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ANTIMANIC MEDICATIONS

Bipolar disorder is characterized by cycling mood changes: severe highs (mania) and lows (depression). Episodes may be predominantly manic or depressive, with normal mood between episodes. Mood swings may follow each other very closely, within days (rapid cycling), or may be separated by months to years. The "highs" and "lows" may vary in intensity and severity and can co-exist in "mixed" episodes.

When people are in a manic "high," they may be overactive, overly talkative, have a great deal of energy, and have much less need for sleep than normal. They may switch quickly from one topic to another, as if they cannot get their thoughts out fast enough. Their attention span is often short, and they can be easily distracted. Sometimes people who are "high" are irritable or angry and have false or inflated ideas about their position or importance in the world. They may be very elated, and full of grand schemes that might range from business deals to romantic sprees. Often, they show poor judgment in these ventures. Mania, untreated, may worsen to a psychotic state.

In a depressive cycle the person may have a "low" mood with difficulty concentrating; lack of energy, with slowed thinking and movements; changes in eating and sleeping patterns (usually increases of both in bipolar depression); feelings of hopelessness, helplessness, sadness, worthlessness, guilt; and, sometimes, thoughts of suicide.

Lithium. The medication used most often to treat bipolar disorder is lithium. Lithium evens out mood swings in both directions--from mania to depression, and depression to mania--so it is used not just for manic attacks or flare-ups of the illness but also as an ongoing maintenance treatment for bipolar disorder.

Although lithium will reduce severe manic symptoms in about 5 to 14 days, it may be weeks to several months before the condition is fully controlled. Antipsychotic medications are sometimes used in the first several days of treatment to control manic symptoms until the lithium begins to take effect. Antidepressants may also be added to lithium during the depressive phase of bipolar disorder. If given in the absence of lithium or another mood stabilizer, antidepressants may provoke a switch into mania in people with bipolar disorder.

A person may have one episode of bipolar disorder and never have another, or be free of illness for several years. But for those who have more than one manic episode, doctors usually give serious consideration to maintenance (continuing) treatment with lithium.

Some people respond well to maintenance treatment and have no further episodes. Others may have moderate mood swings that lessen as treatment continues, or have less frequent or less severe episodes. Unfortunately, some people with bipolar disorder may not be helped at all by lithium. Response to treatment with lithium varies, and it cannot be determined beforehand who will or will not respond to treatment.

Regular blood tests are an important part of treatment with lithium. If too little is taken, lithium will not be effective. If too much is taken, a variety of side effects may occur. The range between an effective dose and a toxic one is small. Blood lithium levels are checked at the beginning of treatment to determine the best lithium dosage. Once a person is stable and on a maintenance dosage, the lithium level should be checked every few months. How much lithium people need to take may vary over time, depending on how ill they are, their body chemistry, and their physical condition.

Side effects of lithium. When people first take lithium, they may experience side effects such as drowsiness, weakness, nausea, fatigue, hand tremor, or increased thirst and urination. Some may disappear or decrease quickly, although hand tremor may persist. Weight gain may also occur. Dieting will help, but crash diets should be avoided because they may raise or lower the lithium level. Drinking low-calorie or no-calorie beverages, especially water, will help keep weight down. Kidney changes--increased urination and, in children, enuresis (bed wetting)--may develop during treatment. These changes are generally manageable and are reduced by lowering the dosage. Because lithium may cause the thyroid gland to become underactive (hypothyroidism) or sometimes enlarged (goiter), thyroid function monitoring is a part of the therapy. To restore normal thyroid function, thyroid hormone may be given along with lithium.

Because of possible complications, doctors either may not recommend lithium or may prescribe it with caution when a person has thyroid, kidney, or heart disorders, epilepsy, or brain damage. Women of childbearing age should be aware that lithium increases the risk of congenital malformations in babies. Special caution should be taken during the first 3 months of pregnancy.

Anything that lowers the level of sodium in the body--reduced intake of table salt, a switch to a low-salt diet, heavy sweating from an unusual amount of exercise or a very hot climate, fever, vomiting, or diarrhea--may cause a lithium buildup and lead to toxicity. It is important to be aware of conditions that lower sodium or cause dehydration and to tell the doctor if any of these conditions are present so the dose can be changed.

Lithium, when combined with certain other medications, can have unwanted effects. Some diuretics--substances that remove water from the body--increase the level of lithium and can cause toxicity. Other diuretics, like coffee and tea, can lower the level of lithium. Signs of lithium toxicity may include nausea, vomiting, drowsiness, mental dullness, slurred speech, blurred vision, confusion, dizziness, muscle twitching, irregular heartbeat, and, ultimately, seizures. A lithium overdose can be life-threatening. People who are taking lithium should tell every doctor who is treating them, including dentists, about all medications they are taking.

With regular monitoring, lithium is a safe and effective drug that enables many people, who otherwise would suffer from incapacitating mood swings, to lead normal lives.

Anticonvulsants. Some people with symptoms of mania who do not benefit from or would prefer to avoid lithium have been found to respond to anticonvulsant medications commonly prescribed to treat seizures.

The anticonvulsant valproic acid (Depakote, divalproex sodium) is the main alternative therapy for bipolar disorder. It is as effective in non-rapid-cycling bipolar disorder as lithium and appears to be superior to lithium in rapid-cycling bipolar disorder.² Although valproic acid can cause gastrointestinal side effects, the incidence is low. Other adverse effects occasionally reported are headache, double vision, dizziness, anxiety, or confusion. Because in some cases valproic acid has caused liver dysfunction, liver function tests should be performed before therapy and at frequent intervals thereafter, particularly during the first 6 months of therapy.

Other anticonvulsants used for bipolar disorder include carbamazepine (Tegretol), lamotrigine (Lamictal), gabapentin (Neurontin), and topiramate (Topamax). The evidence for anticonvulsant effectiveness is stronger for acute mania than for long-term maintenance of bipolar disorder. Some studies suggest particular efficacy of lamotrigine in bipolar depression. At present, the lack of formal FDA approval of anticonvulsants other than valproic acid for bipolar disorder may limit insurance coverage for these medications.

Most people who have bipolar disorder take more than one medication. Along with the mood stabilizer--lithium and/or an anticonvulsant--they may take a medication for accompanying agitation, anxiety, insomnia, or depression. It is important to continue taking the mood stabilizer when taking an antidepressant because research has shown that treatment with an antidepressant alone increases the risk that the patient will switch to mania or hypomania, or develop rapid cycling.⁵ Sometimes, when a bipolar patient is not responsive to other medications, an atypical antipsychotic medication is prescribed. Finding the best possible medication, or combination of medications, is of utmost importance to the patient and requires close monitoring by a doctor and strict adherence to the recommended treatment regimen.

ANTIDEPRESSANT MEDICATIONS

Major depression, the kind of depression that will most likely benefit from treatment with medications, is more than just "the blues." It is a condition that lasts 2 weeks or more, and interferes with a person's ability to carry on daily tasks and enjoy activities that previously brought pleasure. Depression is associated with abnormal functioning of the brain. An interaction between genetic tendency and life history appears to determine a person's chance of becoming depressed. Episodes of depression may be triggered by stress, difficult life events, side effects of medications, or medication/substance withdrawal, or even viral infections that can affect the brain.

Depressed people will seem sad, or "down," or may be unable to enjoy their normal activities. They may have no appetite and lose weight (although some people eat more and gain weight when depressed). They may sleep too much or too little, have difficulty going to sleep, sleep restlessly, or awaken very early in the morning. They may speak of feeling guilty, worthless, or hopeless; they may lack energy or be jumpy and agitated. They may think about killing themselves and may even make a suicide attempt. Some depressed people have delusions (false, fixed ideas) about poverty, sickness, or sinfulness that are related to their depression. Often feelings of depression are worse at a particular time of day, for instance, every morning or every evening.

Not everyone who is depressed has all these symptoms, but everyone who is depressed has at least some of them, co-existing, on most days. Depression can range in intensity from mild to severe. Depression can co-occur with other medical disorders such as cancer, heart disease, stroke, Parkinson's disease, Alzheimer's disease, and diabetes. In such cases, the depression is often overlooked and is not treated. If the depression is recognized and treated, a person's quality of life can be greatly improved.

Antidepressants are used most often for serious depressions, but they can also be helpful for some milder depressions. Antidepressants are not "uppers" or stimulants, but rather take away or reduce the symptoms of depression and help depressed people feel the way they did before they became depressed.

The doctor chooses an antidepressant based on the individual's symptoms. Some people notice improvement in the first couple of weeks; but usually the medication must be taken regularly for at least 6 weeks and, in some cases, as many as 8 weeks before the full therapeutic effect occurs. If there is little or no change in symptoms after 6 or 8 weeks, the doctor may prescribe a different medication or add a second medication such as lithium, to augment the action of the original antidepressant. Because there is no way of knowing beforehand which medication will be effective, the doctor may have to prescribe first one and then another. To give a medication time to be effective and to prevent a relapse of the depression once the patient is responding to an antidepressant, the medication should be continued for 6 to 12 months, or in some cases longer, carefully following the doctor's instructions. When a patient and the doctor feel that medication can be discontinued, withdrawal should be discussed as to how best to taper off the medication gradually. Never discontinue medication without talking to the doctor about it. For those who have had several bouts of depression, long-term treatment with medication is the most effective means of preventing more episodes.

Dosage of antidepressants varies, depending on the type of drug and the person's body chemistry, age, and, sometimes, body weight. Traditionally, antidepressant dosages are started low and raised gradually over time until the desired effect is reached without the appearance of troublesome side effects. Newer antidepressants may be started at or near therapeutic doses.

Early antidepressants. From the 1960s through the 1980s, tricyclic antidepressants (named for their chemical structure) were the first line of treatment for major depression. Most of these medications affected two chemical neurotransmitters, norepinephrine and serotonin. Though the tricyclics are as effective in treating depression as the newer antidepressants, their side effects are usually more unpleasant; thus, today tricyclics such as imipramine, amitriptyline, nortriptyline, and desipramine are used as a second- or third-line treatment. Other antidepressants introduced during this period were monoamine oxidase inhibitors (MAOIs). MAOIs are effective for some people with major depression who do not respond to other antidepressants. They are also effective for the treatment of panic disorder and bipolar depression. MAOIs approved for the treatment of depression are phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan). Because substances in certain foods, beverages, and medications can cause dangerous interactions when combined with MAOIs, people on these agents must adhere to dietary restrictions. This has deterred many clinicians and patients from using these effective medications, which are in fact quite safe when used as directed.

The past decade has seen the introduction of many new antidepressants that work as well as the older ones but have fewer side effects. Some of these medications primarily affect one neurotransmitter, serotonin, and are called selective serotonin reuptake inhibitors (SSRIs). These include fluoxetine (Prozac), sertraline (Zoloft), fluvoxamine (Luvox), paroxetine (Paxil), and citalopram (Celexa).

The late 1990s ushered in new medications that, like the tricyclics, affect both norepinephrine and serotonin but have fewer side effects. These new medications include venlafaxine (Effexor) and nefazadone (Serzone).

Other newer medications chemically unrelated to the other antidepressants are the sedating mirtazepine (Remeron) and the more activating bupropion (Wellbutrin). Wellbutrin has not been associated with weight gain or sexual dysfunction but is not used for people with, or at risk for, a seizure disorder.

Each antidepressant differs in its side effects and in its effectiveness in treating an individual person, but the majority of people with depression can be treated effectively by one of these antidepressants.

Antidepressants may cause mild, and often temporary, side effects (sometimes referred to as adverse effects) in some people. Typically, these are not serious. However, any reactions or side effects that are unusual, annoying, or that interfere with functioning should be reported to the doctor immediately. The most common side effects of tricyclic antidepressants, and ways to deal with them, are as follows:

• Dry mouth--it is helpful to drink sips of water; chew sugarless gum; brush teeth daily.
• Constipation--bran cereals, prunes, fruit, and vegetables should be in the diet.
• Bladder problems--emptying the bladder completely may be difficult, and the urine stream may not be as strong as usual. Older men with enlarged prostate conditions may be at particular risk for this problem. The doctor should be notified if there is any pain.
• Sexual problems--sexual functioning may be impaired; if this is worrisome, it should be discussed with the doctor.
• Blurred vision--this is usually temporary and will not necessitate new glasses. Glaucoma patients should report any change in vision to the doctor.
• Dizziness--rising from the bed or chair slowly is helpful.
• Drowsiness as a daytime problem--this usually passes soon. A person who feels drowsy or sedated should not drive or operate heavy equipment. The more sedating antidepressants are generally taken at bedtime to help sleep and to minimize daytime drowsiness.
• Increased heart rate--pulse rate is often elevated. Older patients should have an electrocardiogram (EKG) before beginning tricyclic treatment.

The newer antidepressants, including SSRIs, have different types of side effects, as follows:

• Sexual problems--fairly common, but reversible, in both men and women. The doctor should be consulted if the problem is persistent or worrisome.
• Headache--this will usually go away after a short time.
• Nausea--may occur after a dose, but it will disappear quickly.
• Nervousness and insomnia (trouble falling asleep or waking often during the night)--these may occur during the first few weeks; dosage reductions or time will usually resolve them.
• Agitation (feeling jittery)--if this happens for the first time after the drug is taken and is more than temporary, the doctor should be notified.
• Any of these side effects may be amplified when an SSRI is combined with other medications that affect serotonin. In the most extreme cases, such a combination of medications (e.g., an SSRI and an MAOI) may result in a potentially serious or even fatal "serotonin syndrome," characterized by fever, confusion, muscle rigidity, and cardiac, liver, or kidney problems.

The small number of people for whom MAOIs are the best treatment need to avoid taking decongestants and consuming certain foods that contain high levels of tyramine, such as many cheeses, wines, and pickles. The interaction of tyramine with MAOIs can bring on a sharp increase in blood pressure that can lead to a stroke. The doctor should furnish a complete list of prohibited foods that the individual should carry at all times. Other forms of antidepressants require no food restrictions. MAOIs also should not be combined with other antidepressants, especially SSRIs, due to the risk of serotonin syndrome.

Medications of any kind--prescribed, over-the-counter, or herbal supplements--should never be mixed without consulting the doctor; nor should medications ever be borrowed from another person. Other health professionals who may prescribe a drug-such as a dentist or other medical specialist-should be told that the person is taking a specific antidepressant and the dosage. Some drugs, although safe when taken alone, can cause severe and dangerous side effects if taken with other drugs. Alcohol (wine, beer, and hard liquor) or street drugs, may reduce the effectiveness of antidepressants and their use should be minimized or, preferably, avoided by anyone taking antidepressants. Some people who have not had a problem with alcohol use may be permitted by their doctor to use a modest amount of alcohol while taking one of the newer antidepressants. The potency of alcohol may be increased by medications since both are metabolized by the liver; one drink may feel like two.

Although not common, some people have experienced withdrawal symptoms when stopping an antidepressant too abruptly. Therefore, when discontinuing an antidepressant, gradual withdrawal is generally advisable.

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