What are the guidelines for using Dosulepin (tricyclic antidepressant) in patients with severe depression or anxiety, particularly those with a history of cardiovascular disease or epilepsy?

Dosulepin (Dothiepin) Use in Depression and Anxiety

Critical Safety Warning: Avoid Dosulepin in Cardiovascular Disease

Dosulepin should be avoided in patients with cardiovascular disease due to its particularly high cardiotoxicity compared to other tricyclic antidepressants, and monoamine oxidase inhibitors and tricyclic antidepressants have significant cardiovascular side effects including hypertension, hypotension, and arrhythmias and should be avoided in patients with cardiovascular disease 1.

Evidence of Cardiovascular Toxicity

• Dosulepin and amitriptyline are particularly toxic in overdose, with cardiovascular toxicity manifested by ECG abnormalities, arrhythmias, and hypotension 2.
• The principal mechanism is cardiac sodium channel blockade, which increases cardiac action potential duration, prolongs the refractory period, and delays atrioventricular conduction 2.
• ECG changes include PR, QRS, and QT interval prolongation, atrioventricular block, right axis deviation, and the Brugada pattern 2.
• Higher dosulepin plasma levels correlate with more marked changes in QRS axis deviation in frontal plane, QRS-STT angle changes, and early myocardium depolarization phase alterations 3.
• Life-threatening arrhythmias and death typically occur within 24 hours of overdose, with rapid deterioration being common 2.

Absolute Contraindication in Epilepsy

Dosulepin is contraindicated in patients with epilepsy, as tricyclic antidepressants lower the seizure threshold and can precipitate seizures (general medical knowledge, though not explicitly cited in provided evidence).

FDA-Approved Indications and Dosing

Approved Indications 4

• Psychoneurotic patients with depression and/or anxiety
• Depression and/or anxiety associated with alcoholism (not to be taken concomitantly with alcohol)
• Depression and/or anxiety associated with organic disease
• Psychotic depressive disorders with associated anxiety including involutional depression and manic-depressive disorders
• Target symptoms include anxiety, tension, depression, somatic symptoms, sleep disturbances, guilt, lack of energy, fear, apprehension, and worry

Dosing Guidelines 4

• Starting dose: 75 mg/day for most patients with mild to moderate illness
• Usual optimum range: 75-150 mg/day
• Severely ill patients: May require gradual increase to 300 mg/day if necessary
• Maximum dose: 300 mg/day (additional therapeutic effect rarely obtained beyond this)
• Very mild symptoms: 25-50 mg/day may suffice
• Once-daily dosing: Maximum 150 mg/day at bedtime (the 150 mg capsule is for maintenance only, not treatment initiation)
• Time to effect: Anti-anxiety effect appears before antidepressant effect; optimal antidepressant effect may not be evident for 2-3 weeks 4

Safer Alternative Recommendations

For Depression in Cardiovascular Disease Patients 1

• SSRIs are the preferred choice, particularly sertraline, which has been studied extensively and has lower risk of QTc prolongation than citalopram or escitalopram
• Mirtazapine has been shown to be safe in patients with cardiovascular disease, though efficacy data are limited
• Psychostimulants such as methylphenidate (onset 1-2 days) may be prescribed by specialists for end-of-life depressive symptoms with monitoring for tachycardia and hypertension

For Anxiety in Cardiovascular Disease Patients 1

• SSRIs or serotonin norepinephrine reuptake inhibitors are effective for neuropathic pain and anxiety, though SSRIs may be preferable in cardiovascular disease
• Cognitive behavioral therapy for insomnia is recommended as first-line before sedating antidepressants

Clinical Considerations from Long-Term Studies

Efficacy Profile 5, 6

• Dosulepin combines antidepressant activity with sedative effects, similar to amitriptyline
• The mood-elevating effect is similar to amitriptyline but probably less marked than imipramine
• More useful than imipramine in depressed patients with sleep disturbances and depression associated with anxiety
• Long-term use (5-15 years) has shown feasibility and efficacy in chronic depression, with lack of adverse drug interactions and high safety in patients with concomitant physical disorders 6

Common Side Effects 5

• Dry mouth, drowsiness, and constipation are most common
• Postural hypotension is uncommon at therapeutic doses
• Generally well tolerated, particularly by elderly patients
• Fewer or less troublesome side-effects than imipramine or amitriptyline at equivalent doses

Discontinuation Considerations

• A 2023 study found that 47% of patients continued dosulepin, 36% were switched to alternatives, and 17% discontinued following a national prescribing indicator to limit use 7
• Of those who discontinued, 92% did not receive another antidepressant prescription during follow-up 7
• Recorded incidence of adverse events was low across all groups with no significant difference between those who continued versus discontinued 7
• This provides reassurance that dosulepin discontinuation can be successful without increased risk of adverse events 7

Critical Pitfalls to Avoid

• Never prescribe dosulepin to patients with known cardiovascular disease due to its particularly high cardiotoxicity profile 1, 2
• Never prescribe to patients with epilepsy due to seizure threshold lowering
• Never exceed 300 mg/day as additional therapeutic effect is rarely obtained 4
• Do not use the 150 mg capsule for treatment initiation - it is for maintenance only 4
• Monitor for rapid deterioration in overdose - life-threatening complications typically occur within 24 hours 2
• Avoid concomitant alcohol use when treating depression associated with alcoholism 4