In two minds

Healthcare Middle East traces the drug treatments that are making their mark on bipolar disorder.

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By  Joanne Bladd Published  September 12, 2006

Healthcare Middle East traces the drug treatments that are making their mark on bipolar disorder.

“Mania often is mistaken for schizophrenia, and hypomania is usually denied or disregarded. Many children diagnosed with attention deficit disorder eventually develop manic and depressive symptoms.”

One of the most troublesome psychiatric disorders has begun to succumb, in part, to medications.

Bipolar (manic-depressive) disorder is estimated to affect 1% of the population worldwide. As one of the most distinct syndromes in psychiatry, its varied, severe, and constantly changing symptoms are an ongoing challenge for physicians and psychiatrists. But many drug treatments are now available and can be adapted to the needs of individual patients.

The extremes of bipolar disorder’s mood cycle are misery and elation, but the hallmark of the illness is mania. Mania is characterised by elevated mood or euphoria, overactivity with a lack of need for sleep and an increased optimism. Patients are energetic, restless, outgoing, and talkative. Their thoughts flow irresistibly, leaping from subject to subject.

They imagine that they have special talents and can soon achieve wealth, power, or ideal love. They are tempted by extravagant spending and grandiose unrealisable projects, and may be disinhibited about sexual matters in their speech or actions.

Their euphoria may turn into severe anxiety, irritability, or rage; their high energy into purposeless agitation; and their racing thoughts and speech into sheer nonsense. However, while manic behaviour is distinct from a patient’s usual personality, its onset may be gradual with weeks or months passing before symptoms become full-blown.

Mania can be of varying severity. Milder episodes without symptoms of being dangerous to oneself or others, that don’t cause severe impairment in social or occupational functioning or require hospitalisation, are categorised as hypomania. This mood is often charming and infectious and may be conducive to enterprise and creativity.

The syndrome of major depressive episodes and hypomanic episodes is defined as bipolar II disorder, as outlined in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, and is distinct from full-blown bipolar I disorder.

The depression that alternates with manic episodes shows more familiar symptoms. Patients lose interest in life and capacity for pleasure. They feel sad, worthless, and hopeless. They cannot concentrate, make decisions, or take initiative. They may be either agitated or lethargic, and this is usually accompanied by physical symptoms, such as appetite loss, fatigue, pain and insomnia.

Depression and mania sometimes cycle rapidly or culminate in a mixed state that combines sleeplessness and hyperactivity with anger, irritability, and despondency. Patients who have four or more episodes of mania or depression per year are considered to be ‘rapid cyclers’, and may be difficult to treat.

Mood swings may also take a moderate form called cyclothymia. Sufferers typically cycle between mild or moderate depression and hypomania. Patients with cyclothymia experience symptoms of hypomania but not full-blown manic episodes.

“Electroconvulsive therapy (ECT) may be considered, primarily as an acute treatment for hospitalised patients who are suicidal, psychotic, or dangerous to others.”|~|Bipolar disorder may take years to diagnose. Alcoholism and drug abuse can complicate or disguise symptom - patients in the depressive stage may self-medicate with alcohol or drugs and patients in the manic phase may crave them as part of the arousal characteristic of mania. Mixed mood states can be mistaken for many other conditions, including personality disorders.

Mania often is mistaken for schizophrenia, and hypomania is usually denied or disregarded. Many children diagnosed with attention deficit disorder eventually develop manic and depressive symptoms.

The most common masquerader is unipolar depression. Depression usually lasts longer than mania and appears first in the bipolar cycle. As many as 40% of patients diagnosed with major depression are later found to have some form of bipolar illness. Bipolar disorder is more likely in a depressed patient with a family history of bipolar disorder or psychotic symptoms (delusions or hallucinations).

In families of persons with bipolar disorder, first-degree relatives are more likely to have a mood disorder than the relatives of those who do not have bipolar disorder. Many studies have suggested that such disorders are familial and may reflect an underlying genetic vulnerability.

Often bipolar patients will feel more anxiety and less sadness than is usual in unipolar depression. Clinicians can look for evidence of past mania or hypomania by asking patients whether they have ever felt “better than normal”. It may also be beneficial to talk to friends and relatives, who often see the damaging effects of mania more clearly than the patient does.

For many years, lithium (usually in the form of lithium carbonate) was seen as the classic mood stabiliser and the only accepted drug treatment for bipolar disorder. Now, many drugs have become available for various stages and phases of the disorder, and more than 80% of patients take two or more.

There are no rigid rules for using or combining medications, but the following are common practices:

For a patient with severe mania or a mixed mood state, the first-line treatment is lithium or the anticonvulsant (antiepileptic) drug valproate (Depakote, Depakene), often adding a second-generation antipsychotic drug. Olanzapine (Zyprexa) is widely used; others are risperidone (Risperdal), ziprasidone (Geodon), quetiapine (Seroquel), and aripiprazole (Abilify). For milder symptoms, lithium or valproate alone may suffice, sometimes with the temporary addition of a benzodiazepine anti-anxiety drug, such as lorazepam (Ativan).

If symptoms persist, any of these drugs may be substituted or a new drug added — again, an anticonvulsant, antipsychotic, or lithium. If mania or a mixed state emerges despite treatment, check blood levels of lithium, possibly add an antiepileptic drug or a benzodiazepine, and consider an antipsychotic drug.

For bipolar depression, either lithium or the anticonvulsant lamotrigine (Lamictal) are commonly prescribed. There is some controversy about using antidepressants in this disorder, because they can trigger a manic episode or rapid cycling. But when symptoms are severe, many clinicians do prescribe a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine (Prozac) or sertraline (Zoloft); or one of the newer drugs venlafaxine (Effexor), mirtazapine (Remeron), or bupropion (Wellbutrin). Electroconvulsive therapy (ECT) may be considered, primarily as an acute treatment for hospitalised patients who are suicidal, psychotic, or dangerous to others.

To prevent the return of depression, consider continuing to prescribe an antipsychotic drug, lithium, or lamotrigine, often with an antidepressant added. The combination of olanzapine and fluoxetine has been found particularly effective.

For rapid cycling bipolar disorder, start with lithium, valproate, lamotrigine, or a combination of two of these drugs. If necessary, add valproate, another anticonvulsant, or an antipsychotic drug.

“In addition to antimanic efficacy, Lithium has been shown to have prophylactic efficacy in bipolar disorder and some efficacy in prophylaxis against bipolar depression.

"Lithium is the oldest mood stabiliser, and in some ways is still the most effective, especially for mania and preventing suicide. In addition to antimanic efficacy, it has been shown to have prophylactic efficacy in bipolar disorder and some efficacy in prophylaxis against bipolar depression. But it takes several weeks to work, and it can be difficult to set a dose that is neither too low to be effective nor too high to be safe. The drug has a narrow therapeutic index and blood levels must be checked periodically and doses adjusted.

Even with regular monitoring, most patients have uncomfortable or worrisome side effects. These include nausea, vomiting and diarrhoea, tremors, weight gain, problems with concentration and memory, sexual difficulties, irregular heart rhythms, thyroid deficiency, and excessive thirst and urination. Thyroid and kidney functions must be monitored. Lithium can also cause birth defects if used in pregnancy.

Valproate, which was initially developed to treat seizures, is also approved for treat bipolar disorder. Side effects include upset stomach, drowsiness, tremors, and weight gain. It can also cause birth defects, liver damage, and inflammation of the pancreas, and lower the clotting capacity of the blood. Tolerance may develop.

Lamotrigine has relatively few side effects, most commonly headache, nausea, and dry skin. But in 1%–2% of patients it causes a rash that can develop into a serious, even potentially fatal skin condition. To prevent this, clincians
are advised to start patients at a low dose and raise it gradually.

Antipsychotic drugs were once prescribed for bipolar patients mainly if they had psychotic symptoms, but now they are much more widely used in both mania and bipolar depression. The chief side effects are drowsiness, dry mouth, headache, weight gain, and a rise in blood sugar and cholesterol. Ziprasidone and aripiprazole present less risk of weight gain and high cholesterol than olanzapine, risperidone, and quetiapine.

The antipsychotic drug clozapine has additional side effects: possible seizures, muscle weakness, and a psychotic withdrawal reaction. It requires expensive and inconvenient weekly blood tests, because about 1% of patients taking it develop agranulocytosis (loss of white blood cells). For these reasons it is not a first choice — and not FDA-approved for the treatment of bipolar disorder — but it may help patients who respond to no other drug.

Antidepressants have minor side effects in most patients. Some common ones are insomnia, headaches, and stomach upset, usually temporary and mild. They sometimes increase anxiety and can reduce the clotting capacity of the blood. SSRIs, but not bupropion, reduce sexual interest and performance. SSRIs can alter the effects of other drugs by occupying the liver enzymes needed to break them down.
Because of the risk of mania or rapid cycling, some experts believe patients with bipolar disorder should be given antidepressants only as a last resort and almost never as the only drug treatment. But recent trials suggest that this danger may have been exaggerated.

Electroconvulsive therapy is generally considered safe. The most troublesome side effect is memory loss for the period surrounding the treatment, and sometimes for longer.

When treating bipolar patients, it is often necessary to change prescriptions, and these changes should not be abrupt. The dose of a drug should be reduced gradually, and the previous drug should not be withdrawn before a new one is introduced. It is also important that patients maintain compliance even when the symptoms disappear.

By using antipsychotic and antiepileptic drugs increasingly as mood stabilisers, clinicians have confirmed that they are treating symptoms rather than an underlying disorder. They often need careful recording of symptom patterns and trial-and-error experimentation to find the right combination of drugs for a patient. The treatment of acute symptoms — especially severe mania and mixed states — is usually effective, but long-term results are much less reliable.

Meanwhile, many patients are not receiving adequate treatment. A report on the first thousand patients to enter the STEP-BD clinical trial found that only 60% were receiving an adequate dose of a mood stabiliser at the time, and few were being treated for anxiety disorders and attention deficit disorder that accompanied bipolar symptoms.

Beyond drug treatment, patients need education about the illness to help them identify the symptoms and recognise signs of relapse. Support groups and psychosocial therapies, including interpersonal therapy and cognitive behavioural therapy, have also proved effective. And it can be especially important to involve families in planning and monitoring treatment. Although the wider choice of medications available in the last two decades is a great advance, we are far from being able to relieve all the symptoms or eliminate the worst consequences of bipolar disorder by drugs alone.

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