A Clinically Relevant Update on Recent Developments in Bipolar Illness

Navigating the bipolar world: While treatment options increase in number, so do the pitfalls, as outlined in this survey of recent developments.

Bipolar disorder is a common psychiatric disease with a lifetime prevalence of about 1%. It is characterized by recurrent episodes of depression and mania or hypomania. The quality of life of bipolar patients is significantly affected by this chronic illness.

Without adequate treatment, a woman with onset of bipolar disorder at age 25 may expect to lose about 14 years of work activity and 12 years of normal health (ref. 1). In addition to its high morbidity effect, bipolar illness is associated with mortality rates higher than in the general population.

The management of bipolar disorder includes treatment of depressive and manic episodes and prophylactic treatment aimed at preventing future episodes. A variety of pharmacologic and non-pharmacologic interventions are necessary for optimal effect on symptom expression of illness course.

Lithium

Lithium is the first drug shown to be effective for the treatment of mania and in the prophylaxis of either manic or depressive recurrences and it still remains the first-line treatment for bipolar illness. Further studies looking at the effect on suicidal behaviour have shown that long-term lithium treatment reduces the risk of suicide, which is about 15 times higher in bipolar patients than in the general population.

About 30% of bipolar patients respond completely to lithium and another 30% show at least a partial benefit. In case of a “non-satisfactory benefit” from lithium, there are a variety of medications that may be used in combination with lithium or might be tried as a monotherapy. These include anticonvulsants and antipsychotics. There is a growing number of medications shown to be effective in the acute or maintenance treatment of bipolar illness.

Pre-treatment criteria that would allow for a prediction of treatment response could be helpful to avoid a trial-and-error approach to the selection of the most appropriate medication for an individual patient. To date, it has been suggested that a detailed assessment of the illness course and family history of response to medication might facilitate the selection of an effective drug. This is particularly true in the case of lithium.

The predictors of positive response to lithium are as follows:

• Episodic course prior to lithium treatment
• Absence of spontaneous rapid cycling
• Low to average frequency of episodes
• Positive family history for bipolar disorder as opposed to schizophrenia (ref. 2)

Anticonvulsants

Valproate and carbamazepine are anticonvulsants that are widely used in the prophylaxis of bipolar disorder and have been shown to be effective in the treatment of acute mania when compared to placebo. .

Valproate has been shown to be effective in the treatment of bipolar rapid cycling. Based on a study of 101 bipolar patients with rapid cycling, Calabresse et al. (ref. 3) suggested what might be the criteria for positive response to valproate for both acute as well as prophylactic treatment in this psychiatric population. For antimanic response - prophylactic or acute - the predictors were as follows:

• Non-psychotic
• Mild mania
• Mixed states
• Decreasing or stable episode frequencies.

For antidepressant response, the predictors were as follows:

• Non-psychotic mania
• Increasingly severe mania
• Absence of borderline personality disorder (ref. 3)

According to a study by Greil et al. (ref. 4), patients who might benefit from long-term treatment with carbamazepine are those with non-classical bipolar illness as opposed to classical illness, which the authors defined as bipolar I disorder without co-morbidity and mood-incongruent delusions.

New thymoleptic compounds

In addition to the now well-established medication treatments, new thymoleptic compounds have undergone recent study: lamotrigine, gabapentin and topiramate. Lamotrigine, one of the newer anticonvulsant drugs, has been reported to be superior to placebo in the treatment of bipolar depression (ref. 5 ).

Some effect has also been shown for treatment of refractory bipolar I or bipolar II disorder (ref. 6). A recent doubleblind placebo-controlled study has evaluated the long-term effect of lamotrigine and lithium.

Both drugs were superior to placebo; lamotrigine was more effective in preventing depressive episodes, lithium in preventing manic episodes (ref. 7). Another study compared clinical characteristics and family history of responders to lamotrigine versus responders to lithium.

The results suggested that patients with co-morbid panic disorder and substance abuse, or bipolar patients with family history positive for panic attacks, schizoaffective disorder and major depression, might particularly benefit from lamotrigine (ref. 8).

Other new anticonvulsants

Gabapentin and topiramate are other new anticonvulsants that are being investigated as a treatment for bipolar disorder. Several open trials have suggested some improvement of mania or depression with gabapentin as an adjunctive treatment.

However, a double-blind placebo-controlled study with adjunctive gabapentin did not find any significant positive effect in favour of gabapentin (ref. 9).With regards to topiramate, current data – mostly from open-label studies – suggest that topiramate may be effective in treatment of refractory bipolar disorder and in acute mania (ref. 10).

Long-term use of antidepressants

It is still being debated whether the use of antidepressants should be reserved for short term treatment of bipolar depression in contradiction to long-term use in bipolar disorder.

Treatment with antidepressants has been complicated with their induction of a rapid cycling pattern of bipolar illness, in which at least four episodes occur during one year, or a switch to mania from depression secondary to antidepressant treatment.

Switch to mania induced by antidepressants has been seen mostly with tricyclics and MAOIs. SSRIs seem to have a lower potential to induce mania switches but debate about this issue continues.

Lamotrigine has been shown to be effective for bipolar depression and has been associated with a low potential to induce switches from depression to mania. Thus, lamotrigine might become the treatment of choice in a patient with a history of antidepressant-induced mania.

Rapid cycling

In a patient with rapid cycling bipolar disorder, antidepressants are not recommended and should be avoided if possible. The options of treatment in this case would be optimisation of current mood stabilizer or adding a second prophylactic medication (ref. 11). Some authors suggest the use of light therapy (Kutcher, personal communication).

Based on the results of studies with valproate and lamotrigine treatment for bipolar rapid cycling, valproate may be tried as the first-line treatment for rapid cycling in bipolar disorder I and lamotrigine in rapid cycling bipolar disorder II.

In addition to increasing the potential for depression-to-mania-switch and the accentuation of rapid cycling, antidepressant use in bipolar illness may contribute to a pattern of increased depressive chronicity over the course of the illness. It has been reported that cessation of an antidepressant may paradoxically lead to recovery from chronic depression in a bipolar patient (ref. 12).

Metabolic aspects

Bipolar disorder has an increased risk of cardiovascular death (ref. 13). From this point of view, the fact that bipolar disorder has been associated with high prevalence of conditions considered to be risk factors for cardiovascular disease, such as diabetes mellitus, obesity and hypercortisolaemia, is of particular interest.

Several authors had already pointed out the association between manic-depressive illness and abnormalities in glucose metabolism in the beginning of the last century. Disturbances in glucose metabolism in manic-depression had been investigated in the 1960's and 1970's, especially in connection with lithium treatment. Since the 1980's, it has been repeatedly reported that the risk of diabetes mellitus in bipolar patients is about three times higher than in the general population.

This comorbidity has recently been re-emphasized after the increasing evidence of the link between treatment with the new-generation antipsychotic drugs and new-onset diabetes mellitus. Several studies, however, have suggested that treatment with antipsychotics alone could not account for the entire risk of developing diabetes mellitus in bipolar patients.

So far, we have insufficient information about the nature of the relationship between the two disorders – bipolar and diabetes. However, for clinical practice, there are some interesting and relevant data already available.

Abnormalities in glucose metabolism

It has been demonstrated that bipolar patients show abnormalities in glucose metabolism during episodes of bipolar illness with a trend towards normalization with remission. In addition, some treatments used in bipolar disorder have been associated with changes in glucose metabolism. .

In particular, tricyclic antidepressants have been associated with both hypo- and hyperglycemias, SSRIs with a positive effect on insulin sensitivity, monoamine oxidase inhibitors (MAOI) with hypoglycaemia and ECT with hypoglycaemia and a decrease in insulin requirement for diabetes mellitus in patients treated for depression.

One study even demonstrated a beneficial response to MAOIs in patients with diabetes who had previously failed to respond adequately to sulfonylurea.

Bipolar disorder and obesity

Overweight and obesity are common in bipolar patients. Several studies have focused specifically on this issue in bipolar patients. In the study by Fagiolini et al. (ref. 14), 68% of bipolar I patients were obese or overweight. In addition, weight gain was related mainly to the acute phase of treatment, while it was less pronounced during the maintenance phase. .

In a controlled study of euthymic bipolar patients reported by Elmslie et al. (ref. 15 ), female patients were more overweight than controls and both males and females were significantly more obese than control subjects. In this study, obesity was associated with antipsychotic treatment.

Except of medication, increase in weight in bipolar patients may be related to changes in appetite, diet, lifestyle and energy expenditure during episodes. However, there may also be as-yet-undefined other metabolic disturbances that may accompany bipolar disorder.

Most psychotropic medications used for treatment of bipolar disorder have been reported to increase weight. Weight gain, especially when excessive or occurring in an already overweight patient, represents a potentially severe side effect of treatment by increasing the patient's risk of various medical problems such as cardiovascular disease or diabetes mellitus or other medical illnesses.

Compliance

In addition to its importance for health maintenance, weight gain is also one of the major concerns with respect to compliance.

Increased weight is associated with poorer compliance. With respect to the increased obesity rates in bipolar subjects and the risks associated with overweight or obesity, the potential of medications to induce weight changes should be considered in individual patients.

Lithium and weight

In patients treated with lithium, increase in weight is a common side effect, occurring in about one-third to two thirds of patients. The mechanism of weight gain in lithium treatment is not fully understood; it might involve hypothyroidism induced by lithium, increased fluid intake or lithium's effect on glucose metabolism.

Valproate and weight

Valproate has also been associated with weight gain. In one study, 21% of bipolar patients gained weight on valproate, which was a significantly higher incidence compared to the placebo group (ref. 16). In another study evaluating the effect of valproate therapy on weight in women with epilepsy, 50% of subjects had substantial weight gain during treatment with valproate (ref. 17).

Gabapentin, lamotrigine and topiramate and weight

In patients with a seizure disorder, gabapentin has been reported to induce weight gain either when used in combination with another anti-epileptic treatment or as a monotherapy. However, lamotrigine and topiramate have not been associated with weight gain.

Moreover, weight loss was reported in bipolar patients treated with topiramate as an adjunctive treatment (ref. 18).

Antidepressants and weight

Regarding antidepressant drugs, the highest potential to induce weight gain has been noted with tricyclic antidepressants and non-selective MAOIs and the new compound mirtazapine. In contrast, SSRIs, selective MAOIs and some of the novel antidepressants (bupropion, venlafaxine) appear to be relatively weight neutral (ref. 19).

Antipsychotics and weight

The biggest concern regarding weight gain in connection with psychiatric medication arises with antipsychotic agents. Both typical- and atypical antipsychotics are known to induce weight gain. A meta-analysis by Allison et al. (ref. 20) evaluated 81 papers on weight change associated with various antipsychotic treatments.

They reported that the estimated weight gain over 10 weeks of treatment is the highest with clozapine (4.45 kg), followed by olanzapine (4.15 kg) and thioridazine (3.19 kg).

Lower but nonetheless significant weight increases have been reported for chlorpromazine (2.58 kg), risperidone (2.10 kg) and haloperidol (1.08 kg). Of interest is that ziprasidone use has not been associated with significant weight gain. Some other antipsychotics such as molindone have also demonstrated only a small effect on weight.

Bipolar disorder and HPA

Bipolar disorder as well as obesity and diabetes mellitus have been associated with changes of the hypothalamic-pituitary-adrenocortical (HPA) axis and a lack of adequate cortisol-suppression in response to dexamethasone.

In affective disorders including bipolar disorder, abnormal response to the dexamethasone suppression test (DST) has been observed during the depressive phase with return to normal on complete recovery or after the switch from depression to mania.

The DST had been proposed to be the first biological correlate in psychiatry, with the promise to become the first laboratory tool useful for the diagnosis of endogenous depression. However, further research has shown that there are many conditions that alter the response to dexamethasone.

Because of the relatively low specificity of the test, DST did not gain much use in clinical practice and its usefulness in bipolar illness is not clear. Little knowledge exists about the mechanism or the nature and the significance of the above described metabolic changes in bipolar patients.

Only speculation so far

It is possible that normalization of metabolic changes is an important consideration for the clinical target of long-term remission of bipolar disorder. Metabolic correlates might be helpful in predicting increased risk of recurrence or may prove to be indicators of an effective or ineffective treatment.

To date these possibilities are only speculation. However, it should be common clinical practice to monitor various metabolic indices (such as the glucose levels), especially in patients with poor treatment outcome in bipolar disorder. Where abnormal, these metabolic states require appropriate treatment.

Importantly, patients with diabetes mellitus may require changes to their diabetic medication at different stages of their bipolar illness or during changes in their psychotropic medication.

Clinically this should not be neglected given the potential complication that may arise in connection with hypoglycaemia. The diagnosis of diabetes mellitus or impaired glucose-tolerance should be considered when selecting a treatment for bipolar disorder. The same is true regarding treatment of obese patients. Growing evidence in the literature documenting the metabolic effects of particular medication may assist in selection of specific medication treatments for these patients.

References

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