up to two years. After one 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 one hour before or after orlistat to avoid change in absorption [99
]. One study in the mentally ill reported that 13 consecutive patients with psychotropic-induced weight gain lost 34.6% of side effect weight gained [100
]. Nine of the 13 subjects suffered from major depressive disorder and were taking serotonergic antidepressants. Patients were deemed obese with a body mass index (BMI) of >30
. The average weight gain 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 was studied [101
] in twelve 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. Implementation of nizatidine (histamine-2 receptor antagonist) was studied in a 16-week, randomized, double-blind, placebo-controlled study in schizophrenia patients. 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 [102
]. 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 tricyclic antidepressants 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 more than 6
kg. After eight weeks, weight gain was reversed in five patients, stopped in two patients, and attenuated in another. However, weight increased 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 [103
], topiramate was administered to a 29-year-old male schizophrenic patient 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
]. Side effects of fatigue, cognitive dulling, ataxia, glaucoma, oligohydrosis, and acidosis are reported at doses of 100–400
mg/day. A recent review of studies using metformin and topiramate has shown more efficacy and fewer side effects with metformin [106
Metformin holds promise as a treatment for weight gain in pediatric patients taking psychotropic medications. In a 12-week open label study [107
] conducted on 19 patients (aged 10–18 years) who had gained over 10% of their baseline weight while on antipsychotics, 500
mg three times a day of metformin was given for 12 weeks in addition to psychotropics. The results of the study showed 15 patients lost weight, 3 gained weight, and one remained unchanged in weight. 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 [108