Weight gain associated with some of the atypical antipsychotics has emerged as a major clinical problem during the treatment of some patients (Sussman, 2001). Weight gain may lead to medical problems such as type 2 diabetes mellitus, coronary artery disease and sleep apnea, as well as noncompliance. Drugs such as chlorpromazine(Drug information on chlorpromazine) (Thorazine), clozapine, olanzapine(Drug information on olanzapine) (Zyprexa), risperidone(Drug information on risperidone) and thioridazine(Drug information on thioridazine) have been associated with significant weight gain, while others, such as molindone(Drug information on molindone) (Moban) and ziprasidone(Drug information on ziprasidone) (Geodon), have not. Some of the antipsychotics may even be associated with elevated levels of insulin and blood lipids (e.g., olanzapine [Melkersson et al., 2000]), while others may have a lowering effect on serum lipids and/or no effect on glucose levels (e.g., ziprasidone [Kingsbury et al., 2001]).Managing Side Effects Management of both SD and weight gain associated with psychotropic drugs can be a challenging clinical problem. For both of these issues, the initial or baseline assessment is an essential and extremely important part of their management. General management strategies for handling side effects of psychotropic drugs include (Balon, 1999):
- Waiting for spontaneous remission or improvement.
- Reducing doses to the minimal effective level. Pollack and Rosenbaum (1987) suggested that, after the patient achieves a satisfactory and stable clinical response, one should embark on a systematic but gradual effort to determine the lowest effective dose, as side effects are usually dose-dependent. However, balancing the minimal effective dose and a subtherapeutic dose can be difficult. In addition, studies from University of Pittsburgh (Frank et al., 1990; Kupfer et al., 1992) indicate that maintenance therapy for depression should be done with a full-dose antidepressant; thus, decreasing the dose may not always be an option.
- Using once-daily, preferably nighttime, dosing.
- Using secondary pharmacological agents or "antidotes." This strategy has been used to manage various side effects, such as extrapyramidal symptoms (benztropine [Cogentin], amantadine(Drug information on amantadine) [Symmetrel]), sexual dysfunction (stimulants, yohimbine [Yocon, Dayto Himbin, Yohimex], cyproheptadine(Drug information on cyproheptadine) [Periactin]), anticholinergic (bethanechol [Duvoid, Urecholine]) and orthostatic hypotension (fludrocortisone [Florinef]).
- Employing medication holidays. This strategy has been used in children treated with psychostimulants and in patients with sexual side effects associated with SSRIs (Rothschild, 1995). However, using drug holidays in patients treated with antidepressants requires caution, as withdrawal may occur. This approach may also actually encourage treatment nonadherence, and its long-term effects are unknown.
- Switching to another drug with a more favorable side-effect profile. This approach could be used for switching an oversedated patient to a less sedating drug or switching a patient with sexual dysfunction to a drug not associated with sexual dysfunction (e.g., from an SSRI to bupropion, mirtazapine(Drug information on mirtazapine) or nefazodone(Drug information on nefazodone)).
These strategies are not always applicable to the management of SD or weight gain associated with all psychotropic medication. In the case of SD, some management strategies are more popular than others. Waiting for spontaneous remission could be difficult, as it takes time and does not occur very frequently (Ashton and Rosen, 1998). Decreasing the dose might be helpful, as SD seems to be dose dependent. However, the symptoms of the treated illness (e.g., depression) may reemerge. Once-daily dosing, with sexual activity scheduled just prior to the daily dose, may work occasionally. Drug holidays could be effective with short half-life drugs, but not with longer half-life drugs such as fluoxetine(Drug information on fluoxetine). In addition, discontinuation symptoms may occur during the drug holiday, and long-term consequences are unknown. Thus, switching to a drug with a lower incidence of SD (antidepressants such as bupropion, mirtazapine and nefazodone) or using an antidote, such as amantadine, bupropion, buspirone (BuSpar), cyproheptadine, yohimbine, stimulants and others, are the most useful and popular strategies. However, solid data from well-designed studies on the use of antidotes are lacking. Antidotes do not work in everybody and may have their own specific problems (e.g., sedation with cyproheptadine or anxiety with yohimbine). Rothschild (2000) suggested that the potential impact on sexual functioning should be a factor in selecting the antidepressant therapy in the first place.
Most of the general strategies may not be applicable for the management of antipsychotic-associated SD. Spontaneous remission can take a very long time -- up to 18 weeks (Segraves, 1999a). Lowering the dose may lead to relapse of psychosis. There are no data on once-daily dosing. Drug holidays do not seem to be feasible for patients with schizophrenia because of the potential for reemergence of symptoms, variation of side effects and noncompliance. While most antidotes do not seem to be theoretically feasible, two recent reports suggested that some may be useful. Segraves (1999b) reported that sildenafil (Viagra) alleviated erectile problems associated with haloperidol(Drug information on haloperidol). In another report (Aizenberg et al., 1996), administering 25 mg to 50 mg of imipramine(Drug information on imipramine) (Tofranil) to patients suffering from thioridazine-associated anorgasmia occasionally alleviated the difficulty. Switching to another antipsychotic drug seems to be the most feasible strategy. Some studies suggest switching from a low-potency to a high-potency conventional antipsychotic or to an atypical antipsychotic (Segraves, 1999a). Among conventional antipsychotics, loxapine(Drug information on loxapine) (Loxitane) and molindone may have a lower incidence of associated SD (Collins and Kellner, 1986). Priapism is generally considered a urological emergency.
Application of general strategies in the management of weight gain associated with psychotropic drugs poses an even greater challenge. Weight gain does not disappear spontaneously. Decreasing the dose may slow or stop the weight gain, yet patients often do not return to their original weight. In the case of mirtazapine, a higher dose is actually associated with less weight gain than a lower dose. Once-daily dosage or drug holidays are not applicable for weight gain. Thus, changing to another medication, selecting a medication with a low potential of weight gain or using an antidote are probably the most useful strategies. Among antidepressants, bupropion and some of the SSRIs are probably the best choices. Among the antipsychotics, switching to molindone or ziprasidone could be a viable strategy. Orlistat (Xenical) and sibutramine(Drug information on sibutramine) (Meridia) have been successfully used in the treatment of obesity (Aronne, 2001) and may be useful in weight gain associated with some psychotropics. They both have some disadvantages (e.g., gastrointestinal side effects such as oily discharge with orlistat(Drug information on orlistat)). Several agents, such as topiramate(Drug information on topiramate) (Topamax) (McIntyre et al., 2001), nizatidine(Drug information on nizatidine) (Axid) (Sacchetti et al., 2000), and amantadine (Floris et al., 2001) have been reported to possibly counteract antipsychotic-induced weight gain; however, amantadine has been shown to worsen psychosis.
Dietary counseling, behavioral modification and exercise should always be included among the management strategies for medication-associated weight gain. Cognitive-behavioral therapy may also be useful (Umbricht et al., 2001).Conclusion Some side effects may be a serious issue during treatment with psychotropic medications. They may be a reason for noncompliance and subsequent treatment failure, relapse or recurrence. Thus, their prevention and management is a very important, yet challenging clinical issue.