Depression

Description

Alternative Names

Drug Treatment Guidelines

Active Antidepressants Versus Placebo. Antidepressants are effective in many patients, but there are some problems in gauging their success. Determining the true value of an antidepressant medication is difficult because between some of their benefits are attributed to the placebo effect. Placebos themselves can achieve a 35% response. Experts point out that people who respond to placebos still show poorer social functioning than those who respond to medication. An interesting 2002 study used electroencephalography (EEG) and reported that placebos and active antidepressants affected different parts of the brains in people who responded to one or the other. (No part of the brain was affected in people who did not respond to either a placebo or an active drug.)

Major Classes of Antidepressants. The primary target of most major antidepressant drug classes is the transport of the important neurotransmitters serotonin and norepinephrine. Such drug classes are the following:

• Selective serotonin-reuptake inhibitors (SSRIs). These have become the standard antidepressants. They are effective and have very moderate side effects. Some may be beneficial in treating anxiety and certain subtypes of depressive disorders unresponsive to previous agents, including premenstrual dysphoric disorder and seasonal affective disorder, atypical depression, and recurrent brief depression.
• Tricyclic antidepressants (TCAs). These are effective but can have severe adverse effects, particularly in older people.
• Monoamine oxidase inhibitors (MAOIs), including newer selective MAOIs. MAOIs are the most effective antidepressants for atypical depression, but have some severe side effects and require restrictive dietary rules.
• Drugs generally referred to as "designer antidepressants" specifically target specific neurotransmitters (brain chemicals) other than or in addition to serotonin. Many are being proving to be effective in patients who do not respond to standard antidepressants or in specific patients, such as smokers who want to quit or patients with chronic pain.
• The herbal remedy St. John's wort is included as a separate category, since it is unregulated and its chemical classification has not yet been determined.

A great deal of leeway exists in choosing an appropriate antidepressant. Overall, they seem to be equally effective, although cost, individual responses, and side effects vary widely.

Approach and Duration of Initial Treatment. The guidelines for the duration of an initial antidepressant regimen is as follows:

• Patients should start at a low dose, which is increased over a period of five to 10 days.
• Some experts recommend that the patients see their physician every one to two weeks until substantial improvement occurs. It is important to note, however, that it may take four to six weeks before a patient experiences the effects of any antidepressant.
• Side effects usually diminish within one to four weeks. (Exceptions may be weight gain and sexual dysfunction.)
• If no improvement occurs within three to four weeks, however, and the patient is not overly distressed by side effects, an alternative agent may be tried. More than 80% of patients respond to some antidepressant, although specific agents are helpful for only about half of patients. This suggests that if one medication fails, another has a good chance of being helpful. Newer agents with different mechanisms are being developed that are improving response rates.
• In general, patients should continue taking antidepressants for at least six months after symptom relief to help prevent relapse. (Patients who improve within two weeks of taking medications may not require lengthy treatment.)

Treating Recurrence. Recurrence of depression is very common. About a third of patients will relapse after a first episode within a year of ending treatment, and more than half will experience a recurring bout of depression at some point during their lives. Among those at highest risk for early relapse and who may require ongoing antidepressants are the following:

• Patients with at least two episodes of major depression or major depression that lasts for two years or longer before initial treatment.
• Patients who continue to have low-level depression for seven months after starting antidepressant treatments.

In one study, 41% of patients relapsed after they stopped treatment compared to only 18% who had continued their antidepressants. Patients, then, may need maintenance therapy. Experts disagree, however, on the optimal length or the appropriate dosage of maintenance therapy. Some patients may need to stay on antidepressants for a year or two--or even indefinitely. Some experts recommend withdrawing from medication after a year. (This should be gradual, over two to three months.) If depression recurs, then the patients should go back on the antidepressants.

There is no risk for addiction with current antidepressants, and many of the common antidepressants, including most standard SSRIs, have been proven safe when taken for a number of years.

Common Side Effects of Most Antidepressants. No matter how well a drug treats depression, the ability of the patient to tolerate its side effects strongly influences his or her compliance with therapy. Lack of compliance is probably the major barrier to success. According to one study, as many as 70% of elderly depressed patients did not adhere to antidepressant drug regimens. Side effects can be avoided or moderated if any regimen is started at low doses and built up over time. Although specific side effects are discussed under individual drugs, there are a few that are common to many of them:

• Sexual dysfunction is a common side effect of nearly all the standard antidepressants and some of the newer drugs. These side effects can be particularly distressing for patients on maintenance treatment who otherwise feel well. Some of the newer antidepressants, such as mirtazapine, bupropion, or nefazodone, may be effective alternatives without as high a risk for this problem. Sildenafil (Viagra), used for erectile dysfunction in men, may help reverse sexual dysfunction from antidepressants in both men and women. It does not heighten sexual interest, however.
• An increased risk of oral health problems caused by dry mouth is associated with long-term use of most antidepressants. The risks appear to be highest with some of the new designer antidepressants, with the use of multiple drugs, and with the presence of oral infections. Patients can increase salivation by chewing gum, taking vitamin C tablets, using saliva substitutes, and rinsing the mouth frequently. (In one small study, drinking coffee reduced dry mouth associated with tricyclic antidepressants.)
• Virtually all antidepressants have complicated interactions with other drugs; some are very serious. A few are mentioned in the individual drug discussions below, but many are not, and patients should inform the physician of any drugs they are taking, including over-the-counter medications.
• Nearly all antidepressants are metabolized in the liver, so anyone with liver abnormalities should use them with caution.
• Abrupt withdrawal from many antidepressants can produce severe side effects; no antidepressant should be stopped abruptly without consultation with a physician.

Selective Serotonin-Reuptake Inhibitors

Selective serotonin-reuptake inhibitors (SSRIs) are now the first-line treatment of major depression. They work by increasing levels of serotonin in the brain. SSRIs include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil, Asimia, Seroxat), fluvoxamine (Luvox), citalopram (Celexa, Cipramil), and escitalopram (Lexapro, Cipralex). There are no significant differences among SSRI brands in effectiveness for treating major depressive disorder, although individual drugs may have different side effects or benefits for specific patients. For example, Lexapro and newer forms of paroxetine may have more specific effects than other SSRIs and so have fewer side effects. SSRIs also appear to be safe and effective for many young people with major depression, but at this time Prozac is the only one of these agents to be approved for children over seven and adolescents.

Because they act on serotonin specifically, SSRIs have fewer side effects than the older antidepressants, which have more widespread effects in the body. Patients taking SSRIs report not only relief of depressive symptoms but also better relationships with other people.

Candidates for SSRIs. SSRIs appear to help people with the following conditions:

• Mild to moderately severe major depression.
• Seasonal affective disorder.
• Dysthymia.
• Severe premenstrual syndrome and premenstrual dysphoric disorder (PMDD). A repackaged form of fluoxetine (Sarafem) is the first SSRI specifically FDA-approved for PMDD. Other SSRIs and newer antidepressants, however, are also proving to be effective.
• Anxiety disorders.
• Bulimia.
• Impulsive and aggressive behaviors in psychiatric patients and in people with no mental health problems.

Duration of Effectiveness and Use. SSRIs take, on average, two to four weeks to be effective in most adults. They may take even longer, up to 12 weeks, in the elderly and in those with dysthymia. By 14 weeks, depression should be in remission in everyone who responds to the drugs. Unfortunately, recurrence is common once the drugs are stopped. Studies to date have indicated that the standard SSRIs are probably safe, although it is still unclear which patients would most benefit from on-going medication. Some experts recommend withdrawing from medication after a year. If depression recurs, then the patients should go back on the antidepressants.

Drug Interactions. SSRIs interact with numerous drugs, and caution should be taken that the physician is well informed of any other medications the patient is taking. In rare cases, taking them with other drugs that affect serotonin levels may result in a reversible narrowing of the blood vessels in the brain causing "explosive headache" and possible seizures or even stroke. Such agents include other antidepressants, anti-migraine agents, decongestants, diet pills, St. John's wort, ecstasy, cocaine, and methamphetamine.

Side Effects of SSRIs. Side effects include the following:

• Nausea and gastrointestinal (GI) symptoms. These effects usually wear off over time.
• Agitation, insomnia, mild tremor, and impulsivity occur in 10% and 20% of people who take SSRIs, these symptoms may be particularly problematic in patients who also suffer from anxiety, sleeplessness, or both. Such side effects may persist. On the other hand, about 20% of SSRI-treated patients experience drowsiness, which may be counteracted by taking the medication at bedtime. Newer SSRIs, such as escitalopram (Lexapro), may have fewer of these adverse effects.
• Dry mouth is common and can increase the risk for cavities and mouth sores.
• Lack of motivation, fatigue, and mental dullness.
• Flu-like symptoms
• Headache.
• Weight gain. Some weight loss during the first few weeks of treatment may occur, but over time patients on maintenance treatment typically return to their pretreatment weight or gain weight. Weight gain varies depending on the SSRI. For example, in one study patients who took paroxetine (Paxil) experienced five times the weight gain as those who took citalopram (Celexa). Patients should be encouraged to maintain a low-calorie diet and to exercise. They should be aware that some of the weight-loss medications, notably sibutramine (Meridia), can have serious interactions with SSRIs.
• Sexual side effects. Sexual dysfunction, including delayed or loss of orgasm and low sexual drive, is now a well-known side effect of SSRIs. One 2002 study suggested that men report higher rates of sexual problems but sexual dysfunction may actually be more severe in women. It should be noted, however, that in one 2001 study, sexual desire increased in 20% of women and 27% of men taking the SSRI. In patients with normal sexual function, only about 15% of patients experienced greater sexual dysfunction, which was generally mild to moderate and mostly took the form of less sexual interest. Taking a supervised drug "holiday" on the weekend may improve sexual function during that time. (Withdrawal symptoms may develop and include return of depression, sleep problems, exhaustion, and dizziness.) Some of the newer SSRIs or designer antidepressants may cause less severe impairment of sexual function. Sildenafil (Viagra), used for erectile dysfunction in men, may help reverse sexual dysfunction from antidepressants in both men and women. It does not heighten sexual interest, however.
• Bleeding. There is an increased risk for bleeding, notably gastrointestinal bleeding, particularly in people who take NSAIDs (such as aspirin and ibuprofen) regularly or in people who require blood thinning agents. Elderly people taking these drugs should take the lowest dose possible, and those with heart problems should be monitored closely.
• There have been some reports of worsened glaucoma in patients taking SSRIs. This is a very rare complication and it isn't clear that there is a causal relationship. Patients with glaucoma who take SSRIs should have their eyes examined regularly.
• Over the years, some patients taking SSRIs have reported a group of side effects, known as extrapyramidal symptoms, which are similar to those in Parkinsons disease and affect the nerves and muscles controlling movement and coordination. They are uncommon, and when they develop they tend to occur within the first month of treatment.
• There is a higher risk for hip fracture, particularly during the early days of treatment (although not as high as with tricyclics).
• High doses may cause hallucinations, confusion, changes in blood pressure, stiffness, and irregular heart beats. Death from overdose is extremely rare.
• The effects of long-term use of SSRIs in young people are not clear. There have been case reports of myoclonus (uncontrolled muscle jerks) with long-term use. In addition, there is some concern that SSRIs may limit growth in children.

Drug Interactions. Serious interactions can occur with other antidepressants, such as tricyclics and, of particular note, monoamine oxidase inhibitors (MAOIs) (see below). Other serious interactions have occurred with meperidine (Demerol) and illegal substances (such as LSD, cocaine, or ecstasy). People who take SSRIs may drink alcohol in moderation, although the combination may compound any drowsiness experienced with SSRIs, and some SSRIs increase the effects of alcohol.

Withdrawal Symptoms. Dizziness, muscle weakness or pain, odd sensations in the limbs, nausea, loose stools, visual disturbances, irritability, insomnia, mood worsening, and headaches have been known to occur with sudden discontinuation of SSRIs. The symptoms are more likely to occur with antidepressants with shorter half-lives as compared with fluoxetine, which has a long half-life. Reducing the dose of the antidepressant before stopping it is recommended.

Designer Antidepressants

A number of drugs have now been developed that target other neurotransmitters, such as norepinephrine or dopamine, alone or in addition to serotonin. In general, the advantages of the new designer antidepressants are as follows:

• They may be more tolerable than the older tricyclic compounds and even some SSRIs, although long-term side effects are not fully known in this group.
• Most of these drugs have fewer adverse effects than SSRIs on sexual function, and some people have even reported enhanced sexuality with some of them.
• They may be more effective than SSRIs for severely depressed patients.
• Some of these agents are helpful for additional problems, such as insomnia, fibromyalgia and similar chronic pain syndromes, or smoking, that may affect people with depression.

They do share some side effects, including dizziness and dry mouth, with other antidepressants. Comparison studies are needed, however, to determine if any of these drugs are superior to standard SSRIs in treating different stages or aspects of depression. Combinations may prove to be the most effective approach.

Dual Inhibitors. Dual inhibitors act directly on two neurotransmitters -- norepinephrine and serotonin. They improve bladder capacity and may be helpful for people who also suffer from urinary incontinence. They also may help patients with chronic pain syndromes or fibromyalgia. On the basis of a review of the literature, in 2002 an expert panel concluded that simultaneous targeting of both serotonin and norepinephrine was currently the optimal approach for patients who failed standard antidepressant therapies.

• Venlafaxine (Effexor) is similar to Prozac in effectiveness and tolerability for most patients. It has a faster action, however. As with the SSRIs, venlafaxine impairs sexual function. Although clinical trials have shown that the drug is safe and effective in most people, of concern are recent reports of changes in blood pressure and heart conduction abnormalities, which may cause serious problems in elderly patients. Some patients report severe withdrawal symptoms, including dizziness and nausea. It can also cause uterine and vaginal bleeding unrelated to menstruation.
• Duloxetine (Cymbalta) also acts on both serotonin and norepinephrine. An estimated 65% of patients with major depressive disorder will respond to this drug, and 43% will go into remission. It also may help patients with chronic pain syndromes, such as fibromyalgia, and those with stress incontinence. To date, side effects are mild and include dry mouth, nausea, and sleepiness. No significant hypertension has been reported.It also appears to pose a lower risk for sexual dysfunction than standard SSRIs.
• Milnacipran (Ixel) is a similar agent but not yet approved in the U.S. It is specifically being researched for helping people with fibromyalgia and other pain syndromes.

Other Antidepressants with Multiple Effects on Neurotransmitters. Other antidepressants are available with different actions. For example, nefazodone and mirtazapine may enhance both serotonin and norepinephrine indirectly. These agents may provide relief from insomnia and anxiety, which are common in many depressed patients. (SSRIs and dual inhibitors generally pose a higher risk for insomnia.) Bupropion has weak effects on serotonin, norepinephrine, and possibly dopamine.

• Bupropion (Wellbutrin, Zyban) has weak effects on the reuptake of serotonin, norepinephrine, and dopamine--a third important neurotransmitter. The actions affect dopamine may be responsible for its benefits in helping smokers to quit. (Dopamine is important in feelings of reward.) Bupropion causes less sexual dysfunction than SSRIs. About 25% of patients experience initial weight loss. Side effects include restlessness, agitation, sleeplessness, headache, rashes, stomach problems, and in rare cases, menstrual irregularities (rare), hallucinations and bizarre thinking. High doses can be toxic and may cause dangerous heart arrhythmias. Seizures have also been reported, usually in patients with eating disorders (anorexia or bulimia) or those with risk factors for seizures.
• Nefazodone (Serzone) is more rapidly effective and has fewer distressing side effects, including sexual dysfunction, than SSRIs. The drug can also be combined with SSRIs or psychotherapies for improved response. Nefazodone is one of the few antidepressants that has a positive effect on sleep efficiency. The drug may cause an abrupt drop in blood pressure after standing up suddenly. Of concern are rare cases of liver failure in patients taking nefazodone.
• Mirtazapine (Remeron) is a unique antidepressant known as a 5-HT2 blocker. It may indirectly enhance the affects of both serotonin and norepinephrine. Compared to some common SSRIs, studies are indicating that it becomes effective more rapidly and has stronger early actions against anxiety in patients who suffer both disorders. It also improves sleep. Patients may be able to safely switch directly from an SSRI to mirtazapine without having to do through a withdrawal period. It has a lower incidence of sexual dysfunction than many other antidepressants. It may elevate cholesterol and triglyceride levels slightly. It also causes blurred vision and may cause slight weight gain.

Selective Noradrenaline Reuptake Inhibitor. Reboxetine (Edronax, Vestra) is at least equal to Prozac in reducing depression and improving social functioning. In one study, however, more patients taking reboxetine dropped out (12% versus 7% for Prozac) because of side effects. It typically causes insomnia during the first week of treatment that resolves over time. Reboxetine is available in other countries, but the FDA has not approved it for marketing in the U.S.

Tricyclic Antidepressants

Before the introduction of SSRIs, tricyclics had been the standard treatment for depression.

Tricyclics are sometimes referred to as belonging to one of two categories: tertiary or secondary amines:

• Tertiary amines include amitriptyline (Elavil, Endep) and imipramine (Tofranil).
• Secondary amines include desipramine (Norpramin) and nortriptyline (Pamelor, Aventyl). Secondary amines may have fewer side effects, including drowsiness, than tertiary amines, but they are as toxic in high amounts.

Less commonly used or investigative tricyclics include doxepin (Sinequan), amoxapine (Asendin), maprotiline (Ludiomill), protriptyline (Vivactil), trimipramine (Surmontil), mianserin (Bolvidon), and dothiepin (Prothiaden).

Tricyclics are as effective for treating depression but they have more adverse effects. They may offer benefits for many people with dysthymia, who generally do not respond to SSRIs. In one clinical trial, men responded far better to the tricyclic imipramine (Tofranil) than they did to the SSRI sertraline (Zoloft).

Side Effects of Tricyclics. Side effects are fairly common with these medications. In fact, in an analysis of studies, more tricyclic users discontinued their drugs due to side effects than did SSRI or MAOI users. Those most often reported include the following:

• Dry mouth. (One intriguing study suggested that drinking coffee may help reduce this side effect.)
• Constipation.
• Blurred vision.
• Sexual dysfunction.
• Weight gain.
• Difficulty urinating.
• Drowsiness (varies by drug).
• Dizziness. Blood pressure may drop suddenly when sitting up or standing.

Tricyclics can have serious, although rare, side effects:

• They tend to cause disturbances in heart rhythm, which can pose a danger for some patients with certain heart diseases. One study comparing nortriptyline with paroxetine, an SSRI, reported nine times more adverse cardiac events with the use of the tricyclic than with the SSRI.
• Also of concern is a study reporting that tricyclics, particularly imipramine, may be responsible for 10% of cases of a lung disease called idiopathic pulmonary fibrosis (IPF), which can cause lung inflammation and scarring. Initial symptoms are breathlessness and dry cough. The two newer tricyclics, mianserin and dothiepin, also increased the risk.
• Tricyclics can be fatal with an overdose.
• A 2000 study showed a small increased risk for non-Hodgkin's lymphoma associated with tricyclic use.

Side effects and their severity may vary among the tricyclics. Examples are the following:

• In one study, mianserin, a newer tricyclic, improved sexual dysfunction caused by SSRIs.
• Protriptyline can cause sun sensitivity, and people who take this should take precautions against sunlight when they go outdoors.

Monoamine Oxidase Inhibitors (MAOIs)

Monoamine oxidase inhibitors (MAOIs) block the enzyme monoamine oxidase, which has negative effects on many of the neurotransmitters that are important for well-being. MAOIs include phenelzine (Nardil), isocarboxazid (Marplan), and tranylcypromine (Parnate). Because these agents can have very severe side effects, they are usually indicated only when other antidepressants prove ineffective.

Newer MAOIs, such as selegiline (Eldepryl, Movergan), also known as deprenyl, and moclobemide (Aurorix, Manerix), target only one form of the MAOI enzyme. They may be effective without the significant side effects of the older MAOIs for patients with dysthymia. One interesting 2002 study reported that selegiline delivered from a skin patch was effective and safe for patients with major depression. At this time moclobemide is not available in the U.S.

Candidates for MAOIs. They may be effective for the following conditions:

• Atypical depression.
• Eating disorders.
• Post-traumatic stress disorder.
• Borderline personality.

Side Effects. MAOIs commonly cause the following side effects:

• Orthostatic hypotension (a sudden drop in blood pressure upon standing).
• Drowsiness or insomnia.
• Dizziness.
• Sexual dysfunction. (Of note, however, in one 2000 study, only 1.9% of patients taking the newer European MAOI moclobemide reported sexual dysfunction related to their antidepressant compared to 21.6% of patients taking SSRIs.)
• The most serious side effect is severe hypertension, which can be brought on by eating certain foods having a high tyramine content. Such foods include aged cheeses, most red wines, sauerkraut, vermouth, chicken livers, dried meats and fish, canned figs, fava beans, and concentrated yeast products.
• MAOIs may also cause birth defects and should not be taken by pregnant women.
• Very dangerous side effects can occur from interactions with other antidepressants, including SSRIs. There should be at least a two to five-week break between taking MAOIs and other antidepressants. MAOIs can have serious interactions with other drugs as well, including some common over-the-counter cough medications, psychostimulants (such as Ritalin), and decongestants.

Azapirones

Azapirones, including buspirone (BuSpar) and gepirone (Ariza, Variza), act on serotonin receptors called 5-HT(1A). Buspirone is primarily used to treat anxiety disorders, but they may have benefits for depression--particularly gepirone in extended release formulations. Studies on gepirone indicate that it may help some people with major and atypical depression. Buspirone (BuSpar) has shown benefits in treating resistant depression when added to the SSRIs citalopram or fluoxetine. More research is needed to determine the role of these agents in depression.

St. Johns Wort and Other Herbal Remedies

General Guidelines. St. Johns wort (Hypericum perforatum) is an herbal remedy that may help some patients with mild to moderate depression. It is not clear, however, how significant the benefits are. Some, but not all, studies report that it is more effective than placebo. Notably, a 2002 study reported no differences between St. John's wort and placebo for patients with moderate depression. A 2000 study on similar patients, however, reported that it was as effective as a tricyclic.

The herb St. John's Wort is believed to be helpful in relieving mild to moderate depression, but should only be taken under a physician's supervision. St. John's Wort may clash with other medications or foods a patient is taking, and the efficacy of the supplement is not regulated or assured.

Even if studies were consistent, this herbal substance is not regulated and there is no guarantee of quality in any brands currently available. In fact, in a 2003 study, out of 54 St. John's products bought in Canada and the US, only two products contained concentrations of the active ingredients that fell within 10% of the claims on the labels. [See Box Warnings for Alternative and So-Called Natural Remedies Used in Depression.]

At this time, the following guidelines are recommended:

• People with severe depression should not take this remedy without a physician's guidance. Even those with mild depression should not use St. John's wort without consulting a physician. Children and pregnant or nursing women should not take this substance.
• People should purchase brands only from well-established manufacturers until regulations have been established for this and other herbal remedies.
• Although no dose levels have been established, trials indicate that 300 milligrams taken three times a day may be effective. (Patients should check with a knowledgeable physician.)
• It takes between two and three weeks for the drug to have an effect.
• Early studies had suggested that the herbal substance might act in the same way as chemical MAOIs, but the MAO-like activity of St. John's wort appear to be minimal. Still, some experts suggest avoiding large amounts of foods and substances that have tyramine, such as red wine, meat, and aged cheese.
• It should not be combined with other antidepressants.

Side Effects. Side effects include nausea, dry mouth, allergic reactions, and fatigue, although, in general, side effects are uncommon. In one study, only 1.1% of patients discontinued the agent because of side effects. Some people have reported temporary nerve damage after sun exposure, specifically pain and tingling on sun-exposed areas, although a 2001 study found that sun sensitivity reactions were low. Some laboratory studies suggest high doses may impair fertility in men.

Interactions. St. John's wort may increase the risk for bleeding when used with anti-clotting agents or with other natural or standard medications that thin blood, such as warfarin or high doses of vitamin E. They may interact with oral contraceptives in women.Notably the herbal agent appears to reduce the effectiveness of certain cancer chemotherapy agents and HIV treatments. In fact, one study indicated that it might alter enzymes that cause a reduction in effectiveness of about half of all common medications.

Augmentation Strategies

Augmentation strategies generally involve the use of drugs not typically thought of as antidepressants in combination with a standard antidepressant. Such strategies are being used for patients who fail standard therapies or who need to quickly speed up the response of the antidepressant. Augmentation therapies include use of the following:

• Mood stabilizers like lithium, carbamazepine, and divalproex sodium.
• Newer antipsychotic drugs (such as risperidone).
• Psychostimulants. Standard psychostimulants include dextroamphetamine (Dexedrine) and methylphenidate (Ritalin). A newer psychostimulant, modafinal (Provigil, Alertec), is also showing promise for augmenting antidepressants. It may also pose less risk for abuse.
• Thyroid hormones. In one small study, high doses of thyroid hormone combined with an antidepressant had very mild side effects and were very effective in half of severely depressed treatment-resistant patients. Another study reported good results when thyroid hormone was followed by small doses of lithium.
• Beta-blockers. Pindolol (Visken), a beta-blocker normally used for heart disease, is proving to be effective in hastening the response of antidepressants. In one study, after ten days, nearly half the patients taking the combination was in remission compared to 25% of patients taking only Paxil. In the study on Prozac, patients reached a sustained response within 19 days on the combination compared to 29 days with Prozac alone.