Does cyproheptadine (antihistamine) increase or decrease symptoms of depression and anxiety?

Cyproheptadine and Depression/Anxiety: Clinical Effects

Cyproheptadine may reduce symptoms of depression and anxiety in select patient populations, but can paradoxically worsen these symptoms in others, particularly those with certain biological markers or when withdrawn abruptly.

Evidence for Beneficial Effects

Depression Reduction

• Cyproheptadine demonstrated antidepressant activity in patients with major depression who had suppressible dexamethasone suppression tests, with significantly lower Hamilton Depression Rating Scale scores during treatment (p < 0.01) 1.
• In HIV-positive patients starting efavirenz-based antiretroviral therapy, cyproheptadine significantly decreased Hamilton Depression Rating Scale scores and Beck Depression Scale scores after 4 weeks compared to controls 2.
• The medication prevented development of depressive symptoms in patients at high risk for neuropsychiatric adverse effects from antiretroviral therapy 2.

Anxiety Reduction

• Cyproheptadine significantly reduced Hamilton Anxiety Rating Scale scores in HIV-positive patients receiving efavirenz compared to controls who experienced increased anxiety scores 2.
• The drug prevented anxiety development as part of its broader neuropsychiatric protective effects in this high-risk population 2.

Additional Neuropsychiatric Benefits

• Cyproheptadine reduced hallucinations, aggressive behaviors, emotional withdrawal, poor impulse control, and suicidal ideation in patients on efavirenz-based therapy 2.
• It improved sleep quality as measured by the Pittsburgh Sleep Quality Inventory 2.

Evidence for Adverse Psychiatric Effects

Paradoxical Worsening

• Two patients with major depression and nonsuppressible dexamethasone suppression tests could not tolerate cyproheptadine due to anxiety and irritability, suggesting the drug may worsen symptoms in certain biological subtypes of depression 1.
• One case series reported worsening nightmares and restlessness as side effects in PTSD patients treated with cyproheptadine 3.

Withdrawal-Related Psychosis

• Sudden withdrawal of cyproheptadine precipitated a psychotic syndrome in a 14-year-old patient, requiring treatment with olanzapine for symptom control 4.
• This suggests abrupt discontinuation can trigger severe psychiatric decompensation 4.

Clinical Context and Mechanism

Pharmacological Properties

• Cyproheptadine functions as a serotonin antagonist (particularly at 5-HT2A and possibly 5-HT1A receptors), H1 antihistamine antagonist, and has anticholinergic properties 3, 5.
• Its antiserotonergic activity may help gastrointestinal symptoms and neuropsychiatric manifestations in mast cell activation syndrome 3.

Sedation and Cognitive Effects

• The medication is sedating and has anticholinergic effects that may cause drowsiness and cognitive decline, particularly in elderly patients 3.
• These anticholinergic properties place it in the category of high-risk medications that should be deprescribed in older adults with cognitive impairment 6.

Clinical Decision Algorithm

For patients considering cyproheptadine:

1. Assess biological markers if treating depression: Consider dexamethasone suppression testing, as patients with suppressible tests may benefit while those with nonsuppressible tests may experience worsening anxiety 1.

2. Evaluate for specific indications: The drug shows clearest benefit in preventing neuropsychiatric adverse effects from serotonergic medications (like efavirenz) rather than as primary treatment for depression/anxiety 2.

3. Monitor for paradoxical effects: Watch for increased anxiety, irritability, or agitation, particularly in the first weeks of treatment 1.

4. Avoid abrupt discontinuation: Taper gradually to prevent withdrawal-related psychiatric symptoms 4.

5. Exercise caution in elderly patients: The anticholinergic burden may worsen cognition and functional status in older adults 6.

Important Caveats

• The evidence for cyproheptadine's psychiatric effects is limited to small studies and case reports, with the strongest data coming from a single randomized trial in HIV patients 2.
• The drug's role appears more preventive than therapeutic for established depression/anxiety 2.
• Individual response varies significantly based on underlying psychiatric diagnosis and biological markers 1.
• Sedation is a common side effect that may be mistaken for mood improvement 3.