Breakthroughs in Bipolar Treatment

"We should continue to repurpose treatments and to recognise the role of serendipity" (Geddes & Miklowitz, 2013).

That quote was from a recent review article in The Lancet, which did not hint at any impending pharmacological breakthroughs in the treatment of bipolar disorder. In other words, the future of bipolar treatment doesn't look much different from the present (at least in the immediate term).

Bipolar disorder, an illness defined by the existence of manic or hypomanic highs, alternating with depressive lows, can be especially difficult to treat. And the mood episode known as a mixed state, where irritability, expansive mood, anxiety, and/or agitation occur simultaneously with depressive symptoms, is an under-recognized, moving-target diagnosis (Koukopoulos et al., 2013). Mood stabilizers such as lithium and divalproex have long been the first line pharmacological choices. But these don't always work, and polypharmacy seems to be the rule, rather than the exception.

The spinning molecule above is haloperidol, a first generation antipsychotic drug developed in 1958 and approved by the FDA in 1967 as a treatment for schizophrenia. It's a dopamine blocker known for producing untoward extrapyramidal side effects, or movement disorders such as tremors and tardive dyskinesia. Nonetheless, haloperidol (Haldol®) is still the most effective drug for the acute treatment of mania, and fairly well tolerated (see HAL in the figure below). The second generation (atypical) antipsychotics risperidone (RIS) and olanzapine (OLZ) also turn out pretty well in the antimanic sweepstakes. But these drugs can also have untoward side effects, notably substantial weight gain that can lead to high cholesterol, diabetes, and metabolic syndrome.

Figure (Geddes & Miklowitz, 2013). Ranking of antimanic drugs according to primary outcomes derived from multiple treatment meta-analysis. Efficacy is shown as a continuous outcome against the dropout rate. Treatments toward the red section combine the worst efficacy and tolerability profiles and treatments towards the green[ish] section combine the best profiles.¹


Clearly, effective medications with fewer side effects are needed. Unfortunately, there doesn't seem to be anything new on the horizon, according to Geddes and Miklowitz:

Overall, advances in drug treatment remain quite modest. Antipsychotic drugs are effective in the acute treatment of mania; their efficacy in the treatment of depression is variable with the clearest evidence for quetiapine. Despite their widespread use, considerable uncertainty and controversy remains about the use of antidepressant drugs in the management of depressive episodes. Lithium has the strongest evidence for long-term relapse prevention; the evidence for anticonvulsants such as divalproex and lamotrigine is less robust and there is much uncertainty about the longer term benefits of antipsychotics.

The article is actually more bullish on combining existing drugs with various psychosocial interventions (e.g., family-focused approaches, strict regulation of social and circadian schedules, etc.), which are touched on below in the Appendix (Table 1 of Geddes & Miklowitz, 2013). That table also mentions some of the usual drug suspects.

To find out what else might be in the works, I looked through ClinicalTrials.gov for open interventional drug studies in adults. There were a few surprises... foremost among these was Methylphenidate for the Treatment of Acute Mania. It seems bizarre to me that methylphenidate (the stimulant drug Ritalin) would be proposed as a treatment for mania, since 40% of patients prescribed stimulants for bipolar depression (or comorbid ADHD) experienced stimulant-induced mania/hypomania (Wingo & Ghaemi, 2008).

The Ritalin trial was submitted to ClinicalTrials.gov in Feb. 2012, but the study is not yet open for patient recruitment 1.5 years later. The investigators recently published the study protocol in BMC Psychiatry, however (Kluge et al., 2013). They proposed the ‘vigilance regulation model of mania’ where:

Unstable vigilance induces a pathogenic circle with vigilance stabilisation syndrome leading to full-blown mania. [NOTE: huh?]

The outlined model ... is related to personality theories about extraversion [9] and sensation seeking [10] which comparably explain these traits as an attempt to compensate for low central nervous system arousal.

Basically, it works for ADHD, and there are a handful of uncontrolled case reports, so.... let's conduct a clinical trial.


Bipolar Depression

Depressive episodes in bipolar disorder are longer in duration and considered more difficult to treat. Again, ClinicalTrials.gov did not disappoint, revealing a grab bag of "repurposed" treatments:

Adjunctive Lisdexamfetamine - another stimulant for ADHD (aka Vyvanse).

Adjunctive Isradipine (a calcium channel blocker prescribed for high blood pressure) - this idea — not a new one — deserves a post of its own.

Adjunctive Minocycline (an antibiotic) - the proposed mechanism of action is to reduce the production of pro-inflammatory cytokines.

Ceftriaxone (another antibiotic) - however, the proposed mechanism here is inactivation of the excitatory neurotransmitter glutamate, via actions on the glutamate transporter.

NMDA Antagonists (i.e., club drug ketamine) - this is complicated and again deserving of its own post.

Tranylcypromine (a monoamine oxidase inhibitor) - old, old school antidepressant with lots of contraindications and dietary restrictions.

Ramelteon (a melatonin receptor agonist used to treat insomnia) - targeting the sleep/wake cycle could be an important approach.

N-Acetyl Cysteine and Aspirin - aspirin? really??

We propose to conduct a double-blind placebo-controlled trial with a widely available and prototypical non-steroidal anti-inflammatory agent, aspirin, and an antioxidant agent, NAC, involving symptomatic Bipolar Disorder type I and II patients having a depressive or mixed episode currently. This will be the first controlled study to test the hypothesis that aspirin and NAC, by themselves or in combination, will be beneficial in treating depression in bipolar disorder patients and in promoting mood stabilization.

For the ultimate in repurposed treatments, see this recent opinion piece in BMC Medicine on Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness.


Footnote

¹ Abbreviations for Geddes and Miklowitz (2013) Figure:  ARI=aripiprazole. ASE=asenapine. CBZ=carbamazepine. VAL=valproate. GBT=gabapentin. HAL=haloperidol. LAM=lamotrigine. LIT=lithium. OLZ=olanzapine. PBO=placebo. QTP=quetiapine. RIS=risperidone. TOP=topiramate. ZIP=ziprasidone.


References

Berk M, Dean O, Drexhage H, McNeil JJ, Moylan S, Oneil A, Davey CG, Sanna L, & Maes M (2013). Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness. BMC medicine, 11 (1). PMID: 23506529

Geddes JR & Miklowitz DJ (2013). Treatment of bipolar disorder. Lancet, 381 (9878), 1672-82. PMID: 23663953

Kluge M, Hegerl U, Sander C, Dietzel J, Mergl R, Bitter I, Demyttenaere K, Gusmão R, Gonzalez-Pinto A, Perez-Sola V, Vieta E, Juckel G, Zimmermann US, Bauer M, Sienaert P, Quintão S, Edel MA, Bolyos C, Ayuso-Mateos JL, & López-García P (2013). Methylphenidate in mania project (MEMAP): study protocol of an international randomised double-blind placebo-controlled study on the initial treatment of acute mania with methylphenidate. BMC psychiatry, 13. PMID: 23446109

Koukopoulos A, Sani G, Ghaemi SN. (2013). Mixed features of depression: why DSM-5 is wrong (and so was DSM-IV). Br J Psychiatry 203:3-5.

Wingo AP, Ghaemi SN. (2008). Frequency of stimulant treatment and of stimulant-associated mania/hypomania in bipolar disorder patients. Psychopharmacol Bull. 41:37-47.


Appendix

- click on image for a larger view -