Medications

Until recently, the anti-anxiety drugs known as benzodiazepines were the primary medications for anxiety. Increasingly, antidepressants, particularly the selective serotonin-reuptake inhibitors (SSRIs), are being used as the initial treatment. They are proving to be effective, nonaddictive, and to have relatively minor side effects.

Many standard antidepressants take 2 - 4 weeks, and sometimes up to 12 weeks, before they are fully effective. People who take them may also experience a temporary period of increased anxiety. Consequently, about a third of patients stop taking antidepressants for anxiety disorders before completing the initial phase of therapy. A combination of a benzodiazepine and an antidepressant is sometimes used to avoid the initial anxiety symptoms and to hasten control of panic symptoms. The benzodiazepine can then be withdrawn, and the antidepressant, with its negligible chance for long-term abuse, is continued.

No one should become disheartened if one drug treatment fails. Another may prove to be very effective, even it is a drug of a similar type. Drug combinations should be tried if a single drug and cognitive-behavior therapy has failed. Because many anxiety disorders are chronic, drug therapy sometimes is needed for prolonged periods, even years.

Antidepressants

Selective Serotonin Reuptake Inhibitors (SSRIs). Selective serotonin-reuptake inhibitors (SSRIs) are the first-line treatment of major depression and proving to be helpful for many anxiety disorders. They work by increasing levels of serotonin in the brain. SSRIs include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa), and escitalopram (Lexapro). Escitalopram is similar to citalopram and may have fewer side effects than other SSRIs. All of these drugs are proving to be very valuable for adults and even for many children with most anxiety disorders. The following are some indications for their use in specific anxiety disorders:

• Obsessive-Compulsive Disorder. SSRIs are the first-line treatment for obsessive-compulsive disorder (OCD). They reduce symptoms by 25 - 35% in about half of all patients. (SSRIs may be less effective with tics, hoarding, and compulsive behaviors than with other OCD symptoms.)
• Panic disorder. SSRIs may also be very useful in treating patients with panic disorder. Some -- but not all -- studies suggest that higher doses than those used for depression may be required in order to achieve benefits. More research is needed on the optimal dosages.
• Phobias. SSRIs may also help people with phobias, including agoraphobia and social phobias. Relapse is common in social phobia patients, and treatment for longer than a year may be needed in some patients. Combining medications with cognitive-behavioral therapy can help prevent relapse.
• Post-Traumatic Stress Disorder. SSRIs may help some people with post-traumatic stress disorder (PTSD). Their benefits may be limited. Victims of child abuse, for example, tend to respond poorly to SSRIs. A study on sertraline suggested that although it was particularly effective in women it may not offer many benefits for combat veterans. At this time sertraline (Zoloft) and paroxetine (Paxil) are specifically FDA-approved for PTSD, although studies suggest that other SSRIs may be helpful.
• Generalized Anxiety Disorder. SSRIs have been less studied for generalized anxiety, but studies on paroxetine (Paxil), sertraline (Zoloft), and escitalopram (Lexapro) suggest that SSRIs may be very effective for many people with GAD.
• Anxiety Disorders in Children. SSRIs may be effective for children who have both OCD and major depression. Fluoxetine (Prozac) is the only SSRI approved for use in children. In addition to depression, it is approved for treating children with OCD. The FDA has strongly advised against prescribing certain SSRIs, such as paroxetine, to children and young adults due to increased risk for suicidal behavior.

SSRIs can cause agitation, nausea, and low sex drive. Over time, many SSRI-treated patients gain weight, although the degree of weight gain varies depending on the drug. (For example, paroxetine poses a greater risk for weight gain than citalopram.) Elderly people taking these drugs should take the lowest effective dose possible, and those with heart problems should be monitored closely.

There have been many concerns about SSRIs and increased risk for suicidal behavior. Both adults and children who are treated with SSRIs should be carefully monitored for any worsening of depressive symptoms or changes in behavior. This is especially important during the first few months of antidepressant treatment.

Paroxetine has been linked to heart-related birth defects when women took this drug during the first trimester of pregnancy. Experts are also advising caution in prescribing other types of SSRIs to pregnant women. A 2006 study in the New England Journal of Medicine indicated that babies born to women who take SSRIs during the second half of pregnancy have an increased risk for persistent pulmonary hypertension, a serious lung condition. Other studies suggest that babies born to women who take SSRIs late in pregnancy may have more problems with irritability and difficulty feeding. Women who are pregnant or who are considering becoming pregnant should discuss the potential risks of these drugs with their doctors.

Designer Antidepressants. A number of newer antidepressants that target other neurotransmitters alone or in addition to serotonin are proving to be very promising for anxiety, including generalized anxiety disorder. They include nefazodone (Serzone), venlafaxine (Effexor), and mirtazapine (Remeron).

• Venlafaxine (Effexor) works well for both short- and long-term treatment of generalized anxiety disorder. It may have some benefits for social anxiety. In 2005, it was approved for treatment of panic disorder in adults. As with the SSRIs, and unlike other newer antidepressants, venlafaxine impairs sexual function. Of concern are 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. Venlafaxine can cause fatal overdose, especially if taken in combination with alcohol or other drugs. Venlafaxine should not be taken during the last trimester of pregnancy because the drug can cause complications in newborn infants.
• Nefazodone (Serzone) has shown some benefit in patients with GAD, social phobias, and panic disorder. The drug is more rapidly effective and has fewer distressing side effects, including sexual dysfunction, than SSRIs. Nefazodone is one of the only antidepressants that has a positive effect on sleep efficiency, which may particularly benefit patients with insomnia. The drug may cause an abrupt drop in blood pressure after standing up suddenly. Nefazodone has been linked with increased risk for liver failure.
• Mirtazapine (Remeron) may be an effective treatment for panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. It may work faster than other SSRIs and have stronger early actions against anxiety in patients who also suffer depression. It may cause less sexual dysfunction than some other antidepressants. It interacts with histamine, a chemical involved in allergic responses. These actions can cause drowsiness, which may make it a useful drug for patients who suffer from insomnia. The drug also causes blurred vision. The drug has been associated with weight gain, although in one study it was not significant. It does not appear to have the adverse acute effects on the heart that other newer antidepressants have, although it may slightly raise cholesterol and triglyceride levels.

Tricyclic Antidepressants. The antidepressant drugs known as tricyclic antidepressants (TCAs) have also been effective in treating panic and obsessive-compulsive disorders. Studies on specific TCAs have suggested the following benefits:

• Imipramine (Tofranil, Janimine) is the most commonly used TCA for panic disorder. It is also effective in treating agoraphobia and GAD. In one study it was helpful in reducing side effects during withdrawal from benzodiazepines, the standard anti-anxiety drugs.
• Doxepin (Adapin, Sinequan) has been beneficial for people with a mix of generalized anxiety disorder and depression.
• Clomipramine (Anafranil) is also effective for panic disorders and has been approved for OCD. The drug causes significant reduction in OCD symptoms for patients, including some children, who can tolerate it. (The other tricyclics do not appear to benefit OCD patients.) Many patients stop using Anafranil, however, because of side effects.

Side effects of TCAs include sleep disturbance, abrupt reduction in blood pressure upon standing, weight gain, sexual dysfunction, and mental disturbance. Elderly patients and those with a history of seizures, cardiac problems, closed-angle glaucoma, and urinary retention or obstruction should be closely supervised when taking tricyclics.

Monoamine Oxidase Inhibitors. Monoamine oxidase inhibitors (MAOIs), typically phenelzine (Nardil) or tranylcypromine (Parnate), are antidepressants used for panic disorder or OCD that does not respond to other treatments. Moclobemide (Manerix, Aurorix) is a newer MAOI available in Canada and Europe that showed some benefits for social phobias in some, but not all studies.

MAOIs commonly cause weight gain, drowsiness, dizziness, sexual dysfunction, and insomnia. The main problem with most of these drugs is the need for dietary restrictions. Severe high blood pressure (hypertension) can be brought on by eating certain foods that have a high tyramine content including cheese, red wine, vermouth, dried meats and fish, canned figs, and fava beans. MAOIs can also lead to serious hypertensive interactions with certain drugs, including some common over-the-counter cough medications and decongestants. They can also cause birth defects and should not be taken by pregnant women.

Benzodiazepines

Benzodiazepines are effective medications for most anxiety disorders and have been the standard of treatment for years. However, their use has been associated with a high risk for dependency and abuse. (Some reports suggest they are harder to withdraw from than heroin.) Therefore, they have been supplanted in most cases by SSRIs and by newer antidepressants. Benzodiazepines include:

• Alprazolam (Xanax) and clonazepam (Klonopin) are effective for panic disorder, some phobias, and generalized anxiety disorder. Benzodiazepines in combination with selective serotonin reuptake inhibitors may be particularly helpful in the treatment of panic attacks, although there is no standard as yet for the safest and most effective method for administering this combination.
• Other benzodiazepines, including diazepam (Valium), lorazepam (Ativan), and chlordiazepoxide (Librium), are used mainly for generalized anxiety.

Side Effects. Benzodiazepines have many side effects. The most common are daytime drowsiness and a hung-over feeling. In rare cases, they can cause agitation. The may worsen respiratory problems. The drugs stimulate eating and can cause weight gain. In one 2002 study, 33% of patients experienced incontinence at least twice a week. Highest risk was in long-acting drugs, such as chlordiazepoxide. Benzodiazepines can interact with certain drugs, including cimetidine (Tagamet), antihistamines, and oral contraceptives. Benzodiazepines are potentially dangerous when used in combination with alcohol. Overdoses can be serious, although they are very rarely fatal.

The elderly are more susceptible to side effects and should usually start at half the dose prescribed for younger people. These drugs increase the risk of falling, which can increase the risk for hip fracture in older people. Also of concern are studies showing a high risk of automobile accidents in people who take benzodiazepines. Benzodiazepines taken during pregnancy are associated with birth defects, and they should not be used by pregnant women or by nursing mothers.

Loss of Effectiveness and Dependence. Eventually these drugs can lose their effectiveness with continued use at the same dosage. As a result, patients may want to increase their dosage to prevent anxiety. This causes dependency, which can occur after as short a time as several weeks of taking these drugs. Some evidence suggests that the risk for abuse exists only in people who are already susceptible to substance abuse.

Withdrawal and its Treatments. Withdrawal symptoms can be very severe, even in people who rapidly discontinue benzodiazepines after taking them for only 4 weeks. Some experts believe that benzodiazepines are harder to withdraw from than heroin. Symptoms include sleep disturbance and anxiety, which can develop within hours or days after stopping the medication. Some patients experience stomach distress, sweating, and insomnia, which can last from 1 - 3 weeks. The longer the drugs are taken and the higher their dose, the more severe these symptoms can become. Simply tapering off gradually helps about 60% of people to withdraw. Certain medications (anti-seizure drugs, antidepressants, buspirone) may also be helpful in assisting with withdrawal.

Azapirones

Azapirones, such as buspirone (BuSpar) and gepirone (Ariza, Variza), act on serotonin receptors called 5-HT(1A). Buspirone has been the most intensively studied. It appears to work as well as a benzodiazepine for treating generalized anxiety disorder. It usually takes several days to weeks for the drug to be fully effective. It is not useful against panic attacks.

Buspirone does not produce any immediate euphoria or change in sensation, so some people believe, erroneously, that the drug doesn't work. Such qualities result in a very low potential for abuse. In fact, unlike the benzodiazepines, buspirone is not addictive, even with long-term use, so it may be particularly useful for the patient whose anxiety disorder coexists with alcoholism or drug abuse.

Buspirone also seems to have less pronounced side effects than benzodiazepines and no withdrawal effects, even when the drug is discontinued quickly. Common side effects include dizziness, drowsiness, and nausea. Buspirone should not be used with monoamine oxidase inhibitors (MAOIs).

Beta-Blockers

Beta-blockers, including propranolol (Inderal) and atenolol (Tenormin), block the nerves that stimulate the heart to beat faster. They affect only the physiologic symptoms of anxiety and are most helpful for phobias, particularly performance anxiety. Beta-blockers are less effective for other forms of anxiety.

Clonidine

Clonidine, a drug that relaxes blood vessels, has been used to treat children with post-traumatic stress disorder. Some experts believe it should be tried for anxiety disorders if other therapies fail. The drug can have severe side effects.

Atypical Antipsychotics

In certain severe cases, drugs called atypical antipsychotics may be useful. They include risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), and others. In one study, risperidone was useful in combination with an SSRI for OCD patients who did not respond to an SSRI alone. They are also possibly useful for severe GAD. Common side effects include sleepiness and dizziness. Most cause weight gain. In high doses they may cause extrapyramidal symptoms, which involve the nerves and muscles controlling movement and coordination. The risk for these side effects, however, are far less than with older antipsychotic drugs. Still, there are many risks associated with all antipsychotic drugs. [For more information on antipsychotics, see In-Depth Report #47: Schizophrenia.]

Anticonvulsants

Pregabalin (Lyrica) and gabapentin (Neurontin) are drugs used to treat seizures and other conditions. Small studies suggest that these drugs may be useful for certain anxiety disorders, such as social phobia, general anxiety disorder, and post-traumatic stress disorder. A 2005 study suggested that pregabalin worked as well as the benzodiazepine alprazolam (Xanax) for treatment of generalized anxiety disorder.

Investigational Drugs

Glucocorticoids. Scientists are investigating whether the stress hormone cortisol can help reduce fear in people with phobias. In a preliminary research study, a cortisone drug helped reduce fear and anxiety in patients with social and spider phobias.

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Review Date: 12/4/2006
Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital