How do we treat resistant adult bipolar disorder? Bipolar Dis:Sep 2012


Gone are the days when bipolar disorder (BD) was considered as a disorder that simple /single treatments can dramatically reinstate lasting normalcy.The concept of the disorder has expanded. The emerging picture is that of a very complex and challenging disorder with cognitive deficits, high substance comorbidity, anxiety, poor treatment response particularly in depressive phase, and subsyndromal symptoms during inter episode periods that  decrease the quality of life.

Defining treatment resistance in BD is extremely difficult.  It would involve unsatisfactory clinical response following at least two,  adequate (by dose and duration), trials of dissimilar treatments within a specific phase of the illness (mania, depression, or subsyndromal breakthrough symptoms during maintenance treatment). Typically, resistance is considered following treatment trials for least 6 weeks in mania, 12 weeks in bipolar depression, and 12 months or more for long-term maintenance treatment.One has to bear in mind that some phases may require prolonged treatment to provide maximal treatment response. Contributions from  social , physical  factors as well as shift, switch and cycling in overall response make the practical application of any definition extremely challenging.

This review by Poon SH, Sim K, Sum MY, Kuswanto CN, Baldessarini RJ looks at treatments that work in resistant BD. All reports of treatment in this group with out applying any  quality criteria were included due to paucity of literature in this area.

Treatment Resistant  Mania:(TRM)

1.Few trials supports use of Clozapine in this group either as mono therapy or as an add on agent.Greater response rates and improved functioning are reported. Manic polarity could predict better response to Clozapine

2. Olanzapine: 88% of the patients with TRM achieved a response  and 78% achieved remission  with olanzapine monotherapy.  (Chen et al 2011)

3. Aripiprazole: Adjunctive use with Clozapine was effective. Uncontrolled study. (Benedetti et al 2010)

4. Donepezil add on to antimanic agents- no benefit observed. In some cases this can cause worsening . (Benazzi ,98, 99)

Treatment Resistant Bipolar Depression (TR B Dep)

1.Lamotrigine augmentaion of on going treatment was better than  adding Inositol or Risperidone. (Nierenberg ,2006)

2. Lamaotrigine found useful in refractory B Dep compared with Gabapentin or placebo (Frye,2000)

3. Retrospective chart review found add on  Lamotrigine useful .No control group. (Sharma 2008)

4. Combination of Lamotrigine plus Quetiapine found useful against either  agents alone or in combination  with  others. Patients on combination had less depression during the 3 months.  (Ahn,2011)

 5. Aripiprazole:  Adjunctive use showed limited evidence of beneficial effect in TR cases.  Akathisia- like restlessness and abnormal mood elevation or confusion observed in as many as half of the patients so treated (Ketter 2006, Kemp 2007)

6. Adjunctive use of T3 :  In 159 cases of TR depression ( BD-II or BD NOS), symptomatic improvement seen in 84% and full clinical remission in 33%, with no evidence of pathological mood elevation  (Kelly 2009).

7.  Adjunctive Bupropion to complex combinations: Uncontrolled pilot study. 13 TR depressed type I or II BD. 62%  experienced improvement in symptoms within 4 weeks of treatment, with no pathological mood elevation (Erfurth, 2002)

8. Ketamine:  18 patients with TR Bipolar depression, with randomization to Ketamine or placebo. Following single doses, 71% of Ketamine-treated patients reported  improved depressive symptoms  compared to only 6% of placebo-treated patients.( Diazgranados,2010)

9. Pramipexole add on Vs placebo add on :  67% responded at 6 weeks against placebo response of 20%  among a total of 22 treatment-resistant BD depressed patients. (Goldberg 2004)

10. ECT: 66–70%  response and remission in 26% in TR Bdep.(Medda 2010). Macedo-Soares et al 2005  studied six BD patients with either refractory mania or depression and found that all the patients responded after 12 sessions of ECT.

11. Combined sleep deprivation with intensive light therapy as an adjunct to standard treatments. 60 TR Bipolar Depression patients. 44% appeared to improve clinically within a week,and 17% at 9 months of follow-up . No controls were included. (Benedetti, 2005)

12. rTMS: In type I or II TR Bipolar Dep, 55% responded in three weeks.  None switched. No controls (Dell’Osso,2009).

13. Deep Brain Stimulation: (of sub callosal cingulate brain white matter): 70% improved and 58% remitted among 17 patients with TR Uni or Bipolar depression at 24 months (Holtzheimer, 2012).

Long-term maintenance treatment:

1. Chart review:Adding sodium valproate to lithium/ carbamazepine, or to lithium plus carbamazepine regimens,  in 63 BD or Schizoaffective disorder patients (74) reported beneficial responses in 75% of subjects, at somewhat higher rates among those previously treated with lithium (84%) than with carbamazepine (69%). (Schaff,93)

2.Olanzapine:  Small, open-label trial involving 23 treatment-resistant subjects who had responded unsatisfactorily to lithium, carbamazepine and valproate, for at least 6 months showed significant reductions in  CGI scores (Vieta, 2001).

3. Topiramate add on:  No benefits in short-term  or when used to supplement standard mood-stabilising treatments in a long-term, placebo-controlled trial (Chengappa, 2006). One uncontrolled trial found Topiramate to be beneficial when added to insufficiently effective standard treatments for 6 months (Vieta, 2002)

4. Calcium-channel blockers lack convincing evidence of efficacy in BD (Casamassima,2010), but an uncontrolled trial of treatment with adjunctive Diltiazem for 12 months was associated with some long-term stabilization in eight BD patients who had failed a series of complex standard treatments (Silverstone 2000)

5. Memantine augmentation:  Improvements in CGI scores for at least a year  (Koukopoulos,2010, 2012)

6. 20 TR Bipolar patients were randomized to Adjunctive psychoeducational and cognitive-behavioral interventions Vs continue with ongoing treatment. There was little difference in clinical status or psychosocial functioning between months 1 and 6 months of  follow up (Gonzalez-Isasi,2010).


There are very few  good quality, methodologically sound, adequately powered studies of enough duration addressing this vital area.

Anticipating  resistance in all bipolar cases would help clinicians to be vigilant about the appearance of resistance and plan appropriate interventions.  Previous research indicate factors like:  very early onset age, rapid cycling, prominent psychotic features and comorbidities.

There is no consensus on what constitutes treatment resistance. Standardised definitions for different phases and types of bipolar disorder is essential to shape the research and practice in  this area.

Summary of the article:

Evidence-based options for treatment-resistant adult bipolar disorder patients.

Poon SH, Sim K, Sum MY, Kuswanto CN, Baldessarini RJ. Bipolar Disord. 2012 Sep;14(6):573-84

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