Harvard Mental Health Letter (May 2006) has a useful article on “Drug treatment of bipolar disorder.”

Here’s the article

One of the most troublesome psychiatric disorders has begun to succumb, in part, to medications. Bipolar (manic-depressive) disorder is a challenge for physicians and psychiatrists because of its varied, severe, and constantly changing symptoms. But many drug treatments are available and can be adapted to the needs of individual patients.


The extremes of bipolar disorder’s mood cycle are misery and elation. At the low end, 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 they usually have physical symptoms — appetite loss, fatigue, pain, insomnia.

At the other extreme, they are energetic, restless, outgoing, and talkative. They get little sleep and don’t mind. 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, impulsive sexual advances, and grandiose unrealizable projects. 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.

Instead of mania (or on the way to mania), a person with bipolar disorder may experience a milder form of elation called hypomania, a mood that is often charming and infectious and may be conducive to enterprise and creativity. In one type of bipolar disorder (called bipolar II), depression alternates with hypomania instead of mania.

Depression and elation sometimes cycle rapidly or culminate in a mixed state that combines sleeplessness and hyperactivity with anger, irritability, and despondency. Mood swings may also take a moderate form called cyclothymia, with less dramatic cycles of activity and lethargy, pessimism and optimism, rising and falling interest in life.

Diagnostic Problems

Bipolar disorder may take years to diagnose. Alcoholism and drug abuse can disguise the symptoms while making them worse. 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). Often the patient 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.” They may also talk to friends and relatives, who often see the damaging effects of mania more clearly than the patient does.

The Drug Treatments

For many years, lithium (usually in the form of lithium carbonate) was 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, a clinician will usually prescribe 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, clinicians will check blood levels of lithium, possibly add an antiepileptic drug or a benzodiazepine, and consider an antipsychotic drug.

For bipolar depression, most clinicians will start with either lithium or the anticonvulsant lamotrigine (Lamictal). 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) is considered especially when there is a serious risk of suicide.

To prevent the return of depression, most clinicians will continue 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 (four or more mood swings per year), a clinician will often start with lithium, valproate, lamotrigine, or a combination of two of these drugs. If necessary, he or she will add valproate, another anticonvulsant, or an antipsychotic drug.

Drug Targets

Lithium: Mania and depression, especially when there is a danger of suicide. Used both to relieve symptoms acutely and as a maintenance treatment (preventing relapse).

Antipsychotic drugs: Acute treatment of depression and mania; maintenance treatment of depression (sometimes preferred to lithium); added to lithium or an antiepileptic drug for severe mania, mixed states, and psychotic reactions.

Valproate: Acute mania, maintenance treatment, mixed states, and rapid cycling.

Lamotrigine: Acute and maintenance treatment of depression (in addition to, or instead of, lithium) and rapid cycling.

Antidepressants: Added to lithium, valproate, or an antipsychotic drug for severe acute depression or to prevent recurrent depression.

Benzodiazepines: Agitation, anxiety, and insomnia in mania, mixed states, and rapid cycling.


Lithium is the oldest mood stabilizer, and in some ways still the most effective, especially for mania and preventing suicide. 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. Blood levels have to be checked periodically and the dose adjusted. Even so, most patients have uncomfortable or worrisome side effects. These include nausea, vomiting and diarrhea, 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 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, clinicians start 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.

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 continue to take the drugs even when the symptoms go away.

Not by Drugs Alone

By using antipsychotic and antiepileptic drugs increasingly as mood stabilizers, 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 (see “STEP-BD”) found that only 60% were receiving an adequate dose of a mood stabilizer at the time, and few were being treated for anxiety disorders and attention deficit disorder that accompanied bipolar symptoms.


The largest clinical trial of treatments for bipolar disorder began in 1998 and ended in 2005. This study, sponsored by the National Institute of Mental Health, is called the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). More than 4,000 patients with various bipolar symptoms as well as other psychiatric and medical disorders participated. The investigators took into account costs, dropout rates, and the effect of treatment on the overall quality of life as well as mood symptoms.

The study was designed to resemble everyday clinical practice more than most clinical trials. Patients began with what was called the Best Practice Pathway, meaning the treatment recommended by knowledgeable psychiatrists and other clinicians. Patients who relapsed or did not improve could switch to clinical trials in which they were assigned at random to various medications, talk therapy, or both. About 1,500 patients were eventually enrolled in at least one of these clinical trials, called Randomized Care Pathways.

Some early findings have been reported in two articles in the American Journal of Psychiatry in 2006. The first study found that among 1,500 patients who spent at least two years in the Best Practice Pathway, nearly 60% recovered for at least two months at some time, but almost half had a recurrence (usually an episode of depression). The second study, a Randomized Care Pathways clinical trial, compared the effects of lamotrigine, risperidone, and the sugar inositol (which has been found to be an effective antidepressant in a few studies) in patients who had not responded to standard care for bipolar depression. The recovery rate was low and equal for all three treatments. Further results, which are just coming in, will provide an opportunity to evaluate the familiar treatments for bipolar disorder and possibly suggest new ones.

Beyond drug treatment, patients need education about the illness to help them identify the symptoms and recognize signs of relapse. Support groups and psychosocial therapies, including interpersonal therapy and cognitive behavioral 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.


Bipolar Disorder Resource Center

Depression and Bipolar Support Alliance
800-826-3632 (toll free)

NIMH Public Inquiries
Depression Information Program
866-615-6464 (toll free)

Systematic Treatment Enhancement Program for Bipolar Disorder


American Psychiatric Association Work Group on Bipolar Disorder. Practice Guideline for the Treatment of Patients with Bipolar Disorder (Revision). American Psychiatric Association, 2002.

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Jones RM, et al. “A Systematic Review of the Efficacy and Safety of Second-Generation Antipsychotics in the Treatment of Mania,” European Psychiatry (January 2006): Vol. 21, No. 1, pp. 1-9.

Keck PE, Jr., et al. “The Expert Consensus Guideline Series: Treatment of Bipolar Disorder 2004,” Postgraduate Medicine Special Report (December 2004), pp. 1-120. Also at http://www.psychguides.com.

Thase ME. “Bipolar Depression: Issues in Diagnosis and Treatment,” Harvard Review of Psychiatry (September-October 2005): Vol. 13, No. 5, pp. 257-71.