Does Risperidone (atypical antipsychotic) have antidepressant properties?

Risperidone as Augmentation for Treatment-Resistant Depression

Risperidone does not have primary antidepressant properties, but demonstrates significant efficacy as an augmentation agent for treatment-resistant major depressive disorder when added to standard antidepressants, particularly SSRIs. 1, 2

Mechanism of Action in Depression

Risperidone's therapeutic effects in depression are mediated through its antagonism at serotonin Type 2 (5HT2) and dopamine Type 2 (D2) receptors, rather than through direct antidepressant mechanisms 1. At low doses (0.5-2 mg/day), risperidone acts primarily as a 5-HT2 antagonist, which may enhance serotonergic neurotransmission and augment the effects of SSRIs 3, 2.

The FDA-approved mechanism for risperidone involves combined D2 and 5HT2 receptor antagonism, with additional activity at α1, α2 adrenergic, and H1 histaminergic receptors 1. This pharmacological profile explains why risperidone functions as an augmentation agent rather than a standalone antidepressant.

Evidence for Augmentation Therapy

Efficacy Data

The highest quality evidence comes from a 2007 multicenter, double-blind, placebo-controlled trial showing that risperidone augmentation (1-2 mg/day) produced significantly greater symptom reduction than placebo in treatment-resistant depression 4. Key outcomes included:

• Mean HRSD-17 score improvement: 13.4 vs 16.2 for placebo (difference -2.8, P <0.001) 4
• Remission rates: 24.5% with risperidone vs 10.7% with placebo (P = 0.004) 4
• Response rates: 46.2% with risperidone vs 29.5% with placebo (P = 0.004) 4

A 2009 randomized trial demonstrated even more robust effects, with 52% remission in the risperidone group versus 24% in placebo (OR=3.33, p=.011) 5. Patients receiving risperidone also reported significantly better quality of life compared to placebo 5.

Rapid Onset of Action

Multiple studies demonstrate that risperidone augmentation produces rapid therapeutic effects, with remission occurring within 1 week of addition in some case series 3. The 2009 trial showed more rapid response in the risperidone group, though groups were converging by 4 weeks 5.

Clinical Algorithm for Use

Patient Selection

Risperidone augmentation should be considered for:

• Adults with major depressive disorder without psychotic features who have failed adequate trials (4-6 weeks) of standard antidepressants 4, 5
• Patients who have not responded to first-line agents from different classes or combinations of different antidepressant classes 2

Dosing Strategy

Start risperidone at 0.5-1 mg/day and increase to 1-2 mg/day based on response 2, 4. The 2007 trial used 1 mg/day initially, with increases to 2 mg/day after 4 weeks in some cases 4. Doses ranging from 0.25-3 mg/day have been studied, but most evidence supports 0.5-2 mg/day as the optimal range 2, 5.

Duration of Trial

Assess response after 4-6 weeks of augmentation therapy 2, 4. Some patients may show improvement within 1 week, but a minimum 4-week trial is recommended before concluding ineffectiveness 3, 5.

Safety Profile and Monitoring

Common Adverse Effects

The most frequently reported adverse effects in augmentation trials were:

• Headache (8.8% vs 14.5% with placebo) 4
• Somnolence (5.1% vs 1.5% with placebo) 4
• Dry mouth (5.1% vs 0.8% with placebo) 4
• Increased appetite 2
• Weight gain (significantly higher than placebo) 5

Metabolic and Neurological Risks

Extreme weight gain is the most common significant metabolic problem with risperidone 6. Extrapyramidal symptoms (EPS) are dose-dependent, with risk increasing significantly at doses >6 mg/day 6. At the low doses used for depression augmentation (0.5-2 mg/day), EPS risk is minimal, as evidenced by no reported extrapyramidal symptoms in the combination therapy study 7.

Risperidone causes more EPS than most other atypical antipsychotics and carries the highest risk among this class 8. However, at augmentation doses, this risk remains low 7.

Critical Monitoring Parameters

Monitor for:

• Weight gain and metabolic parameters (baseline and ongoing) 8, 6
• Orthostatic hypotension 6
• Hepatic transaminase elevations 6
• Extrapyramidal symptoms, particularly if doses exceed 2 mg/day 8, 6

Important Clinical Caveats

Not a First-Line Antidepressant

Risperidone should never be used as monotherapy for major depression 9, 2. The American College of Physicians guidelines list risperidone among atypical antipsychotics evaluated for augmentation therapy, not as primary treatment 9.

Limited Long-Term Data

Study durations ranged from 4-24 weeks, so long-term effectiveness and safety cannot be determined 2. The 2007 trial was limited to 6 weeks of augmentation therapy 4.

Patient Education Required

Before initiating risperidone augmentation, ensure patients understand:

• The off-label nature of this use for depression 2
• Potential benefits (faster response, higher remission rates) 4, 5
• Adverse effects, particularly weight gain and metabolic risks 2, 5
• The need for ongoing monitoring 8, 6

Alternative Augmentation Strategies

The American College of Physicians guidelines also recognize other augmentation options including aripiprazole, quetiapine, lithium, and thyroid hormone 9. Consider these alternatives, particularly in patients with metabolic risk factors where risperidone's weight gain profile is concerning 6, 5.