Treatment-resistant depression with a buried hypomanic episode
A 34-year-old bank accountant is referred with a 14-month major depressive episode (PHQ-9 21, GAD-7 12). She has had three prior episodes since age 22. She has failed adequate trials of sertraline 200 mg for 10 weeks, escitalopram 20 mg plus bupropion 300 mg, and is currently on venlafaxine 225 mg with mirtazapine 30 mg for 10 weeks, with only partial response. She is adherent, denies alcohol or drug use, and TSH and B12 are normal. She has never taken lithium. BMI is 33. She asks specifically about ketamine infusions and ECT. Careful history reveals that at age 24, while taking fluoxetine, she had 5 days of decreased need for sleep, pressured speech, overspending KD 700 in a week and intrusive irritability, followed by a crash; her father has bipolar I disorder. She is functioning poorly at work and has passive death wishes but no plan or intent.
1. Reappraise the diagnosis. What features change your formulation, what would you do to confirm it, and why does the distinction alter management?
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The 5-day episode of decreased need for sleep, pressured speech, overspending and irritability on fluoxetine meets the threshold for a hypomanic episode (at least 4 days, observable change, not attributable to a substance or another illness). That makes bipolar II disorder a better fit than unipolar major depression, particularly with a father who has bipolar I disorder and an early onset at 22.
Confirm with a structured interview (SCID or CIDI), the MDQ as a screening aid only, and collateral from her husband. Review old records for antidepressant-induced activation, postpartum episodes, seasonal pattern and rapid cycling. The history is easy to miss because patients present depressed and do not volunteer 'good' periods.
The distinction changes management because antidepressants - especially venlafaxine and tricyclics - carry the highest switch risk. Continuing antidepressant monotherapy risks mixed states, rapid cycling and worsening treatment resistance. Bipolar depression should be treated with a mood stabiliser or an evidence-based agent such as quetiapine, lurasidone, lithium or lamotrigine. It also changes counselling about prognosis, pregnancy and long-term maintenance.
2. Compare ECT, ketamine and mood-stabiliser strategies for this patient and give a sequenced plan, including what to do with her current medications.
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Sequenced plan: (1) Do not stop venlafaxine abruptly - taper over 2–4 weeks to avoid a discontinuation syndrome, reducing or stopping the antidepressant as the mood stabiliser comes on board, because of switch risk. (2) Start lithium, targeting 0.6–0.8 mmol/L, given the family history of bipolar I and its maintenance and anti-suicide evidence; lamotrigine (slow titration to 200 mg, with rash warning) is an alternative, particularly for depressive predominance. Quetiapine XL 300 mg is an option if insomnia and agitation dominate, but metabolic risk is a concern at BMI 33.
ECT: strongly consider it. She has 14 months of treatment-resistant depression, marked functional impairment and passive death wishes. ECT has the best evidence in treatment-resistant and bipolar depression and acts faster than drug manipulation; it requires anaesthetic assessment, informed consent and continuation pharmacotherapy afterwards.
Ketamine/esketamine: rapid but transient benefit; evidence in bipolar depression is weaker, and it can cause dissociation, hypertension and mood switching. If used, it must be with a mood stabiliser and in a monitored setting; it is a bridge, not a substitute for maintenance treatment.
Given severity and chronicity, ECT is the more defensible acute choice while lithium is loaded, with lamotrigine or quetiapine for maintenance.
3. What would you tell her about risks and monitoring - mood switching, lithium, metabolic effects and suicide?
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Explain that an antidepressant may have triggered her hypomania, that bipolar illness is lifelong and relapsing, and that the goal is mood stability rather than simply 'a stronger antidepressant'. Give her a written relapse signature and urgent access.
Lithium: baseline eGFR, TSH, calcium, pregnancy test and ECG if cardiac risk; check the level 5 days after starting and after every dose change, then 3-monthly. Warn about tremor, thirst, weight gain, hypothyroidism and toxicity with dehydration, NSAIDs and ACE inhibitors.
Lamotrigine: warn about rash and the need to stop and seek review if a rash appears.
Metabolic: record weight, waist, HbA1c, lipids and BP at baseline and 3-monthly, especially on quetiapine; BMI 33 already warrants diet and exercise input.
Suicide: passive death wishes require direct questioning, a safety plan, means restriction and close follow-up; lithium has the strongest anti-suicide evidence and is a further reason to use it.
Pregnancy: discuss plans early - lithium and valproate are teratogenic; refer to perinatal psychiatry before conception. Finally, involve the family in understanding the diagnosis so that early warning signs are not dismissed as 'just stress'.