Bipolar disorder - Medication

Principles
Medications called mood stabilizers are used to prevent or mitigate manic or depressive episodes. Because mood stabilizers are generally more effective at treating mania than bipolar depression, periods of depression are sometimes also treated with antidepressants. However, as stated above, antidepressants carry the risk of inducing mania, especially in bipolar patients who are not taking a mood stabilizer.

In severe cases where the mania or the depression is severe enough to cause psychosis (and recently sometimes in less severe cases as well, although this remains controversial), The antipsychotic drugs may also be used. A new class of "atypical" antipsychotics has also become more widely used for bipolar episodes. The FDA has only approved them for acute episodes, if at all (with the exception of olanzapine, which is approved as a mood stabilizer). Like most doctors, psychiatrists use medication for "off-label" uses, even when such uses are not supported by available research. It is becoming accepted practice to use atypical antipsychotics as mood stabilizers at this point, and there is support in the literature for their effectiveness in mood stabilization.

Some people have reported that antipsychotics cause mania, panic attacks, or psychosis. Any agitation should be reported to the doctor immediately. Antipsychotics also carry a risk of causing tardive dyskinesia, a potentially disfiguring and sometimes irreversible movement disorder that may case the arms, legs, face or head to jerk or twitch. The risk is thought to be proportionate to the length of duration of neuroleptic/antipsychotic use (roughly 5% per year in non-elderly patients) and has recently been linked to an equally high occurrence in both typical and atypical antipsychotics, in contrast to claims of lower risks when the atypicals were introduced. Patients and physicians need to be careful to watch for symptoms of this side effect carefully so that an antipsychotic can be reduced in dosage, or changed to another medication, before the condition progresses. The doctor should, of course, be consulted about any change in dosage. The only antipsychotic with no apparent association with tardive dyskinesia is clozapine.

Medications work differently in each person, and it takes considerable time to determine in any particular case whether a given drug is effective at all, since bipolar disorder is by nature episodic, and patients may experience remissions whether or not they receive treatment. For this reason, neither patients nor their doctors should expect immediate relief, although psychosis with mania can respond quickly to antipsychotics, and bipolar depression can be alleviated quickly with electroconvulsive therapy (ECT). Many doctors emphasize that patients should not expect full stabilization for at least 3-4 weeks (some antidepressants, for example, take 4-6 weeks to take effect), and should not “give up” on a medication prematurely, nor should they discontinue medication with the disappearance of symptoms as the depression may return.

Compliance with medications can be a major problem, because some people as they become manic lose the awareness of having an illness, and they therefore discontinue medications. Patients also often quit taking medication when symptoms disappear, erroneously thinking themselves "cured", and some people enjoy the effects of unmedicated hypomania.

Depression does not respond instantaneously to resumed medication, typically taking 2–6 weeks to respond. Mania may disappear slowly, or it may become depression. Other reasons cited by individuals for discontinuing medication are side effects, expense, and the stigma of having a psychiatric disorder. In a relatively small number of cases stipulated by law (varying by locality but typically, according to the law, only when a patient poses a threat to himself or others), patients who do not agree with their psychiatric diagnosis and treatment can legally be required to have treatment without their consent. Throughout North America and the United Kingdom, involuntary treatment or detention laws exist for severe cases of bipolar disorder and other mental illnesses.

Prognosis
While bipolar disorder can be one of the most severe and devastating medical conditions, indeed the sixth highest cause of disability in the world according to the World Health Organization, fortunately many individuals with bipolar disorder can also live full and mostly happy lives with correct management of their condition. Compared to patients with schizophrenia, persons with bipolar disorder are more likely to have periods of normal functioning in the absence of medication. Although schizophrenic patients may have remissions with relatively high levels of functioning, schizophrenic patients tend to suffer some impairment during these intervals in contrast to persons with bipolar disorder who often appear completely healthy when they are between mood swings.

Lithium salts
The use of lithium salts as a treatment of bipolar disorder was first discovered by Dr. John Cade, an Australian psychiatrist who published a paper on the use of lithium in 1949.

Lithium salts had long been used as a first-line treatment for bipolar disorder. In ancient times, doctors would send their mentally ill patients to drink from "alkali springs" as a treatment. They did not know it, but they were really prescribing lithium, which was present in high concentration in the waters. The therapeutic effect of lithium salts appears to be entirely due to the lithium ion, Li+. The two lithium salts used for bipolar therapy are lithium carbonate (mostly) and lithium citrate (sometimes). Approved for the treatment of acute mania in 1970 by the FDA, lithium has been an effective mood-stabilizing medication for many people with bipolar disorder. Lithium is also noted for reducing the risk of suicide. Although lithium is among the most effective mood stabilizers, persons taking it may experience side effects similar to the effects of ingesting too much table salt, such as high blood pressure, water retention, and constipation. Regular blood testing is required when taking lithium to determine the correct lithium levels since the therapeutic dose is close to the toxic dose.

The mechanism of lithium salt treatment is believed to work as follows: some symptoms of bipolar disorder appear to be caused by the enzyme inositol monophosphatase (IMPase), an enzyme that splits inositol monophosphate into free inositol and phosphate. It is involved in signal transduction and is believed to create an imbalance in neurotransmitters in bipolar patients. The lithium ion is believed to produce a mood stabilizing effect by inhibiting IMPase by substituting for one of two magnesium ions in IMPase's active site, slowing down this enzyme.

Lithium orotate is used as an alternative treatment to lithium carbonate by some sufferers of bipolar disorder, mainly because it is available without a doctor's prescription. It is sometimes sold as "organic lithium" by nutritionists, as well as under a wide variety of brand names. There seems to be little evidence for its use in clinical treatment in preference to lithium carbonate.

Anticonvulsant mood stabilizers
Anticonvulsant medications, particularly valproate and carbamazepine, have been used as alternatives or adjuncts to lithium in many cases. Valproate (Depakote and Depakene, Epival) was FDA approved for the treatment of acute mania in 1995, and is now considered by some doctors to be the first line of therapy for bipolar disorder. For some, it is preferable to lithium because its side effect profile seems to be less severe, compliance with the medication is better, and fewer breakthrough manic episodes occur. However, valproate is not as effective as lithium in preventing or managing depressive episodes, so patients taking valproate may also need an antidepressant as an adjunct medicinal therapy. Some research suggests that different combinations of lithium and anticonvulsants may be helpful. Anticonvulsants are also used in combination with antipsychotics. Newer anticonvulsant medications, including lamotrigine and oxcarbemazepine, are also effective as mood stabilizers in bipolar disorder. Lamotrigine is particularly promising, as it alleviates bipolar depression and prevents recurrence at higher rates. Topiramate has not done well in clinical trials; it seems to help a few patients very much but most not at all. It appears to be useful in some treatment resistant cases. Gabapentin has failed to distinguish itself from placebo as a mood stabilizer.

According to studies conducted in Finland in patients with epilepsy, valproate may increase testosterone levels in teenage girls and produce polycystic ovary syndrome in women who began taking the medication before age 20. Increased testosterone can lead to polycystic ovary syndrome with irregular or absent menses, obesity, and abnormal growth of hair. Therefore, young female patients taking valproate should be monitored carefully by a physician. It should be noted, however, that the therapeutic dose for a patient taking valproate for epilepsy is very different than the therapeutic dose of valproate for an individual with bipolar disorder.

Other anticonvulsants effective in some cases and being studied closer include phenytoin, levitiracetam, pregabalin and valnoctimide. Clonazepam and other benzodiazepines are also antimanic agents.

Atypical antipsychotic drugs
The newer atypical antipsychotic drugs such as risperidone, quetiapine, and olanzapine are often used in acutely manic patients, because these medications have a rapid onset of psychomotor inhibition, which may be lifesaving in the case of a violent or psychotic patient. Parenteral and orally disintegrating (in particular, Zydis wafers) forms are favoured in emergency room settings. These drugs can also be used as adjunctives to lithium or anticonvulsants in refractory bipolar disorder and in prevention of mania recurrence. In light of recent evidence, olanzapine (Zyprexa) has been FDA approved as an effective monotherapy for the maintenance of bipolar disorder. A head-to-head randomized control trial in 2005 has also shown olanzapine monotherapy to be just as effective and safe as lithium in prophylaxis. Eli Lilly also offers Symbyax, a combination of olanzapine and fluoxetine.

Omega-3 fatty acids
Omega-3 fatty acids may also be used as a treatment for bipolar disorder, particularly as a supplement to medication. An initial clinical trial by Stoll et. al. produced positive results. However, since 1999 attempts to confirm this finding of beneficial effects of omega-3 fatty acids in several larger double-blind clinical trials have produced inconclusive results. It was hypothesized that the therapeutic ingredient in omega-3 fatty acid preparations is eicosapentaenoic acid (EPA) and that supplements should be high in this compound to be beneficial. Omega-3 fatty acids may be found in fish, fish oils, and to a lesser degree in other foods such as flaxseed, flaxseed oil and walnuts. Researchers have not determined if flaxseed oil or supplements have the same effect that was observed when bipolar patients were given omega-3 fatty acids through fish products.

Psychotherapy
Certain types of psychotherapy or psychosocial interventions, generally used in combination with medication, often can provide tremendous additional benefit. These include cognitive-behavioral therapy, interpersonal and social rhythm therapy, interpersonal group therapy, family systems therapy, and psychoeducation. Although bipolar patients will not be cured of the illness through "talking," therapy often can be invaluable in helping to address the effects of disruptive manic or depressive episodes that have hurt a patient's career, relationships or self-esteem. Therapy is available not only from psychiatrists but from social workers, psychologists and other licensed counselors.

Electroconvulsive therapy
Electroconvulsive therapy (ECT) is sometimes used to treat severe bipolar depression in cases where other treatments have failed. Although it has proved to be a highly effective treatment, doctors are reluctant to use it except as a treatment of last resort because of the side-effects and possible complications of ECT, particularly when repeated treatments ("maintenance ECT") are needed.

Medical Marijuana
There are many anecdotal claims that medical marijuana can help control the mood swings associated with bipolar disorder. The euphoriant effect of THC can elevate depressive phases, while the tranquilizing effects of THC are effective at controlling manic phases. This is only a theory. It should be noted that THC has different effects on different brains, and some studies suggest that marijuana can actually increase anxiety and depression. While most anti-depressants take several weeks to work at full strength, smoked marijuana is effective in minutes, and eaten marijuana is effective within an hour or two. Also, negative side effects associated with pharmaceutical anti-depressants such as nausea, sleep disruption, and loss of libido are usually non-existant with medical marijuana. Of course, marijuana legality issues makes this treatment medically unavailable and/or difficult to obtain for those looking for an alternative.

Some controlled medical studies have concluded that data suggests adults do not increase their risk for depression by using marijuana.

One opinion popular among proponents of medical marijuana suggests that since plants cannot be patented, and because marijuana is easily grown, there has been a concerted effort by the pharmaceutical industry to suppress the use of medical marijuana as a treatment for many disorders and illnesses, including bipolar disorder. In contrast, a UK company, GW Pharmaceuticals, has recently begun marketing Sativex, which is a whole-plant Cannabis extract, and is also pursuing studies of its use for various illnesses, such as cancer and depression.

Alternative treatments
Complementary non-Western treatments, such as acupuncture and orthomolecular therapy, are used by people with bipolar disorder, and some research shows that some of them may have some scientific merit.

Treatment issues
Nearly all bipolar treatment studies have involved treating patients in the acute (initial) mania stage, where use of medication may be justified in removing a patient from danger. Less is known, however, about long-term treatment, where relapse prevention and full remission are the main treatment goals.

Until recently, depression was largely overlooked in bipolar disorder. The anticonvulsant medication, lamotrigine is often used for treating bipolar depression, particularly where other drugs have failed and the patient's disorder has a strong depressive component. New clinical trials are finding that certain new-generation antipsychotics such as olanzapine and quetiapine show some beneficial effect in treating bipolar depression. Lithium also has a mild antidepressant effect.

Because there is a danger of antidepressant medications such as SSRIs switching bipolar patients into mania, these medications are used with caution, nearly always with a mood stabilizer..

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Papers

 * Llewellyn A, Stowe ZN, Strader JR Jr. The use of lithium and management of women with bipolar disorder during pregnancy and lactation. Journal of Clinical Psychiatry, 1998; 59(Suppl 6): 57-64; p65.
 * Rothschild AJ, Bates KS, Boehringer KL, Syed A. Olanzapine response in psychotic depression. Journal of Clinical Psychiatry, 1999; 60(2): 116-8.
 * Sachs GS, Printz DJ, Kahn DA, Carpenter D, Docherty JP. The expert consensus guideline series: medication treatment of bipolar disorder 2000. Postgraduate Medicine, 2000; Spec No:1-104.
 * Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ. Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania. American Journal of Psychiatry, 1999; 156(8): 1164-9.
 * Thase ME, Sachs GS. Bipolar depression: pharmacotherapy and related therapeutic strategies. Biological Psychiatry, 2000; 48(6): 558-72.
 * Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa KN, Daniel DG, Petty F, Centorrino F, Wang R, Grundy SL, Greaney MG, Jacobs TG, David SR, Toma V. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. American Journal of Psychiatry, 1999; 156(5): 702-9.

Papers

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