While ziprasidone (Geodon) is primarily indicated for the treatment of schizophrenia and acute mania, its unique pharmacological profile has sparked interest in its potential benefits regarding weight management, especially compared to other antipsychotics known to cause weight gain. This article aims to provide a comprehensive overview of the existing evidence on ziprasidone and its effects on weight, drawing from clinical studies and expert opinions.
Introduction
Antipsychotic medications, including second-generation agents, are widely used for treating schizophrenia, related psychotic disorders, mood, anxiety, and behavior disorders. The choice of antipsychotic medication involves considering multiple factors, including efficacy and side effects. Weight gain is a significant concern associated with many antipsychotics, leading to interest in agents like ziprasidone, which have a more neutral effect on weight.
Pharmacology of Ziprasidone
Ziprasidone exhibits a high binding affinity for dopamine (D2, D3), serotonin (5-HT2A, 5-HT2C, 5-HT1A, 5-HT1B/1D, 5-HT7), and adrenergic (α1) receptors, and moderate affinity for histaminic H1 and dopamine D4 receptors. Several pharmacologic actions of ziprasidone have long been predicted to confer an antidepressant and anti-anxiety effect with chronic use.
Receptor Binding Profile
The antagonism of 5-HT2C receptors disinhibits both dopamine and norepinephrine neurons in the cortex. Ziprasidone has a low affinity for histaminergic H1, muscarinic M1, and α1-noradrenergic receptors, predicting a lower likelihood of orthostatic hypotension, sedation, and anticholinergic side effects.
Dopamine Receptor Occupancy
Using an imaging protocol, 60% or greater D2 dopamine receptor occupancy is generally predictive of antipsychotic activity.
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Pharmacokinetics
Ziprasidone achieves peak concentration approximately 6-8 hours post ingestion and steady-state concentration by the end of the second day of dosing. It is extensively metabolized, two-thirds by aldehyde oxidase and one-third by P450 oxidation (3A4 > > 1A2). Potent inducers and inhibitors of CYP 3A4 may result in clinically relevant changes in ziprasidone clearance.
Unlike most antipsychotics, the bioavailability of ziprasidone is approximately halved in the fasting state. Absorption appears to be consistent whether the meal is low or high in protein or fat content. Dose and concentration are linearly correlated when taken with a ≥500 kcal meal but not in the fasting state.
Ziprasidone and Weight: Comparative Studies
Several studies have compared ziprasidone with other antipsychotics regarding weight gain. These studies suggest that ziprasidone is associated with a lower propensity for weight gain and central fat deposition compared to olanzapine.
Ziprasidone vs. Olanzapine
One study randomized adult patients experiencing a new-onset psychotic episode to ziprasidone 40-160 mg/day or olanzapine 5-20 mg/day for 12 weeks. Olanzapine-treated patients showed significant weight gain, particularly fat gain, increased low-density lipoprotein cholesterol (LDL-C), and decreased high-density lipoprotein cholesterol (HDL-C) concentrations. In contrast, ziprasidone was associated with a lower propensity for weight gain and central fat deposition than olanzapine.
After 12 weeks, the median increase in body weight in the olanzapine group was 6.25 kg, representing an increase of 10.35% from first to last observation, whereas the median weight gain in the ziprasidone group was 2.00 kg, representing an increase of 3.43% from first to last observation. BMI increased significantly in olanzapine-treated patients but did not change significantly in the ziprasidone group.
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The percent changes in body weight, BMI, and waist-to-hip ratio were significantly greater in patients treated with olanzapine than with ziprasidone. Fat mass increased significantly in the olanzapine group but was not significantly changed in the ziprasidone group. In contrast, lean body mass (LBM) and muscle mass increased significantly in the ziprasidone group but not in the olanzapine group, despite the significant increase in total body weight in the latter.
Energy Expenditure and Metabolic Parameters
Ziprasidone-treated patients showed a significant increase in resting energy expenditure normalized to LBM without significant changes in absolute 24-hour resting energy expenditure and respiratory quotient. Olanzapine therapy did not significantly change these parameters.
LDL-C and prolactin concentrations increased significantly in olanzapine-treated patients, but not in ziprasidone-treated patients. Total cholesterol and HDL-C concentrations increased significantly in the ziprasidone group but not in the olanzapine group.
Implications of Weight Gain
The significant weight gain in the olanzapine group was primarily due to an increase in body fat, accounting for about 61% of the total weight gain. This suggests that these subjects maintained a positive energy balance and deposited this energy in the form of triglycerides in adipose tissue.
Appetite and Caloric Intake
Subjective appetite did not differ significantly before and after treatment in both groups, but ziprasidone-treated patients tended to show a greater percent change in appetite than olanzapine-treated patients.
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Limitations
The study findings should be considered preliminary due to the small sample size. The lack of blinding could have introduced potential bias when measuring symptom severity by the PANSS and the patients estimated their appetite. However, most outcomes were obtained objectively from physical measurement or laboratory assay, which may not be biased due to non-blinding.
Clinical Implications
The findings suggest that ziprasidone may be a preferable option for patients concerned about weight gain or metabolic side effects. However, it is essential to consider other factors, such as efficacy in treating specific psychiatric conditions and individual patient characteristics.
Schizophrenia
Ziprasidone is effective for its indicated uses in schizophrenia. In a 156-week extension study, mean PANSS negative subscale change scores per week were −4.86 for ziprasidone 80-160 mg, -3.17 for haloperidol 5-20 mg, and −2.87 for ziprasidone 80-120 mg. The least squares mean results of ziprasidone 80-160 mg/d compared to haloperidol were statistically different, but not for haloperidol compared to ziprasidone 80-120 mg/d. Kaplan-Meier Survival curves indicated greater rates of remission of negative symptoms with both dosage groups of ziprasidone versus haloperidol. The findings suggest an advantage for ziprasidone for negative symptoms and indicate the extended duration of treatment required to observe substantial improvement in negative symptoms.
Bipolar Disorder
For patients with mania, some antipsychotics have been studied more extensively than others. Meta-analyses demonstrate a standardized mean difference in YMRS scores of −0.44 (95% CI −0.65 to −0.23) with ziprasidone compared to placebo. Another meta-analysis found a number needed to treat of 5.9 (95% CI 3.9 - 14.3) for mania management with ziprasidone compared to placebo.
In a 6-month, randomized double-blind trial of ziprasidone or placebo added to either lithium or valproate, approximately 67% and 80% of participants were relapse-free in the placebo and ziprasidone groups at 6 months (p = 0.01). The mean difference for ziprasidone versus placebo in the mania rating scale (MRS) total score was −3.27 (95% CI −4.91 to −1.62).
Potential advantages of ziprasidone in terms of metabolic-related side effects maintain interest in this medication for bipolar disorder. However, experiences of agitation and insomnia have limited its clinical utility in some manic and hypomanic patients.
Major Depressive Disorder
The evidence for the use of ziprasidone for the treatment of major depressive disorder (MDD) is sparse. Ziprasidone’s pharmacological actions, including its 5-HT2A antagonism and reuptake inhibition of 5-HT and NE, suggest an antidepressant effect. However, making explicit linkages between receptor binding profiles and clinical results in various patient groups is not straightforward.
At present, there are no randomized, double-blind, controlled trials of ziprasidone in MDD published in peer-reviewed journals.
Ziprasidone and Weight Loss in Specific Populations
Bipolar Disorder Patients on Weight-Gaining Medications
One open-label study evaluated the effectiveness of adjunctive ziprasidone for weight loss in obese/overweight bipolar disorder (BD) patients taking weight gain-implicated psychotropic medications. The study included 22 obese and three overweight BD patients with a mean baseline BMI of 31.8 kg/m2 who received ziprasidone (mean final dose 190 mg/day) for a mean of 79.2 days. Weight and BMI decreased from baseline to endpoint by 4.5 kg and 1.6 kg/m2, respectively, at weekly rates of 0.37 kg and 0.13 kg/m2, respectively (all p < 0.00001). 48% of patients had at least 5% weight loss. Obesity rate decreased from 88% to 35% (p < 0.0001). Overall, mood did not change. Patients with at least moderate baseline mood symptoms experienced significant mood improvement, despite 72% patients decreasing/discontinuing weight gain-implicated psychotropic medications. It has been suggested that open adjunctive ziprasidone may be effective for weight loss in obese/overweight BD patients taking weight gain-implicated psychotropic medications.
Patients with Mental Retardation
Forty patients with mental retardation and maladaptive behaviors who had gained excessive weight or were inadequately responsive to other agents were switched to ziprasidone. Ziprasidone treatment was associated with a significant weight loss of 8.1 lb (3.6 kg) as well as a significant reduction in total cholesterol and triglycerides. The monthly frequency of the maladaptive behavior remained unchanged or improved in 72% of the patients in whom maladaptive behavior was assessed. It has been suggested that ziprasidone effectively reduces the frequency of maladaptive behavior in a patient group with mental retardation without causing weight gain or metabolic disturbances.
Adverse Effects and Tolerability
Key challenges in practice include the need for dosing on a full stomach and managing its early-onset adverse effect of restlessness.