What are drug therapies?

Introduction

Before 1950, no truly effective drug therapies existed for mental illness. Physicians treated mentally ill patients with a combination of physical restraints, bloodletting, sedation, starvation, electric shock, and other minimally effective therapies. They used some drugs for treatment, including alcohol and opium, primarily to calm agitated patients. Interest in drug therapy in the early twentieth century was high, based on the rapidly increasing body of chemical knowledge developed during the late nineteenth century. Researchers in the first half of the twentieth century experimented with insulin, marijuana, antihistamines, and lithium, with varying success. The term
psychopharmacology
, the study of drugs for the treatment of mental illness, dates to 1920.

In 1951, a French scientist, Paul Charpentier, synthesized chlorpromazine (Thorazine) for use in reducing surgical patients’ anxiety and preventing shock during surgery. Physicians noted its calming effect and began to use it in psychiatry. Previously agitated patients with schizophrenia become calmer, their thoughts became less chaotic, and they became less irritable. Chlorpromazine was truly the first effective psychotropic drug (that is, a drug exerting an effect on the mind) and is still used.

The discovery of chlorpromazine ushered in a new era in the treatment of psychiatric illness. Pharmaceutical companies have developed and introduced dozens of new psychotropic drugs. Many long-term psychiatric treatment facilities have closed, and psychiatrists have released the vast majority of their patients into community-based mental health care. Patients with mental health problems are treated on an outpatient basis, with brief hospitalizations for stabilization in some cases. Treatment goals are no longer simply to sedate patients or to protect them and others from harm but rather to provide them with significant relief from their symptoms and to help them function productively in society. As scientific knowledge about the brain and its function increases, researchers are able to create drugs targeting increasingly specific areas of the brain, leading to fewer adverse side effects.

This psychotherapeutic drug revolution has had some negative consequences, however. Drug side effects range from annoying to life threatening. Community mental health treatment centers have not grown in number or received funding sufficient to meet the needs of all the patients released from long-term care facilities. Many mentally ill patients have fallen through the cracks of community-based care and live on the streets or in shelters for the homeless. In addition, some physicians and patients have come to expect a “pill for every ill” and fail to use other, equally or more effective treatment methodologies. The majority of prescriptions for psychotropic drugs are written by generalist physicians rather than by psychiatrists, raising concerns about excessive or inappropriate prescribing. Some people abuse these drugs, either by taking their medications in excess of the amount prescribed for them or by obtaining them illicitly. Studies have shown that prescription drug abuse causes more injuries and deaths than abuse of all illicit drugs combined. Feminist scholars have pointed out that physicians tend to prescribe psychotropic drugs more readily for women than for men.

Despite the negative effects, psychotropic drugs are extremely important in the provision of health care, not only for those people traditionally thought of as mentally ill but also for people with chronic pain, serious medical illness, and loss and grief, and those who have experienced traumatic events.

How Psychotropic Drugs Work

To understand how these mind-affecting drugs work, it is necessary to understand a little of how the brain works. The brain is made up primarily of neurons (nerve cells) that form circuits controlling thoughts, emotions, physical activities, and basic life functions. These nerve cells do not actually touch one another but are separated by a gap called a synapse. An electrical impulse moves along the neuron. When it reaches the end, it stimulates the release of chemicals called neurotransmitters into the synapse. These chemicals then fit into receptors on the next neuron and affect its electrical impulse. The neurotransmitters act by either causing the release of the electric impulse or inhibiting it so the neuron does not fire. Any neurotransmitter left in the synapse is then reabsorbed into the original neuron. This process is called reuptake.

Problems can arise in one of two ways: either too much or too little neurotransmission. Too much transmission may occur when the neuron fires in the absence of a stimulus or when too many neurotransmitters attach to the receptors on the far side of the synapse (the postsynaptic receptors). Too little transmission can occur when too few neurotransmitters attach to these postsynaptic receptors. The primary neurotransmitters involved in mental illnesses and their treatment are dopamine, serotonin (5-HT), norepinephrine, and gamma-aminobutyric acid (GABA).

Antidepressant Drugs

Some scientists believe that depression
is caused by insufficient norepinephrine, serotonin, or dopamine in the synapse. Others theorize that depression has to do with the number and sensitivity of postsynaptic receptors involved in the neuron’s response. Drugs for the treatment of depression fall into four major classes: the monoamine oxidase inhibitors (MAOIs), the tricyclic antidepressants, the selective serotonin reuptake inhibitors (SSRIs), and atypical antidepressants. None of these drugs is addictive, although patients need to be weaned from them slowly to avoid rebound depression or other adverse effects.

MAOIs were the first modern antidepressants. Monoamine oxidase is an enzyme that breaks down serotonin, norepinephrine, and dopamine. Inhibiting the enzyme increases the supply of these neurotransmitters. MAOI drugs available in the United States include phenelzine (Nardil) and tranylcypromine (Parnate). These drugs are not used as commonly as are the other antidepressants, mostly because of their side effects. However, they are used when other treatments for depression fail. In addition, they may be used to treat narcolepsy, phobias, anxiety, and Parkinson’s disease. Common side effects include drowsiness, fatigue, dry mouth, and dizziness. They may also cause orthostatic hypotension (a drop in blood pressure when arising) and sexual dysfunction. Most important, the MAOIs interact with tyramine-containing foods, such as hard cheese, red wine, and smoked or pickled fish. Consuming these foods along with an MAOI can cause a hypertensive crisis in which the patient’s blood pressure rises to potentially deadly levels. Patients taking MAOIs must also avoid other drugs that stimulate the nervous system to avoid blood pressure emergencies.

The tricyclic antidepressants were introduced in 1958. They all inhibit the reuptake of neurotransmitters but differ in which one is involved. Some affect primarily serotonin, some norepinephrine, and some work equally on both. Tricyclics available in the United States include amitriptyline (Elavil), imipramine (Tofranil), doxepin (Sinequan, Adapin), desipramine (Norpramin), nortriptyline (Pamelor, Aventyl), amoxapine (Asendin), protriptyline (Vivactil), and clomipramine (Anafranil). Primarily used for depression, these drugs may also be helpful in the treatment of bed-wetting, agoraphobia (fear of being out in the open) with panic attacks, obsessive-compulsive disorder, chronic pain, nerve pain, and migraine headaches. An important treatment issue is that it takes two to three weeks of drug therapy before the depressed patient feels much improvement in mood and energy. During this time, the side effects tend to be the most bothersome, leading patients to abandon the treatment before it becomes effective. Another important treatment issue is that tricyclic antidepressants are highly lethal in overdose. Common side effects include dry mouth, blurred vision, constipation, urinary retention, orthostatic hypotension, weight gain, sexual dysfunction, cardiac problems, and jaundice. Some of the tricyclics are highly sedating and so may be useful in patients who are having difficulty sleeping. On the other hand, a patient who is already feeling sluggish and sleepy may benefit from a tricyclic that is less sedating. Any antidepressant may precipitate mania or hypomania in a patient with a predisposition to bipolar disorder. Elderly patients may be at increased risk for falls or confusion and memory impairment when taking tricyclics and should be started on very low doses if a tricyclic is indicated.

The newer selective SSRIs have several advantages over the tricyclics: They are much less lethal in overdose, are far safer in the elderly, and do not cause weight gain. They work, as the name implies, by decreasing serotonin reuptake, thereby increasing the amount of neurotransmitter available at the synapse. Like the tricyclics, SSRIs may need to be taken for several weeks before a patient notices significant improvement in mood and energy level. SSRIs available in the United States include fluoxetine (Prozac), sertraline (Zoloft), fluvoxamine (Luvox), paroxetine (Paxil), trazodone (Desyrel), nafazodone (Serzone), and venlafaxine (Effexor). In addition to depression, the SSRIs are used for treatment of bulimia nervosa and obsessive-compulsive disorder. Possible side effects include nausea, diarrhea, nervousness, insomnia, anxiety, and sexual dysfunction.

Other drugs used in the treatment of depression, known collectively as atypical antidepressants, include mianserin (Tolvon), maprotiline (Ludiomil), and bupropion (Wellbutrin). The mechanisms by which these drugs work are not clear, but they may be useful in patients for whom the other antidepressants do not work or are contraindicated.

Mood Stabilizers

Some patients who have depression also have episodes of elevated mood and erratic, uncontrolled behavior. These patients are diagnosed with bipolar disorder, formerly known as manic-depression. The underlying cause for this disorder is unknown, but there is a strong genetic predisposition. Evidence suggests it is due to overactivity of the neurotransmitters. Treatment for bipolar disorder consists of mood-stabilizing drugs. These drugs control not only the “highs” but also the episodes of depression.

Lithium is a naturally occurring mineral that was observed to calm agitated behavior as long ago as in ancient Egypt. Its usefulness as a mood stabilizer was first scientifically established in the 1940s, and it was approved in 1970 for use in the United States. It is effective not only in stabilizing the mood during a manic episode but also in the prevention of future episodes. A significant problem with the use of lithium is that the dose at which it becomes effective is quite close to the dose that produces toxicity, characterized by drowsiness, blurred vision, staggering, confusion, irregular heartbeat, seizures, and coma. Patients taking lithium must therefore have blood drawn on a regular basis to determine drug levels. Patients who have poor kidney function should not take lithium because it is excreted primarily through the urine. Lithium’s side effects include nausea, diarrhea, tremor of the hands, dry mouth, and frequent urination.

Drugs usually used for the treatment of seizures may also help stabilize mood in bipolar patients, usually at lower doses than would be used for seizure control. These include carbamazepine (Tegretol), divalproex sodium (Depakote), gabapentin (Neurontin), lamotrigine (Lamictal), and topiramate (Topamax). It is believed that these drugs increase the amount of GABA at the synapse. GABA has a calming or inhibitory effect on the neurons. Side effects of these medications include dizziness, nausea, headaches, and visual changes.

Psychostimulants

Attention-deficit hyperactivity disorder (ADHD)
is found in both children and adults. Children with ADHD have difficulties at school because of impulsivity and inattention. The underlying cause of ADHD is extremely complex, and the ways in which drugs used to treat it work are equally complex. The most successful treatments are with psychostimulants, drugs that stimulate the central nervous system. Drug therapy is most effective when combined with behavioral treatments. The most commonly used psychostimulant is methylphenidate (marketed in varying formulations as Concerta, Daytrana, Metadate, Methylin, and Ritalin), but amphetamines are sometimes used as well. Formerly, depressed patients were treated with amphetamines and similar compounds; occasionally this use is still found. These stimulant drugs do improve school performance; however, they may cause growth retardation in both height and weight. They may also cause insomnia and nervousness. These drugs may be abused, leading ultimately to addiction, paranoia, and severe depression during withdrawal.

Antianxiety Drugs

Antianxiety drugs
or anxiolytics are central nervous system depressants. Many of these drugs, in higher doses, are also used as sedative-hypnotics, or calming and sleep-inducing drugs. They seem to act by enhancing the effect of GABA in the brain. The earliest of these depressant drugs included chloroform, chloral hydrate, and paraldehyde, and they were used for anesthesia and for sedation.

Barbiturates were introduced in Germany in 1862 and were widely used for treatment of anxiety and sleep problems until the 1960s. Barbiturates are still available today, including pentobarbital (Nembutal), secobarbital (Seconal), amobarbital (Amytal Sodium), and phenobarbital (Solfoton, Luminal). Their major adverse effect is respiratory depression, particularly when used in combination with alcohol, another central nervous system depressant. With the advent of the safer benzodiazepines, use of the barbiturates has declined steadily.

Benzodiazepines are used for two major problems: anxiety and insomnia. Anxiety disorders appropriate for this kind of treatment include generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobic disorder, and dissociative disorder. The benzodiazepines commonly used for anxiety include alprazolam (Xanax), chlordiazepoxide (Librium), clonazepam (Klonopin), clorazepate (Tranxene), diazepam (Valium), lorazepam (Ativan), and oxazepam (Serax). For most of these disorders, however, behavioral, cognitive, group, and social therapy, or one of these therapies plus medication, are more effective than medication alone. Benzodiazepines used for insomnia include estazolam (Prosom), flurazepam (Dalmane), midazolam (Versed), quazepam (Doral), temazepam (Restoril), and triazolam (Halcion). Benzodiazepines may also be used to prevent the development of delirium tremens during alcohol withdrawal. Patients become tolerant to the effects of these drugs, meaning they have the potential for physical dependency and addiction. In addition, benzodiazepines interact with many other drugs, including alcohol. Their use should be limited to brief periods of time, particularly in the treatment of insomnia. Long-term treatment for anxiety should be monitored carefully by the health care provider. Elderly people are more likely to suffer adverse effects (such as confusion or falls) from benzodiazepine use.

Another drug developed for treatment of anxiety is buspirone (Buspar). Propranolol (Inderal) and atenolol (Tenormin), usually used to treat high blood pressure, are useful in treating stage fright or performance anxiety, and clonidine (Catapres), another blood pressure medication, is successfully used in treatment of anxiety. Nonbenzodiazepine sleep agents include zolpidem (Ambien) and zaleplon (Sonata).

Antipsychotic Drugs

Formerly known as major tranquilizers or neuroleptics, the antipsychotic drugs
have revolutionized the treatment of schizophrenia and other psychoses. The underlying cause of psychosis is not known, but it is thought to be related to the neurotransmitter dopamine. Most of the antipsychotics block the dopamine receptors in the brain. The older antipsychotic drugs, some of which are no longer on the market, include chlorpromazine (Thorazine), thioridazine (Mellaril), perphenazine (Trilafon), trifluoperazine (Stelazine), fluphenazine (Prolixin), thiothixene (Navane), and haloperidol (Haldol). These older drugs treat the so-called positive symptoms of schizophrenia—hallucinations and delusions—but they have little effect on the negative symptoms, which include withdrawal, poor interpersonal relationships, and slowing of the body’s movement. They also have multiple serious side effects, including severe muscle spasm, tremor, rigidity, shuffling gait, stupor, fever, difficulty speaking, blood pressure changes, restlessness, and involuntary movements of the face, trunk, arms, and legs. Some of these are treatable using other drugs, but some are neither treatable nor reversible. In an effort to overcome these problems, newer antipsychotics have been developed. The first of these was clozapine (Clozaril), which was successful in treating about one-third of the patients who did not respond to other antipsychotic drugs. Although it has fewer of the serious side effects listed above, a small percentage of patients experience a severe drop in the white blood cells, which puts them at risk for serious infection. For this reason, patients on clozapine must participate in frequent blood tests. Other newer antipsychotics include risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel). In addition to fewer of the serious side effects, the newer antipsychotics seem to have some effect on the negative symptoms.

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