Due to its recurrent nature, bipolar disorder is one of the main causes of disability for people between the ages of 15 and 44 years. All aspects of this disorder — its definition, clinical boundaries, etiology and treatment — are subjects of debate. There’s no objective measure to make the diagnosis. The DSM IV definition is a syndrome based on reported mood symptoms. The requirement of manic or hypomanic states for diagnosis is problematic because for most patients the illness starts with a depression, delaying the bipolar diagnosis. Some researchers wonder whether earlier recognition and treatment would improve the current outcome statistics. Bipolar disorder is not mania or depression — it’s an illness that creates an abnormal susceptibility to those mood states. The biology of this isn’t yet understood.

Measuring up treatments

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) published in 2006 was an efficacy study of 1,469 subjects. It showed that people primarily had depressive moods with the illness and that recurrence and relapse was common, even with optimal treatment. There have been few comparative studies in bipolar disorder to guide clinicians on treatment choices. A recent international multicentre study, the result of 10 years of work, offers some new evidence (The BALANCE collaborators, The Lancet 2010;375:385-95).

Three-hundred thirty patients, 16 years and older with diagnosed Bipolar I disorder, were randomly allocated to treatment with lithium alone, valproate alone or combination therapy with both drugs. The research question was whether combination therapy was more effective at long-term prevention of mood destabilization. Patients were followed for up to 24 months. The primary outcome was the time before any new treatment was initiated due to an emerging mood episode.

This trial showed that lithium monotherapy and lithium-valproate combination appear to be more effective than valproate alone. The benefit in relapse prevention appeared regardless of baseline severity of illness. This was a “real-world” study design with a diverse patient population and a clinical endpoint (change in treatment). Study limitations included its open label design and lack of a placebo group. The authors suggest that recent tendencies in the U.S. to favour valproate over lithium in bipolar illness aren’t supported by their data.

Monitor lithium

Lithium remains at the centre of current treatment of bipolar disorder, and family physicians often have to monitor this medication. Maintenance blood levels should be 0.6-1.0 mmol/L. Once-a-day dosage to decrease renal toxicity and urine volume is preferable, if the patient can tolerate it. Feelings of fatigue, weakness and restlessness often coincide with peaks in lithium concentration and are usually transient. Many people experience some cognitive blunting and up to 28% have memory problems. Sometimes use of a slow release preparation will help these symptoms. A fine tremor is common and can be exacerbated by use of caffeine. Up to 60% of patients gain weight on lithium. The mean gain has been reported to be 7.5 kg. Clinical hypothyroidism can occur in 34% of patients, often in the first year of lithium treatment. Subclinical hypothyroidism with a high TSH and normal free T4 can also be common. Finally, hypercalcemia has been reported in 10-40% of patients on maintenance therapy. Signs of mild lithium toxicity (1.5-2.0 mmol/L) include slurred speech, ataxia, coarse tremor and drowsiness. Higher serum levels can present as acute delirium.

• Investigations when starting lithium
  • electrolytes
  • CBC, Diff
  • BUN, creatinine
  • TSH, total T4
  • calcium
  • ECG, if over 45 or a cardiac history
• Once stable: every 6 months
  • Check lithium levels
  • CBC, Diff
  • TSH, total T4
• Every year: BUN, creatinine
• Every 2 years: calcium
• Every 5 years: ECG

In the BALANCE study, the relapse rate was 54% in the combination group, compared with 59% in the lithium monotherapy group and 69% in the valproate monotherapy group. In the STEP-BD study, 58% of patients achieved remission but 48.5% of these people then had a relapse during the study. The high relapse rates are striking and show how badly we need new treatments for this illness.