Section 7: Clinical Vignettes

Vignette 1: The First Manic Episode on an Antidepressant

Presentation. Dr. Santos, a family medicine physician, sees Keisha, a 28-year-old woman who was started on sertraline 100 mg six weeks ago for a major depressive episode. Her husband called the clinic concerned that over the past 10 days, Keisha has slept only 2 to 3 hours per night without fatigue, has taken on three new "business ventures," has been spending heavily on equipment for these projects, and has been speaking so quickly he can barely follow her. Keisha insists she has "finally found her purpose" and is frustrated that her husband wants to "hold her back."

Clinical reasoning. This presentation is consistent with a manic episode. Although it emerged during antidepressant treatment, it has persisted for 10 days at full syndromal intensity, well beyond the pharmacokinetic effect of sertraline, meeting the DSM-5 threshold for a bipolar I diagnosis (Section 6.1). The immediate priority is discontinuing sertraline, as continued exposure worsens mania and increases mixed feature risk (Section 1.2, all guidelines). Dr. Santos must also assess suicide and violence risk, particularly screening for mixed features (concurrent depressive symptoms, which elevate suicide risk; Section 1.1), and rule out substance use as a contributing factor (Section 6.1).

Management. Dr. Santos discontinues sertraline immediately. Given the moderate severity (reduced sleep need, grandiosity, excessive spending, pressured speech, but no psychotic features or imminent danger), monotherapy with an atypical antipsychotic is appropriate as a bridging intervention while psychiatric referral is arranged (Section 6.2). Quetiapine (starting at 100 mg at bedtime on day 1, increasing to 200 mg on day 2, 300 mg on day 3, and titrating to 400 to 600 mg by day 4 to 7) would address both the manic symptoms and the severe insomnia. Alternatively, aripiprazole 15 mg daily offers a more weight-neutral option if metabolic risk is a concern, though it will not provide the same sedative benefit for sleep restoration. Dr. Santos explains to Keisha and her husband that this is likely bipolar disorder, that the antidepressant appears to have triggered the switch, and that psychiatric evaluation is needed within the next few days.

Teaching point. This vignette illustrates the most common pathway to a bipolar diagnosis: a patient treated for presumed unipolar depression who develops mania on an antidepressant. Primary care providers and therapists are often the first to encounter this scenario. The critical actions are stopping the antidepressant immediately (Section 1.2), recognizing the presentation as mania rather than an antidepressant side effect, and initiating a bridging antimanic agent while arranging specialist evaluation.

Vignette 2: The Lithium-Stabilized Patient in Primary Care

Presentation. Marcus, a 52-year-old man with bipolar I disorder, has been stable on lithium 900 mg daily (serum level 0.72 mEq/L) for six years. He presents to his PCP, Dr. Okafor, with a two-week history of knee pain. After examination, Dr. Okafor diagnoses osteoarthritis and considers prescribing naproxen 500 mg twice daily.

Clinical reasoning. This is a high-risk prescribing scenario. NSAIDs inhibit renal prostaglandin synthesis, causing afferent arteriolar vasoconstriction, decreased GFR, and dramatically increased lithium reabsorption (Section 2.6). Naproxen can quickly double Marcus's lithium level from a safe 0.72 mEq/L to a toxic 1.4 mEq/L or higher, producing the nausea, coarse tremor, ataxia, and confusion described in Section 2.7. This interaction is one of the most common preventable causes of iatrogenic lithium toxicity.

Management. Dr. Okafor prescribes acetaminophen at standard dosing (up to 3000 to 4000 mg/day in divided doses for adults without liver disease) instead, which does not affect renal hemodynamics (Section 2.6). She adds topical diclofenac gel for local relief if needed (topical NSAIDs have minimal systemic absorption and are generally considered lower-risk with lithium based on clinical convention rather than formal guideline endorsement; this should be confirmed with the prescribing psychiatrist). She documents the interaction alert in Marcus's chart and ensures the pharmacy has a drug interaction flag for lithium-NSAID combinations. If Marcus's knee pain is not adequately controlled with acetaminophen and topical therapy, Dr. Okafor consults with his psychiatrist before considering any systemic anti-inflammatory.

Teaching point. This vignette targets the non-psychiatrist audience. The PCP, NP, or PA managing a lithium-stabilized patient for a routine medical complaint must check every new prescription against lithium's interaction profile (Section 2.6). The same caution applies to ACE inhibitors for new hypertension (use calcium channel blockers instead) and thiazide diuretics for edema or hypertension (essentially contraindicated with lithium). This is not a theoretical risk; it is one of the most frequent causes of lithium-related emergency department visits.

Vignette 3: Valproate, Pregnancy Planning, and the Switching Dilemma

Presentation. Jasmine, a 31-year-old woman with bipolar I disorder, has been stable on divalproex 1500 mg daily for four years. She and her partner are considering starting a family within the next year. She has a history of three severe manic episodes requiring hospitalization, two of which occurred after previous attempts to switch from valproate to other medications (once to lithium, which she discontinued due to intolerable tremor and polyuria, and once to quetiapine, which led to a manic relapse within three months). She asks her psychiatrist, Dr. Rivera, whether she can continue valproate during pregnancy.

Clinical reasoning. This is the central clinical dilemma discussed in Sections 3.9 and 3.10. Valproate carries an approximately 11% risk of major congenital malformations and documented neurodevelopmental harm (7 to 11 point IQ reduction; Section 3.9). These risks are severe and well-established. However, discontinuing the only medication that has kept Jasmine stable after failing lithium and quetiapine carries a 50 to 70% risk of severe mood relapse, with its own downstream risks to both mother and fetus (Section 3.10). The 2024/2025 MHRA regulations require two-specialist consensus to continue valproate in any patient under 55, and enrollment in the Pregnancy Prevention Programme (Section 3.10).

Management. Dr. Rivera initiates a preconception consultation, ideally 6 to 12 months before planned conception. She considers a trial of lamotrigine (which has the best reproductive safety profile among mood stabilizers; Section 4.3) as maintenance, with the understanding that lamotrigine will not protect against mania (the same episode type that has required hospitalization three times). If lamotrigine is trialed, it must be combined with a second agent that provides antimanic coverage. If no alternative achieves stability, Dr. Rivera documents a formal shared decision-making process: Jasmine and her partner are counseled on the 11% malformation risk and 40% neurodevelopmental risk with explicit documentation, iron-clad contraception is maintained until a final plan is agreed upon, and the two-specialist sign-off required by MHRA guidelines is obtained. If Jasmine becomes pregnant while still on valproate, abrupt discontinuation is contraindicated; instead, urgent collaborative management with a perinatal psychiatrist and high-risk obstetrician is required (Section 3.10).

Teaching point. There is no risk-free option for Jasmine. This vignette illustrates that the valproate-pregnancy dilemma is not a simple "stop the medication" decision but a carefully documented, shared decision-making process that should begin months to years before conception. The role of the therapist in this scenario is to support Jasmine through the anxiety of this decision and to help her and her partner process the risk information without feeling pressured to choose between equally difficult options.

Key Takeaways for Clinical Practice

Combination therapy (mood stabilizer plus atypical antipsychotic) is the evidence-based standard for moderate-to-severe acute mania. Network meta-analyses consistently show approximately 20% higher response rates and faster time to improvement compared to monotherapy, without significantly worse tolerability. Monotherapy is appropriate for mild to moderate presentations without psychotic features.
Lithium's anti-suicidal effect is unique among all psychiatric medications. The NNT of approximately 23 to prevent one suicidal act (completed suicide or severe attempt) over one year is among the strongest mortality-prevention effects in medicine. For any bipolar patient with elevated suicide risk, this property should explicitly inform treatment selection.
Lithium's long-term safety profile is more manageable than commonly perceived. The 2025 population-level data shows lithium is associated with mild Stage 3 CKD risk (aHR 1.35) but not Stage 4 CKD or end-stage renal disease. Hypothyroidism occurs in 10 to 20% of patients but is easily managed with levothyroxine. Standard maintenance targets of 0.6 to 0.8 mEq/L are well-established; some experts advocate lower targets of 0.4 to 0.6 mEq/L for stable patients, though this practice has not been validated in prospective trials.
The three drug classes that can cause life-threatening lithium toxicity are NSAIDs, ACE inhibitors/ARBs, and thiazide diuretics. Every clinician managing a lithium-treated patient must check new prescriptions against this interaction profile. Acetaminophen and calcium channel blockers are safe alternatives.
Valproate is the preferred mood stabilizer for mixed features and rapid cycling, but its reproductive risks have reshaped global prescribing. The 2024/2025 MHRA restrictions (UK-specific, though reflecting universally recognized teratogenic evidence) require two-specialist consensus to initiate valproate in any patient under 55, male or female. The teratogenic evidence itself is universal: approximately 11% major malformation rate and documented neurodevelopmental harm (7 to 11 point IQ reduction). US and other jurisdictions maintain FDA Boxed Warnings and pregnancy prevention requirements but have not adopted the identical two-specialist rule. All clinicians should be aware of the teratogenic data regardless of jurisdiction.
Lamotrigine does not treat mania. Its role is preventing bipolar depression in maintenance (discussed further in Module 4). Prescribing lamotrigine as the sole agent for a manic episode is a serious prescribing error. Its mandatory slow titration (5 to 6 weeks to therapeutic dose) further limits its utility in acute settings.
Atypical antipsychotics vary enormously in metabolic risk. Olanzapine and clozapine carry the highest risk (severe weight gain, direct diabetogenic effects). Aripiprazole, ziprasidone, cariprazine, and lurasidone are weight-neutral or near weight-neutral. The ADA/APA metabolic monitoring protocol (weight, fasting glucose, lipids, blood pressure at baseline and scheduled intervals) is mandatory for all patients on antipsychotic therapy. Metabolic monitoring is not optional; it is the standard of care.
Therapists and non-prescribing clinicians play a critical role in lithium safety and mania recognition. Sudden onset of ataxia, slurred speech, or worsening tremor in a lithium-treated patient may indicate toxicity, not psychiatric decompensation; this requires immediate emergency evaluation. Therapists who see patients weekly are often the first to notice emerging hypomanic or manic symptoms that the patient does not recognize.
School psychologists working with bipolar students should understand medication effects on school functioning. Mood stabilizers and antipsychotics can affect cognition, energy, appetite, and weight, any of which may manifest as changes in academic performance or peer engagement. A student on lithium who develops sudden coordination problems, confusion, or slurred speech needs immediate medical evaluation, not a behavioral referral. Weight gain from antipsychotics can significantly affect self-esteem and peer relationships in school-age patients.
ECT is the most effective treatment for refractory, catatonic, and psychotic mania. The 80% remission rate in the Mukherjee review exceeds the response rates of any pharmacological regimen. It should be considered earlier rather than later for catatonic presentations, where delays carry mortality risk.
The transition from acute to maintenance treatment should follow the continuation principle. The medication that resolved the acute episode should be continued for at least 6 months before considering regimen simplification. Premature discontinuation of the antipsychotic component is a common cause of early relapse.

Key References

Starred (★) papers are recommended for clinicians who want to read further.

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★ Chan, E. W., et al. (2025). Lithium for bipolar disorder and risk of thyroid dysfunction and chronic kidney disease. JAMA Network Open.

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★ Cipriani, A., Hawton, K., Stockton, S., & Geddes, J. R. (2013). Lithium in the prevention of suicide in mood disorders: Updated systematic review and meta-analysis. BMJ, 346, f3646.

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★ Geddes, J. R., Goodwin, G. M., Rendell, J., et al. (2010). Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): A randomised open-label trial. Lancet, 375(9712), 385-395.

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★ Pillinger, T., McCutcheon, R. A., Vano, L., et al. (2020). Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: A systematic review and network meta-analysis. Lancet Psychiatry, 7(1), 64-77.

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Clinical Vignettes & Key Takeaways