When bipolar treatment fails: What’s your next step?

Combine mood stabilizers. After optimizing the dose of a single mood stabilizer, add a second one from a different class. In an open trial, adding oxcarbazepine, up to 2,400 mg/d, helped approximately one-third of 20 patients with refractory mood cycling.¹⁰ Lithium is generally considered less effective than anticonvulsants in rapid cycling, but at least one study showed it was equivalent to carbamazepine for this problem.³⁵ Lithium combined with other mood stabilizers may be more effective than lithium monotherapy in refractory bipolar states.

Other options to consider in combination with mood stabilizers:

• an antipsychotic, especially in the presence of psychotic symptoms, when mixed symptoms are present
  
• clozapine, which can be a highly effective adjunct for refractory mood cycling and mixed states³⁶ (but is a later adjunct because of required monitoring, common adverse effects, and risk of interactions with carbamazepine and benzodiazepines)
  
• nimodipine, which has empiric support for complex mood cycling³⁷ and is well-tolerated with fewer interactions than other mood stabilizers (but cost and need for frequent dosing make it a second-line adjunct)
  
• supraphysiologic doses of thyroxine (≤0.4 mg/d, with T4 levels in the hyperthyroid range), which can improve response to mood-stabilizing regimens³⁴ (but risks of inducing hyperthyroidism make this intervention third-line).
  

ECT can be effective for refractory rapid cycling, but some patients need more treatments than are usually necessary for mania or depression.

Related resources

• Dubovsky SL. Clinical guide to psychotropic medications. New York: WW Norton; 2005.
  
• Dubovsky SL. Treatment of bipolar depression. Psychiatr Clin North Am 2005;28:349-70.
  
• Phillip Long, MD. Internet Mental Health. Online psychiatric diagnosis for the two-thirds of individuals with mental illness who do not seek treatment. www.mentalhealth.com/dis/p20-md02.html.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Carbamazepine • Tegretol
  
• Clonazepam • Klonopin
  
• Clozapine • Clozaril
  
• Fluoxetine • Prozac
  
• Gabapentin • Neurontin
  
• Lamotrigine • Lamictal
  
• Levetiracetam • Keppra
  
• Lithium • Lithobid, others
  
• Lorazepam • Ativan
  
• Memantine • Namenda
  
• Methylphenidate • Concerta, Ritalin, others
  
• Modafinil • Provigil
  
• Nimodipine • Nimotop
  
• Olanzapine/fluoxetine • Symbyax
  
• Oxcarbazepine • Trileptal
  
• Paroxetine • Paxil
  
• Pramipexole • Mirapex
  
• Pregabalin • Lyrica
  
• Quetiapine • Seroquel
  
• Riluzole • Rilutek
  
• Selegiline • Eldepryl
  
• Topiramate • Topamax
  
• Tranylcypromine • Parnate
  
• Valproate • Depakene, Depakote
  
• Venlafaxine • Effexor
  
• Verapamil • Calan, Isoptin, others
  
• Zonisamide • Zonegran
  

Disclosures

Dr. Mostert reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Dubovsky receives research/grant support from Eli Lilly and Company, Organon, Pfizer, UCB Pharma, anhd Forest Laboratories. He is a consultant to Oganon and Biovail Pharmaceuticals.