Pharmacological Interventions

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When nonpharmacological interventions fail to control weight gain, and when switching to another antipsychotic has been unsuccessful or is not possible, adjunctive pharmacotherapy may be considered. Drugs that are currently approved by the FDA for the treatment of obesity include orlistat and sibutramine, both of which should be used cautiously with psychotropic medications. These medications should be used only in combination with appropriate diet, exercise, and behavioral programs.

Orlistat is an enteric inhibitor of pancreatic lipase, thus lowering the absorption of dietary fat. Adverse effects include flatulence and steatorrhea if too much fat is consumed. Orlistat was tested for 16 weeks in a randomized, double-blind, placebo-controlled clinical trial in overweight or obese patients treated with clozapine or olan-zapine (n = 63, diagnosis not reported) [68]. Adherence to a behavioral program or diet was not required to participate in the study. No statistically significant effect was observed in the whole population, but male patients experienced modest weight loss (-2.36 vs. +0.62 kg on placebo). Weight loss of at least 5% of baseline was observed in 16% of the patients receiving adjunctive orlistat versus 6% receiving placebo (NNT 11, not statistically significant). All 4 patients who discontinued because of diarrhea were receiving orlistat. There is a report that orlistat did not alter bioavailability of haloperidol, clozapine, clomipramine, desipramine, or carbamazepine in 8 patients, however the authors noted the possibility of decreased absorption of concomitantly administered drugs in some individuals, and recommended plasma level monitoring [69].

Sibutramine affects the reuptake of norepinephrine, serotonin and dopamine, and was originally thought to be a potential antidepressant compound, but was ultimately commercialized as a weight loss agent. Sibutramine was tested in a 12-week doubleblind, randomized, placebo-controlled study in 37 overweight and obese subjects taking olanzapine for schizophrenia or schizoaffective disorder [70]. For the first 8 weeks all subjects participated in weekly group sessions focused on nutrition and behavioral modification. Although the sibutramine group exhibited a mean increase in systolic blood pressure of 2.1 mm Hg, and presented with a higher rate of anticholinergic side effects and sleep disturbances, greater weight loss was observed at week 12 versus placebo (-3.8 vs. -0.8 kg). A similarly designed study with clozapine conducted among 21 patients by the same research group failed to demonstrate a therapeutic advantage for adjunctive sibutramine [71]. Because sibutramine affects serotonin and norepinephrine reuptake, these two studies [70, 71] excluded patients who received tricyclic, selective serotonin reuptake inhibitor, or monoamine oxidase inhibitor antidepressants in the prior month. When compared with adjunctive topiramate in a 24-week randomized open-label clinical trial, adjunctive sibutramine resulted in similar amounts of weight loss as adjunctive topiramate [72], but generalizability of that study to schizophrenia is limited as the subjects had bipolar disorder and only 35% were receiving antipsychotic medication.

Rimonabant is a cannabinoid antagonist that acts to control appetite and can lead to weight reduction. The proposed indication was to be weight management in people with a BMI of 30, or with a BMI of 27 and at least one comorbid medical condition. However, the manufacturer withdrew its application to sell this agent in the USA amid concerns that it may increase suicidal thinking and depression [73]. There are no published reports of its use in patients with schizophrenia receiving antipsychotics.

Several attempts have been made in managing weight gain with adjunctive therapy utilizing non-FDA approved uses of several classes of medications, including oral hypoglycemics (metformin), anticonvulsants (topiramate), histamine H-2 receptor antagonists (nizatidine, famotidine), antiparkinsonian and antiviral agents (amantadine), antidepressants (reboxetine, fluoxetine, fluvoxamine), and others [74, 75]. However, few randomized clinical trials exist that test these agents among overweight or obese patients with schizophrenia. Approaches include the prevention of excessive weight gain when starting an antipsychotic, or the loss of weight already gained after receiving an antipsychotic for some time. Most of the studies enrolled small numbers of subjects and have mainly focused on ameliorating the weight gain observed with olanzapine. The randomized double-blind studies of these adjunctive agents [76-101] are summarized in table 4. Results are generally inconsistent. Many interventions as tested do not show a clinically significant benefit. Moreover, all adjunctive

Table 4. Double-blind, randomized, clinical trials for non-FDA-approved adjunctive pharmacological interventions for weight gain among patients with schizophrenia

Author

Study medication (dose or dose range, with reported frequency)

Antipsychotic received Study length (and other qualifications) weeks

n

Helpful? Weight change observed in intervention group (vs. control group)

Graham [77]

amantadine (up to 300 mg/day)

olanzapine (and weight gain of at least 5 lb)

12

21

yes

BMI -0.07 (vs. +1.24)

Deberdt [78]

amantadine (100-300 mg/day)

olanzapine (and weight gain of at least 5%)

16 (24)

125

maybe

-0.19 kg (vs. +1.28 kg) but results at 24 weeks were not statistically significantly different

Cavazzoni [79]

nizatidine (150 mg b.i.d. or 300 mg b.i.d.)

olanzapine (newly started)

16

175

no

difference was not statistically significant at 16 weeks

Atmaca [80]

nizatidine (150 mg b.i.d.)

olanzapine (and weight gain in the range of 2.6-10.8 kg)

8

35

yes

-4.5 kg (vs. +2.3 kg)

Atmaca [81]

nizatidine (150 mg b.i.d.)

quetiapine (and weight gain in the range of 2.3-7.2 kg)

8

28

no

difference was not statistically significant

Assunçao [82]

nizatidine (300 mg BID)

olanzapine (and weight gain of at least 5% from baseline)

12

54

no

difference was not statistically significant

Poyurovsky [83]

famotidine (40 mg/day)

olanzapine (first-episode patients)

6

14

no

difference was not statistically significant

Baptista [76]

metformin (850 mg/day

- 10 mg b.i.d.)

olanzapine

12

28

no

difference was not statistically significant

Wu [88]

metformin (250 mg t.i.d.)

olanzapine (drug-naïve first-episode patients)

12

40

yes

+ 1.9 kg (vs. +6.87 kg); number experiencing weight gain greater than 7% was 16.7% (vs. 63.2%)

Wu [89]

metformin (250 mg t.i.d.) and/or lifestyle intervention

clozapine, olanzapine, risperidone, sulpiride (and weight gain of more than 10%)

12

128

yes

lifestyle-plus-metformin group BMI -1.8 (vs. metformin-alone group -1.2 vs. lifestyle-plus-placebo group -0.5 vs. placebo group + 1.2)

Author

Study medication (dose or dose range, with reported frequency)

Antipsychotic received Study length (and other qualifications) weeks

n

Helpful? Weight change observed in intervention group (vs. control group)

Klein [90]

metformin (500 mg/day - 850 mg b.i.d.)

olanzapine, risperidone, or quetiapine (and weight gain of more than 10%; children ages 10-17 years)

16

B9

yes

stable weight (vs. +0.31 kg/week)

Baptista [91]

metformin (850-1,700 mg/day)

olanzapine

14

40

no

difference was not statistically significant

Baptista [92]

metformin (850-2,550 mg/day)

olanzapine

12

80

no

difference was not statistically significant

(50 mg b.i.d. or 100 mg b.i.d.)

risperidone, olanzapine, quetiapine, or clozapine (and BMI of at least 25)

12

66

yes

-5.35 kg for topiramate 200 mg/ day (vs. -1.68 kg for topiramate 100 mg/ day vs. -0.3 kg for placebo)

Kim [85]a

topiramate (50 mg b.i.d.)

olanzapine

12

60

yes

+2.66 kg (vs. +4.02 kg)

Nickel [86] Egger [87]

topiramate (250 mg/day)

olanzapine (only women who had gained at least 5 kg; psychosis or bipolar)

10

43

yes

-4.4 kg (vs. +1.2 kg); at the end of an open-label 18 month observation period, -9.4 kg (vs. +5.5 kg)

McElroy [72]a

topiramate (25-600 mg/day) or sibutramine (5-15 mg/day)

various (bipolar patients, of which only 16 were receiving antipsychotics, and BMI of at least 30, or at least 27 kg/m2 with concomitant obesity-related risk factors or diseases)

24

46

maybe

patients randomized either to sibutramine or topiramate lost comparable amounts of weight (4.1 and 2.8 kg, respectively)

Poyurovsky [98]

reboxetine (2 mg b.i.d.)

olanzapine (first-episode patients)

6

60

yes

+3.31 kg (vs. +4.91 kg); number experiencing weight gain greater than 7% was 19.4% (vs. 46.4%)

Author

Study medication (dose or dose range, with reported frequency)

Antipsychotic received Study length (and other qualifications) weeks

n

Helpful? Weight change observed in intervention group (vs. control group)

Poyurovsky [97]

reboxetine (2 mg b.i.d.)

olanzapine (first-episode patients)

6

26

yes

+2.5 kg (vs. +5.5 kg); number experiencing weight gain greater than 7% was 20% (vs. 70%)

Poyurovsky [94]

fluoxetine (20 mg/day)

olanzapine (first-episode patients)

8

30

no

difference was not statistically significant

Bustillo [95]

fluoxetine (20-60 mg/day)

olanzapine (and gained at least 3% of weight)

16

30

no

+3 kg (vs. +1.7 kg)

Lu [96]a

fluvoxamine (50 mg/day)

clozapine (250 mg/day or less or 600 mg/d or less)

12

68

maybe

+0.9 kg (vs. +3.2 kg)

Borovicka [93]

phenylpropanolamine (75 mg/day)

clozapine (and weight gain of more than 10%)

12

16

no

difference was not statistically significant

Goodall [99]

fenfluramine (15 mg b.i.d.)

depot fluphenazine, flupenthixol, or clopenthixol (and BMI of at least)

12

29

maybe

rate of weight loss was significantly greater in those taking

D-fenfluramine among the completers

Modell [100]

dextroamphetamine (5 mg/day)

thioridazine, chlorpromazine

8

20

no

+0.11 kg/week (vs. +0.01 kg/week)

Ding [101]

ling gui zhu gan tang mixture

clozapine, chlorpromazine, perphenazine, risperidone, sulpiride, trifluoperazine (and body weight exceeding 20% of standard)

8

100

yes

-4.5 kg (vs. +5.0 kg)

a Although randomized, this study was not double-blind.

a Although randomized, this study was not double-blind.

medications may pose a tolerability problem for some patients, for example topiramate may be associated with cognitive dulling which can complicate the successful treatment of a patient with schizophrenia who may already be experiencing cognitive dysfunction [102]. Adjunctive reboxetine may be useful in preventing weight gain in first-episode patients [97, 98], but is currently not available in the USA. There are some non-Western treatments that may be helpful [101]. The adjunctive agent that holds the most promise, at least for persons early on in their illness, is adjunctive metformin [88-92].

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