A patient with bipolar depression on lamotrigine 300 mg (up‑titrated from 150 mg) who has stopped all antidepressants now shows manic‑type behavior, severe anxiety, PTSD, and a history of substance use; what antimanic or mood‑stabilizing medication should be added before considering restarting an SSRI/SNRI?

Management of Acute Manic Behavior in Bipolar Disorder on Lamotrigine Monotherapy

Add an atypical antipsychotic (aripiprazole 10–15 mg/day or risperidone 2–3 mg/day) or a mood stabilizer (lithium or valproate) immediately to address the acute manic symptoms, as lamotrigine lacks antimanic efficacy and may have contributed to the manic switch after antidepressant discontinuation. 1

Why Lamotrigine Alone Is Insufficient for Acute Mania

• Lamotrigine has not demonstrated efficacy in treating acute mania and is specifically effective only for preventing depressive episodes in bipolar disorder maintenance therapy 2, 3, 4
• The American Academy of Child and Adolescent Psychiatry explicitly states that first-line treatments for acute mania include lithium, valproate, or atypical antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine, ziprasidone)—not lamotrigine 1
• Lamotrigine's antidepressant properties (related to decreased glutamate release) may actually precipitate manic episodes in vulnerable patients, particularly those with bipolar I disorder, manic predominant polarity, or history of antidepressant-induced switches 5
• In the clinical case series, LTG-induced mania occurred within 1–3 weeks of initiation or dose increase, with YMRS scores of 31–35, and remitted rapidly (within 7–10 days) after LTG withdrawal and addition of antimanic agents 5

Immediate Treatment Algorithm

Step 1: Add Antimanic Agent Without Delay

Option A: Atypical Antipsychotic (Preferred for Rapid Control)

• Aripiprazole 10–15 mg/day provides rapid symptom control with favorable metabolic profile and is recommended as first-line for acute mania 1
• Risperidone 2–3 mg/day is effective when combined with mood stabilizers and has strong evidence in open-label trials 1
• Quetiapine 400–800 mg/day (divided doses) plus valproate is more effective than valproate alone for adolescent mania 1
• The American Academy of Child and Adolescent Psychiatry notes that atypical antipsychotics provide more rapid symptom control than mood stabilizers alone 1

Option B: Mood Stabilizer (Lithium or Valproate)

• Lithium (target 0.8–1.2 mEq/L for acute treatment) shows response rates of 38–62% in acute mania and has superior long-term efficacy 1
• Valproate shows higher response rates (53%) compared to lithium (38%) in children and adolescents with mania and mixed episodes 1
• Combination therapy with lithium or valproate plus an atypical antipsychotic is considered for severe presentations, with approximately 20% more patients responding to combination than monotherapy 1, 6

Step 2: Decision on Lamotrigine Continuation

Reduce or discontinue lamotrigine temporarily during the acute manic episode, as:

• Lamotrigine may have contributed to the manic switch, particularly given the recent antidepressant discontinuation and dose increase from 150 mg to 300 mg 5
• In documented cases of LTG-induced mania, symptoms remitted within 7–10 days after LTG withdrawal and addition of antimanic treatment 5
• Once acute mania resolves, lamotrigine can be cautiously reintroduced at low doses (25–50 mg/day) with extended tapering if depressive symptoms remain a concern, but only in combination with an antimanic agent 5

Step 3: Do NOT Restart Antidepressants During Acute Mania

• The American Academy of Child and Adolescent Psychiatry explicitly warns that antidepressant monotherapy can trigger manic episodes or rapid cycling 1
• Antidepressant monotherapy is not recommended due to risk of mood destabilization, and any future antidepressant use must be combined with a mood stabilizer 1
• The FDA label for quetiapine (applicable to all antidepressants in bipolar disorder) warns that treating a depressive episode with an antidepressant alone may increase the likelihood of precipitating a mixed/manic episode in patients at risk for bipolar disorder 7

Addressing Comorbid Anxiety, PTSD, and Substance Use

For Severe Anxiety and PTSD

• Cognitive-behavioral therapy (CBT) has strong evidence for both anxiety and depression components of bipolar disorder and should be initiated once acute mood symptoms stabilize 1
• Prioritize treatment of manic symptoms first, as anxiety often improves concurrently when mood is stabilized 1
• Avoid benzodiazepines as monotherapy but consider low-dose lorazepam 0.5–1 mg PRN (maximum 2 mg/day, not more than 2–3 times weekly) for acute anxiety while mood stabilizers reach therapeutic effect 1
• Clonidine 0.1 mg BID as needed is a reasonable approach for anxiety symptom management without risking mood destabilization 1

For Substance Use History

• The American Academy of Child and Adolescent Psychiatry warns that overlooking comorbidities such as substance use disorders complicates treatment 1
• Cognitive-behavioral therapy specifically targeting substance use patterns and triggers should be implemented once acute mood symptoms stabilize (typically 2–4 weeks) 1
• Lithium reduces suicide attempts 8.6-fold and completed suicides 9-fold, an effect independent of mood-stabilizing properties, making it particularly valuable in high-risk patients with trauma and substance use 1

Monitoring and Maintenance Planning

Baseline Laboratory Assessment Before Starting New Agents

For Lithium:

• Complete blood count, thyroid function tests (TSH), urinalysis, BUN, creatinine, serum calcium, pregnancy test in females 1
• Check lithium level after 5 days at steady-state dosing, targeting 0.8–1.2 mEq/L for acute treatment 1
• Monitor lithium levels, renal and thyroid function, urinalysis every 3–6 months 1

For Valproate:

• Liver function tests, complete blood count with platelets, pregnancy test in females 1
• Target therapeutic range 50–100 μg/mL, with monitoring of serum drug levels, hepatic function, hematological indices every 3–6 months 1

For Atypical Antipsychotics:

• BMI, waist circumference, blood pressure, fasting glucose, fasting lipid panel at baseline 1
• BMI monthly for 3 months then quarterly; blood pressure, fasting glucose, lipids at 3 months then yearly 1

Duration of Treatment

• Maintenance therapy must continue for 12–24 months minimum after mood stabilization, as >90% of noncompliant adolescents relapsed versus 37.5% of compliant patients 1
• Withdrawal of maintenance therapy, especially lithium, dramatically increases relapse risk within 6 months 1
• Some individuals may need lifelong treatment when benefits outweigh risks, particularly with multiple severe episodes or rapid cycling 1

Critical Pitfalls to Avoid

• Never use antidepressant monotherapy in bipolar disorder—this is the most likely contributor to the current manic presentation after the provider discontinued all antidepressants while increasing lamotrigine 1, 7
• Do not delay antimanic treatment waiting for laboratory results—start an atypical antipsychotic immediately while ordering baseline labs 1
• Avoid inadequate trial duration—systematic medication trials require 6–8 weeks at adequate doses before concluding an agent is ineffective 1
• Never discontinue mood stabilizers abruptly—if lamotrigine is to be reduced, taper by 25% every 1–2 weeks over minimum 2–4 weeks 1
• Do not overlook the need for psychosocial interventions—psychoeducation and family-focused therapy should accompany pharmacotherapy to improve medication adherence and outcomes 1

1, 7, 2, 3, 4, 6, 5