Subsyndromal depression

Address iatrogenic causes. In addition, identify and eliminate medications and treatments that may be perpetuating patients’ bipolar symptoms. Stimulants such as methylphenidate and amphetamines may contribute to sleep disturbance and manic relapse and might be minimized or eliminated in a patient with continued symptoms and sleep disturbance.¹⁹

Antipsychotics. Quetiapine and the combination olanzapine/fluoxetine are FDA-approved for acute bipolar depression episodes, but not all atypical antipsychotics show antidepressant effects in bipolar disorder:

• Two trials of aripiprazole for bipolar depression failed to show benefit.²⁰
  
• A trial that compared risperidone with lamotrigine and inositol for treatment-resistant bipolar depression suggested that risperidone may have hindered recovery.²¹
  

Other agents. Lamotrigine’s benefit in acute bipolar depression is controversial, as no trial has shown unequivocally that it is more effective than placebo. Modafinil, 100 to 200 mg/d, was significantly more effective than placebo as an adjunct to mood stabilizer therapy in a 6-week study of bipolar depression.²² This result in a cohort of 85 patients has not been replicated, however, and modafinil’s long-term safety in bipolar disorder is unknown.

Table 2

Subsyndromal bipolar depression: Recommended medications*

Medication	Initial and maximum dosages	Clinically important side effects
Quetiapine	Start at 50 mg and titrate to 300 mg within 4 to 7 days; maximum 600 mg	Sedation, somnolence, weight gain, gastrointestinal side effects, lipid abnormalities, increased fasting glucose, increased risk of diabetes
Olanzapine/fluoxetine	Start at 6 mg/25 mg; maximum 12 mg/50 mg	Weight gain, sedation, gastrointestinal side effects, lipid abnormalities, increased fasting glucose, increased risk of diabetes
Lamotrigine	Must be titrated per package labeling; start at 25 mg and titrate to 200 mg (12.5 mg titrated to 100 mg if patient is on valproate, 50 mg titrated to 400 mg if on carbamazepine or other enzyme inducer); maximum (per label) 500 mg	Rash, headache, balance difficulties, clumsiness; Stevens-Johnson syndrome or toxic epidermal necrolysis are rare but potentially fatal
Lithium	Start at 300 to 600 mg and use moderate blood levels (0.4 to 0.7 mEq/L); if no improvement in 4 to 8 weeks, titrate to 0.8 to 1.1 mEq/L	Tremor, nausea, diarrhea, increased thirst, increased urination, hair loss, thyroid abnormalities, weight gain, acne, worsening of psoriasis, diabetes insipidus, renal insufficiency
Divalproex	Start at 500 to 750 mg and increase to 15 to 20 mg/kg; usual target blood levels are >50 mg/dL	Nausea, abnormal liver function tests, weight gain, hair loss
Olanzapine	Start at 5 mg; maximum 30 mg	Weight gain, sedation, somnolence, lipid abnormalities, increased fasting glucose, increased risk of diabetes
Modafinil	Start at 50 to 100 mg and increase to 200 mg; higher dosages have not been systematically studied in bipolar disorder	Nervousness, insomnia
EPS: extrapyramidal symptoms
* Medications are listed in from most to least evidence supporting their use in treating bipolar depression

CASE CONTINUED: Distressed by psychotherapy

You ask Mr. W about his psychodynamic psychotherapy, and he says that exploring his early life experiences and his work difficulty is increasing his anxiety. You recommend switching to cognitive-behavioral therapy (CBT) to work on delegating tasks that are not his strong areas and focusing on his marketing talents. You also encourage him to maintain regular sleep-wake cycles.

Some psychodynamic psychotherapies are thought to increase anxiety and mood instability in bipolar disorder patients. Examine the form and content of psychosocial approaches for their role in worsening your patients’ symptoms. As with medications, validated psychotherapeutic interventions—such as CBT for bipolar disorder, family-focused treatment, interpersonal social rhythm therapy, and long-term group psychotherapy^23,24—are preferred over those not specifically studied in bipolar disorder.

In clinical practice, medication management of bipolar disorder is more effective when combined with psychoeducation and psychosocial interventions. Advise patients to:

• Establish a social rhythm that includes a regularized sleep-wake cycle and predictable daily schedules, with planned contact with people and organized activities.
  
• Decrease behaviors associated with mood fluctuation, such as substance use, irregular hours of sleep, conflicts in relationships and work, poor adherence to medications, and lack of regard for physical health.
  

Include psychoeducation about bipolar disorder’s course and treatment when communicating with patients and their families.^23,25 Behavior change may come slowly, but monitor the patient’s progress and focus on that goal.

CASE CONTINUED: Changes for the better

After several months of CBT and medication changes, Mr. W is continuing to work and shows some symptom improvement. His QIDS-SR scores have decreased to 6, indicating minimal to mild depressive symptom burden. He reports that most weeks he has no depressive symptoms, but he remains unable to focus on specific tasks for long periods. He continues to have difficulties when his work requires detailed, intensive activities.