Antidepressants and Drug Treatment Guidelines

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 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, 2 - 4 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 indicate that the standard SSRIs are generally 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.

Side Effects of SSRIs. Side effects may include:

• Nausea and gastrointestinal (GI) symptoms usually wear off over time.
• Agitation, insomnia, mild tremor, and impulsivity occur in 10 - 20% of people who take SSRIs. These symptoms may be particularly problematic in patients who also suffer from anxiety, sleeplessness, or both.
• Drowsiness affects about 20% of SSRI-treated patients. 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.
• Patients may lack motivation, feel tired, be confused, and experience mental dullness.
• Headache and flu-like symptoms may occur.
• Heart palpitations and chest pain may occur.
• 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 include delayed or loss of orgasm and low sexual drive. They are a well-known side effect of SSRIs. Taking a supervised drug "holiday" on the weekend may improve sexual function during that time. Some of the newer SSRIs or designer antidepressants may cause less severe impairment of sexual function.
• Paroxetine (Paxil) may cause birth defects if taken during the first 3 months of pregnancy. Most reported defects have been heart-related. The most common heart abnormalities are ventricular septal defects, which are holes in the muscular wall that separate the main pumping chambers of the heart. Venlafaxine (Effexor) has also been associated with birth defects. Recent research suggests that SSRIs may also cause complications. However, due to high risk for relapse, pregnant women who are being treated for major depression should not stop taking antidepressants without first talking to their doctors. [For more information on antidepressant treatment guidelines during pregnancy, see Depression in Women in Causes section.]

Drug Interactions. SSRIs can interact with other antidepressants such as tricyclics and, in particular, monoamine oxidase inhibitors (MAOIs). SSRIs should never be taken in combination with an MAOI or within 2 weeks after discontinuing MAOI treatment. 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. Cognitive problems, sleep disturbances, increase in depressive symptoms, and electric shock-like symptoms 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

These newer antidepressants target other neurotransmitters, such as norepinephrine or dopamine, alone or in addition to serotonin. In general, the advantages of the new designer antidepressants are:

• 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 drugs 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.

Dual Inhibitors. Dual inhibitors act directly on two neurotransmitters -- norepinephrine and serotonin. 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. The drug can increase blood pressure and heart rate and should be used with caution in patients with high blood pressure or heart disease. It can also cause uterine and vaginal bleeding unrelated to menstruation. Venlafaxine should not be taken during the last trimester of pregnancy as it can cause complications in newborn infants. Some patients report severe withdrawal symptoms, including dizziness and nausea and there are also reports that the drug is associated with a higher rate of overdose than SSRIs. In 2006, the drug’s manufacturer warned of this increased overdose risk and advised doctors to prescribe their patients only small amounts of venlafaxine pills.
• Duloxetine (Cymbalta) also acts on both serotonin and norepinephrine. The drug was granted FDA approval in the summer of 2004 for treatment of major depressive disorder and is one of the newest antidepressants on the market. Side effects are generally mild and include dry mouth, nausea, and sleepiness. Patients with narrow-angle glaucoma or patients with liver or kidney diseases should not take duloxetine. Because duloxetine can cause liver damage, patients who drink large quantities of alcoholic beverages should not take it. Signs of liver damage include itching, dark urine, yellowing of skin and eyes (jaundice), and fatigue. Patients should immediately contact their doctor if they experience these symptoms.

Other Antidepressants with Effects on Multiple Neurotransmitters.

• Bupropion (Wellbutrin, Zyban) affects the reuptake of serotonin, norepinephrine, and dopamine -- a third important neurotransmitter. In addition to depression, bupropion is also approved for smoking cessation and for treating seasonal affective disorder (SAD). 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 and sleep disorders, than SSRIs. Its safety for pregnant women is unknown. Nefazodone has been linked with increased risk for liver failure. Patients should consult their doctor concerning the relative risks and benefits of taking this nefazodone. The drug was withdrawn from the Canadian market in 2003 due to its risk for liver failure, but is still available in the United States.
• 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 indicate it works 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. However, 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 fluoxetine in reducing depression and improving social functioning, but it has many side effects including insomnia. Reboxetine is available in many countries, but not the United States.

Tricyclic Antidepressants

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

Tricyclics are sometimes grouped into two categories:

• 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 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 many side effects. They may offer benefits for many people with dysthymia, who generally do not respond to SSRIs.

Side Effects of Tricyclics. Side effects are 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:

• Dry mouth
• Constipation
• Blurred vision
• Sexual dysfunction
• Weight gain
• Difficulty urinating
• Drowsiness
• 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 are reports that tricyclics, particularly imipramine as well as mianserin and dothiepin, may increase the risk for a lung disease called idiopathic pulmonary fibrosis (IPF), which can cause lung inflammation and scarring. Initial symptoms are breathlessness and dry cough.
• Tricyclics can be fatal with an overdose.
• A 2000 study showed a small increased risk for non-Hodgkin's lymphoma associated with tricyclic use.
• Protriptyline can cause sun sensitivity. People who take this drug should take precautions against sunlight when they go outdoors.

Monoamine Oxidase Inhibitors (MAOIs)

Monoamine oxidase inhibitors (MAOIs) block monoamine oxidase, an enzyme 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 drugs can have very severe side effects, they are usually prescribed only when other types of antidepressants prove ineffective.

Newer MAOIs, such as selegiline (Eldepryl, Movergan), target only one form of the MAOI enzyme. They may cause fewer side effects than older MAOIs. In 2006, a skin patch form of selegiline (Emsam) was approved for treatment of major depressive disorder in adults.

Candidates for MAOIs. MAOIs 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
• The most serious side effect is severe hypertension (high blood pressure), which can be brought on by eating certain foods having 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 can cause birth defects and should not be taken by pregnant women.
• Very dangerous side effects, such as serotonin syndrome, can occur from interactions with other antidepressants, including SSRIs. Serotonin syndrome is a potentially fatal condition that is caused by the interaction of serotonergic drugs. Symptoms include confusion, agitation, sweating and shivering, and muscle spasms. There should be at least a 2-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 drugs in depression.

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:

• Mood stabilizers, such as lithium, carbamazepine, and divalproex sodium
• Newer antipsychotic drugs, such as risperidone
• Psychostimulants. Standard psychostimulants include dextroamphetamine (Dexedrine) and methylphenidate (Ritalin). A newer psychostimulant, modafinil (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, may help speed the response of antidepressants. In one study, after 10 days, nearly half the patients taking the combination were in remission compared to 25% of patients taking only paroxetine. In a study on fluoxetine, patients reached a sustained response within 19 days on the combination compared to 29 days with Prozac alone.

Investigational Drugs

Ketamine. Ketamine, an anesthetic drug, may be helpful for patients with severe treatment-resistant depression. In a small preliminary study, a single intravenous dose of ketamine helped patients quickly recover from depression within 2 hours, and some patients sustained benefits for up to a week. (Standard antidepressant drugs usually take about 8 weeks to have an effect.) Ketamine blocks the NMDA brain protein receptor, which is involved in glutamate regulation. Glutamate is a brain chemical that is thought to be involved in depression.