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psychopharmacology

psychopharmacology (sī´kōfär´məkŏl´əjē), in its broadest sense, the study of all pharmacological agents that affect mental and emotional functions. The term is usually applied more specifically to the study and synthesis of drugs used in the control of psychiatric illnesses, namely the antipsychotic, antianxiety, antidepressant, and antimanic medications. The widespread use of drugs among individuals suffering from mental illness is a relatively recent phenomenon, developing since the 1950s.

Antipsychotic Drugs

Antipsychotic drugs can ameliorate the types of delusions and hallucinations characteristic of bipolar disorder (see depression) and schizophrenia. The first drug of this type was reserpine, whose use dates from ancient Hindu medicine but whose reintroduction as an antipsychotic agent in 1954 marked the beginning of the large-scale use of antipsychotic drugs. Because of side effects, including depression, reserpine has been supplanted by phenothiazine drugs. The phenothiazine chlorpromazine (Thorazine) was the first to be widely applied to mental disorders and remains one of the standard drugs. Drugs of the phenothiazine family are most useful in the treatment of schizophrenia. They are thought to act in part by blocking dopamine receptors at the synapse, reducing brain activity. The phenothiazines and clozapine have been credited with a revolutionary transformation of mental health care, enabling increasing numbers of psychotic persons to function outside the hospital. Antipsychotic drugs may have negative side effects, such as the dulling of physical and mental functioning, tardive dyskinesia, and sedation.

Antianxiety Drugs

Antianxiety drugs, including the propanediol meprobamate (Miltown or Equanil), and the more recent benzodiazephines—such as diazepam (Valium)—have found wide use in reducing tension and anxiety among individuals with less serious mental disorders, but may lead to addiction if abused. Although they form a chemically diverse group, the physiological effects of each are similar; in small doses they relieve anxiety by reducing muscular tension, and in larger doses they produce sedation, sleep, and anesthesia (see depressant). Antianxiety drugs are the most frequently prescribed pharmaceuticals in the United States.

Antidepressants

Antidepressants appeared in the late 1950s, and have been used in the treatment of individuals suffering from major depression or the depression phase of bipolar disorder. Antidepressants include the tricyclics and monoamine oxidase (MAO) inhibitors. These drugs have the effect of increasing the concentration in the nervous system of catecholamines such as epinephrine. The toxic effects of the MAO inhibitors have been largely overcome in recent years, and the drugs are still used in many instances. They have been supplanted in many uses, however, by tricyclic compounds, such as amitriptyline (Elavil), and the newer serotonin increasers, such as fluoxetine (Prozac) and sertraline HCL (Zoloft). Tricyclics are chemically similar to phenothiazines, but that activate rather than tranquilize (see stimulant). The choice of an antidepressant often has more to do with its side effects than efficacy.

Antimanic and Hallucinogenic Drugs

The element lithium, in the form lithium carbonate, has been widely used as an antimanic in cases of bipolar disorder (manic-depression), particularly to control manic episodes. Lithium alters the transport of sodium ions in nerve and muscle cells and affects the metabolism of catecholamines; the exact mechanism of action is unknown. The hallucinogenic drugs, such as mescaline and LSD, have been of research interest because they often mimic natural psychotic states.

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Psychopharmacology

Psychopharmacology

Psychopharmacology

How Do Psychiatric Medications Work?

What Are the Beneficial Effects of Psychiatric Medications?

What Are the Adverse Effects of Psychiatric Medications?

What Is Next in Psychopharmacology?

Resources

Medications for mental, emotional, behavioral, and mood disorders are prescribed by medical doctors called psychiatrists, often as part of a treatment plan that includes psychotherapy (talk therapy)

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Neurotransmitters

Pharmacotherapy

Psychiatry

Psychopharmacology

Psychopharmacology

Psychopharmacology (SY-koe-far-ma-KOL-o-jee) is the study of how medications affect moods, thoughts, and feelings. Psychopharmacology is an exciting new science. When our grandparents were young, there were no medications that helped people with attention deficit hyperactivity disorder concentrate at school or work, no medications that helped people with schizophrenia quiet the voices in their heads, and no medications that helped people with depression find the energy to face a new day. Today there are prescription medications for these disorders and many others.

Psychiatric medications generally are classified into categories that reflect the chemistry of how they work in the body (mechanisms of action) or the symptoms they help relieve. Many medications fall into more than one category. For example, the same medication might improve symptoms of both depression and anxiety. These are some major types of psychiatric medications:

  • antidepressant medications, which include tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRIs)
  • antianxiety medications (tranquilizers), which include barbiturates, benzodiazepines, and the atypical anxiolytic buspirone
  • antimanic medications (mood stabilizers)
  • anticonvulsant medications
  • antipsychotic medications (neuroleptics)
  • stimulants.

Physicians Desk Reference (PDR)

Psychiatrists and psychopharmacologists study the research about medications before prescribing them. They attend training sessions, read medical journals, and review descriptions in the Physicians Desk Reference (PDR) medical directory for details about how specific medications work (mechanisms), how they help patients (beneficial effects), whether they cause side effects (adverse effects), and whether they can be used safely with a patients regular diet and other prescription medications (drug interactions).

The PDR lists medications by generic name (fluoxetine, for example) and also by the trade name given to a particular medication by the company that sells it (Prozac, in this case). Important psychiatric medications include:

Antidepressants

  • amoxapine (Asendin)
  • bupropion (Wellbutrin)
  • clomipramine (Anafranil)
  • doxepin (Sinequan or Adapin)
  • maprotiline (Ludiomil)
  • mirtazapine (Remeron)
  • nefazodone (Serzone)
  • trazodone (Desyrel)
  • venlafaxine (Effexor)

Antidepressants/Tricyclics (TCAs)

  • amitriptyline (Elavil)
  • desipramine (Norpramin, Pertofrane)
  • imipramine (Tofranil)
  • nortriptyline (Pamelor, Aventyl)

Antidepressants/Monoamine Oxidase Inhibitors (MAOIs)

  • isocarboxazid (Marplan)
  • phenelzine (Nardil)
  • tranylcypromine (Parnate)

Antidepressants/Selective Serotonin Reuptake Inhibitors (SSRIs)

  • citalopram (Celexa)
  • fluoxetine (Prozac)
  • fluvoxamine (Luvox)
  • paroxetine (Paxil)
  • sertraline (Zoloft)

Antianxiety Medications (Anxiolytics, Minor Tranquilizers)

  • alprazolam (Xanax)
  • buspirone (BuSpar)
  • chlordiazepoxide (Librium, Librax, Libritabs)
  • clorazepate (Tranxene, Azene)
  • diazepam (Valium)
  • halazepam (Paxipam)
  • lorazepam (Ativan)
  • oxazepam (Serax)
  • prazepam (Centrax)

Antimanic Medications (Mood Stabilizers)

  • carbamazepine (Tegretol)
  • divalproex sodium (Depakote)
  • lithium carbonate (Eskalith, Lithane, Lithobid)
  • lithium citrate (Cibalith-S)

Anticonvulsants

  • carbamazepine (Tegretol)
  • clonazepam (Klonopin)
  • divalproex sodium (Depakote)
  • gabapentin (Neurontin)
  • lamotrigine (Lamictil)
  • oxcarbazepine (Trileptal)
  • topiramate (Topamax)
  • valproic acid (Depakene)

Antipsychotic Medications

  • chlorpromazine (Thorazine)
  • chlorprothixene (Taractan)
  • clozapine (Clozaril)
  • fluphenazine (Prolixin, Permitil)
  • haloperidol (Haldol)
  • loxapine (Loxitane, Daxolin)
  • mesoridazine (Serentil)
  • molindone (Moban, Lidone)
  • olanzapine (Zyprexa)
  • perphenazine (Trilafon)
  • pimozide (Orap)
  • quetiapine (Seroquel)
  • risperidone (Risperdal)
  • thioridazine (Mellaril)
  • thiothixene (Navane)
  • trifluoperazine (Stelazine)
  • triflupromazine (Vesprin)
  • ziprasidone (Geodone)

Stimulants

  • dextroamphetamine (Adderall, Dexedrine)
  • methylphenidate (Concerta, Ritalin)
  • pemoline (Cylert)
  • mixed amphetamine salts (Adderall)

Examples of well-known psychiatric medications include Prozac and Paxil (antidepressants); Valium, Xanax, and BuSpar (antianxiety medications); lithium (antimanic medication); Tegretol and phenobarbital (anticonvulsants); Thorazine and Haldol (antipsychotics); and Ritalin and Concerta (stimulants).

How Do Psychiatric Medications Work?

Psychiatric medications target the complex chemistry of neurons and neurotransmitters in the brain and central nervous system. Neurotransmitters such as serotonin (ser-o-TONE-in) and dopamine (DOPE-ameen) are manufactured in neurons (nerve cells) to carry messages from cell to cell, crossing the synaptic gap between the axon (transmitting terminal) of one neuron to the dendrites (receiving terminals) of the next neuron. The chemical structure of each neurotransmitter is designed to fit its neuroreceptor the way a key fits a lock. A change in a neurotransmitters chemical structure, or an imbalance at any point in this complex process, may affect emotions, moods, thoughts, behaviors, and mental states. Psychiatric medications help restore proper balance. Important neurotransmitters include serotonin, dopamine, epinephrine, norepinephrine (monoamines), acetylcholine, gamma-aminobutyric acid (GABA), glutamic acid, enkephalins, and endorphins.

What Are the Beneficial Effects of Psychiatric Medications?

Psychiatric medications can help improve many of the most distressing symptoms of mental, emotional, and mood disorders. They can reduce the stress of living with chronic diseases and conditions, and they can improve the effectiveness of counseling and psychotherapy. Among their most beneficial effects are:

  • decreasing feelings of hopelessness, darkness, and apathy in depression
  • preventing relapse of depression
  • reducing cravings, anxiety, obsessions, compulsions, and phobias
  • preventing panic attacks
  • reducing hallucinations, delusions, inappropriate behaviors, and the voices that often accompany schizophrenia
  • calming impulsivity, hyperactivity, and mania
  • improving concentration, memory, and sleep.

Selecting the right medication and the right dosage are complicated tasks, requiring that doctors take detailed medical histories from their patients and their patients families. Doctors must know about other medical conditions the patient may have, about other medications the patient may be taking (including aspirin, alcohol, herbal supplements, and tobacco), and about the patients diet and daily life. Doctors also must monitor patients who are taking medications to ensure that symptoms improve and to adjust dosages or change prescriptions if side effects occur.

Psychiatric medications can help correct imbalances in the neurotransmitters that affect mood and behavior. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), fit into the serotonin neuroreceptors on neuron dendrites. This blocks serotonin from entering the neuron and keeps it active for longer periods of time in the synaptic gaps between transmitting and receiving neurons. Serotonin (5-Hydroxytryptamine) is a calming neurotransmitter that is manufactured in nerve cells from the amino acid tryptophan. Turkey is one good source of tryptophan, which may help explain why people often feel relaxed and sleepy after Thanksgiving dinner.

What Are the Adverse Effects of Psychiatric Medications?

Adverse effects are unwanted side effects, and psychiatric medications can have serious adverse effects if not monitored carefully by a doctor. Depending on the medication, adverse effects may include:

Methylphenidate (Concerta, Ritalin) is a stimulant. It often is prescribed to treat the symptoms of attention deficit hyperactivity disorder (ADHD). When misused, however, methylphenidate can harm the body in the same manner as other forms of amphetamine abuse. Photo Researchers, Inc.

  • drowsiness or sleepiness at the wrong time of day, making it dangerous to operate machinery or drive a car
  • restlessness or wakefulness at night
  • headache, dizziness, or blurry vision
  • dry mouth or increased thirst
  • high blood pressure
  • skin rashes
  • nausea or vomiting
  • unwanted weight loss or unwanted weight gain
  • unwanted changes in thoughts or behavior, such as losing interest in dating, losing interest in creativity, or having suicidal thoughts that never occurred before
  • seizures, especially if a medication interacts with certain foods or other medications
  • muscle spasms, slurred speech, or a movement disorder called tardive dyskinesia.

The complex chemistry of psychiatric medications and the central nervous system also can affect other body organs and systems, such as the blood, bone marrow, thyroid gland, liver, and kidneys. MAOIs can interact with cheeses, wines, or cold medications to cause seizures. Some medications can interfere with a childs normal growth and development. Others can pose serious risks to pregnant women, nursing mothers, and their babies. Older adults who are taking multiple prescriptions are at particular risk for harmful drug interactions. Some psychiatric medications also can lead to addiction, withdrawal symptoms if the medication is stopped, and accidental overdoses. People who use psychiatric medications must see their doctors regularly and report side effects as soon as they notice them.

What Is Next in Psychopharmacology?

The science of psychopharmacology is less than 50 years old, and discoveries are still being made at a rapid pace. Researchers are developing new medications that target more than one neurotransmitter at the same time, which means that they can improve symptoms in multiple categories at once. Also in development and clinical trials are newer medications with fewer adverse effects, reduced risk of addiction and withdrawal symptoms, and less chance for tardive dyskinesia.

Psychiatric medications are most effective when the people who take them work with psychiatrists and medical doctors to update their prescriptions as often as necessary.

Tardive Dyskinesia

Tardive dyskinesia (TAR-div DIS-kuhNEE-zhuh) is one of the most distressing adverse effects of antipsychotic medication. It is a disorder of the neuromuscular system that causes muscle spasms and tics, which are involuntary movements affecting the eyes, tongue, face, neck, fingers, arms, toes, or legs. Tardive dyskinesia may disappear if the medication is stopped, but sometimes it becomes a chronic condition. People who develop tardive dyskinesia often continue taking their medication because the beneficial effects outweigh this very serious adverse effect.

See also

Anxiety and Anxiety Disorders

Attention Deficit Hyperactivity Disorder

Bipolar Disorder

Brain Chemistry (Neurochemistry)

Depression

Obsessive-Compulsive Disorder

Psychosis

Schizophrenia

Tourette Syndrome

Resources

Organizations

American Academy of Child and Adolescent Psychiatry, 3615 Wisconsin Avenue Northwest, Washington, DC 20016-3007. This professional organization for psychiatrists provides information about medications for children and teenagers. Telephone 202-966-7300 http://www.aacap.org

American Psychiatric Association, 1400 K Street Northwest, Washington, DC 20005. The leading professional organization for psychiatrists in the United States offers expert information about medications. Telephone 888-357-7924 http://www.psych.org

U.S. Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857-0001. This government agency provides the latest information on new drugs and sound advice about the proper use of medications. Telephone 888-463-6332 http://www.fda.gov

U.S. National Institute of Mental Health, 6001 Executive Boulevard, Room 8184, MSC 9663, Bethesda, MD 20892-9663. This government institute publishes an informative booklet for families called Medications (publication 95-3929), which also can be downloaded from its website in PDF format. It also posts many other fact sheets at its website offering safe and reliable information. Telephone 301-443-4513 http://www.nimh.nih.gov

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psychopharmacology

psychopharmacology Study of how drugs affect behaviour. Drugs are classified according to their effect: sedative hypnotics, such as barbiturates; stimulants, such as amphetamines; opiate narcotics, such as heroin; and psychedelics and hallucinogens, such as LSD.

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psychopharmacology

psychopharmacology (sy-koh-farm-ă-kol-ŏji) n. the study of the effects of drugs on mental processes and behaviour, particularly psychotropic drugs.

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Psychopharmacology

Psychopharmacology

Psychopharmacology is a branch of science that studies the effects that drugs have on the brain, thinking, and behavior. These drugs act on the central nervous system (the brain and spinal cord) and also interact with other body systems, affecting various functions including blood pressure, heart rate and rhythm, breathing rate, and metabolism, the way the body processes and uses nutrients for energy and growth. Drugs studied include medications that are used to treat mental conditions, such as medications to treat depression, anxiety, mania, and psychosis . Drugs of abuse may also be studied, including cocaine, marijuana, hallucinogens, and prescription drugs that may be abused for their affects on mood and consciousness.

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Psychopharmacology

PSYCHOPHARMACOLOGY

•••

Psychopharmacology is the study of drugs used to treat disturbances in mood, behavior, and mental functioning across a broad range of illnesses and conditions. While many drugs used in general medicine (e.g., antihypertensives, hormonal therapies) can cause behavioral changes or psychological symptoms, psychopharmacologic agents are used specifically for their behavioral or mental effects. The classes of psychopharmacologic medications include the following: antipsychotics, antidepressants, antianxiety agents, and mood stabilizers. There are numerous ethical issues in psychopharmacology. This entry focuses on issues related to consent to treatment, the inclusion of severely mentally ill persons in psychopharmacologic research, involuntary out-patient treatment, and the cost of newer psychotropic medications.

The main classes of psychopharmacologic agents, which are antipsychotics, antidepressants, antianxiety agents, and mood stabilizers, are discussed below. Under each category, the U.S. Food and Drug Administration (FDA) approved drugs as well as their therapeutic and adverse effects are described. Cognitive enhancers (e.g., donepezil or Aricept), used to treat Alzheimer disease, are not included in this entry.

Antipsychotics

As the first effective medications to be introduced into treatment of psychosis, antipsychotic drugs revolutionized the treatment of schizophrenia and other severe psychiatric disorders. Prior to the introduction of the first antipsychotic(i.e., chlorpromazine [Thorazine]) in 1952, the principal treatment for a person with schizophrenia was long-term hospitalization. Often this hospitalization was aimed primarily at protecting society from patients with mental illness. The arrival of antipsychotic medications that could actually reduce psychiatric symptoms heralded a new era in the history of mental healthcare. Over the ensuing years, care for schizophrenia and other psychotic disorders changed from a largely custodial, institution-based system to a more community-based model emphasizing treatment and rehabilitation of individuals with psychiatric disorders (Grob).

Although they have been used to treat a variety of psychiatric conditions, antipsychotic drugs are primarily intended for psychotic disorders, the best example being schizophrenia. Schizophrenia affects approximately 1 percent of the population worldwide, and the vast majority of patients receive antipsychotic medication. Antipsychotics are especially useful in treating the hallucinations (perceptual disturbances such as hearing voices or seeing things), delusions (fixed false beliefs), and disorganized behavior. In addition antipsychotics can reduce the associated agitation, hostility, and unsafe behaviors that frequently impact the quality of life of patients, family members, and caregivers of persons with schizophrenia. Antipsychotic medications can reduce the symptoms of schizophrenia but do not cure the underlying illness, so a person who stops taking his medications is likely to have a relapse. In addition symptoms such as social withdrawal, loss of motivation, reduced emotional expression, and slowed thinking often persist, despite the use of antipsychotics.

There are different types of antipsychotics, each with a distinct chemical structure. With the advent of a newer generation of antipsychotics beginning in the late 1980s, drugs are now categorized as either conventional or atypical. The conventional agents were the only drugs available for treating schizophrenia for the first thirty-five years of the pharmacologic treatment era.

Conventional antipsychotics block receptors for a chemical messenger called dopamine in certain areas of the brain that are believed to mediate psychotic behavior. Hence increased dopamine activity is believed to be associated with psychosis, whereas blocking dopamine is believed to reduce psychosis. At the same time, blocking dopamine in other areas of the brain can produce uncomfortable muscular symptoms (stiffness, rigidity, tremor, restlessness) as well as abnormal breast milk production and sexual dysfunction.

The newer atypical antipsychotics may be of greater clinical benefit compared to the conventional antipsychotics. These atypical antipsychotics have fewer side effects and are better tolerated by patients. Patients may be more likely to take the newer medications regularly (Dolder et al.) and these medications may facilitate improved emotional expression, motivation, and social interaction in patients with schizophrenia.

ADVERSE EFFECTS. In the short term, dopamine receptors in brain regions responsible for involuntary movement system often produces rigidity, tremor, slowing of movement, and an unpleasant feeling of muscular restlessness. Over the long term, a substantial proportion of patients treated with conventional antipsychotics develop tardive dyskinesia, a potentially irreversible neurological disorder of involuntary movements of the mouth, face, neck, and body. The condition can be quite incapacitating, and there is currently no effective treatment. Each additional year of antipsychotic exposure increases a person's chance of developing tardive dyskinesia. Elderly patients are particularly at risk for this condition, especially if there is a pre-existing movement disorder such as drug induced parkinsonism (Jeste et al., 1999b; 1999a).

The newer antipsychotics have been found to be much less likely to induce abnormal movements including tardive dyskinesia. To that end, clozapine (Clozaril), the first atypical agent to become available in the United States, is recommended for patients who either have not responded to other antipsychotic medications or have developed severe abnormal movements or tardive dyskinesia while taking other agents. The use of Clozaril has been limited by other unpleasant adverse effects such as excessive sedation, weight gain, low blood pressure, cognitive clouding, blurred vision, hypersalivation, and increased risk of seizures. In addition Clozaril has a rare tendency to cause a drop in the white blood cell count, which can be potentially life-threatening. For that reason, any patient who begins treatment with Clozaril is required to have a blood test every week to monitor his or her white blood cell count.

In the late 1990s and early 2000s, five other atypical antipsychotics were approved by the FDA: risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole (Abilify). Each agent has a somewhat unique side effect profile. Some of the newer agents have been found to be associated with metabolic changes such as weight gain, development of diabetes and lipid abnormalities, and risk for serious cardiac arrhythmia. Additional experience with the newer agents over the coming years will provide a better knowledge base regarding their more serious side effects.

Antidepressants

The arrival of antidepressant drugs closely followed that of antipsychotics, and eventually paved the way for a new approach to the treatment of depression. Like the antipsychotics, antidepressants have contributed to reduced hospitalization and a move to a more rehabilitative model of treatment. The tricyclic antidepressants (TCAs), named for their three-ring chemical structure, were found to block the reuptake of the chemical messengers (i.e., neurotransmitters) norepinephrine and serotonin at the junction between nerve cells. Ordinarily unused neurotransmitter substance is taken back into the cell to be reused, a process known as reuptake (Stahl). By blocking reuptake, tricyclic antidepressant agents were found to make more neurotransmitters available to the nerve cell. A second class of antidepressants blocks monoamine oxidase, the enzyme that degrades both norepinephrine and serotonin; drugs belonging to this class became known as monoamine oxidase inhibitors (MAOIs).

Despite the therapeutic effects of these drugs, their use is complicated by adverse effects. Like the conventional antipsychotics, these agents frequently produce sedation, hypotension, and anticholinergic effects. These side effects can be particularly problematic for older individuals who may be cognitively impaired and at risk for falls. In addition these agents can be lethal in overdose, as they cause serious cardiac arrhythmias. Nevertheless clinical experience with these medications ultimately led to the current prevailing theory of depression as a deficiency in certain neurotransmitters in predisposed individuals.

The introduction of fluoxetine (Prozac) in 1985 was arguably the single most influential development in contemporary treatment of depression. As the first in a family of new antidepressants, Prozac revolutionized the treatment of psychiatric illness. Because of its significantly improved side effect profile, Prozac provided a more convenient treatment alternative for patients. With the improved safety and tolerability of antidepressants beginning with Prozac, depression has come to be understood even by the lay public as a treatable medical condition frequently compared to diabetes or hypertension. This has been a critical step in destigmatizing depression as a mental illness. Moreover it has made possible improved recognition and treatment of depression as well as other psychiatric disorders in the United States and worldwide.

The newer family of antidepressants ushered in by Prozac became known as selective serotonin reuptake inhibitors (SSRIs). In contrast to the TCAs and MAOIs that act on both serotonin and norepinephrine, SSRIs primarily increase the availability of serotonin. The SSRIs have fewer side effects than the older antidepressants, are easier for physicians to dose, and do not have the risk of heart conduction problems that TCAs have, nor do the SSRIs require special dietary restrictions like the MAOIs. Although they were developed for the treatment of depression, SSRIs have become widely used for the treatment of various conditions including certain anxiety disorders, eating disorders, and disorders of impulse control.

There are five other SSRIs currently available in the United States: sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), and fluvoxamine (Luvox), and escitalopram (Lexapro). All are FDA approved for depression with the exception of Luvox, which is indicated for obsessive-compulsive disorder. All SSRIs are equally effective for the treatment of depression and the choice of an agent is largely dependent on other effects (see below). The availability of different agents allows clinicians to customize treatment to some extent. For example a patient with prominent apathy and fatigue may benefit from an antidepressant that is activating, such as Prozac. Conversely a patient with severe insomnia and anxiety may be better served by an agent that is more sedating, such as Paxil.

Since the arrival of SSRIs, several newer antidepressants have been developed with unique mechanisms of action. Venlafaxine (Effexor), nefazodone (Serzone), bupropion (Wellbutrin), and mirtazapine (Remeron) are antidepressants that were designed with the benefit of even more recent pharmacological knowledge. Effexor is an agent that exerts its effect on different neurotransmitters according to the dosage selected by the clinician. At lower doses, its effect is mediated primarily via increasing serotonin, whereas at higher doses of the drug, norepinephrine and dopamine effects predominate. Lower doses tend to be appropriate for milder depressive states and higher doses for more severe disorders.

ADVERSE EFFECTS. Adverse effects of antidepressants can be problematic. The TCAs tend to produce dry mouth, constipation, and sedation, but the sedative effect can be used to treat the insomnia that frequently accompanies depression. In cases of overdose, MAOIs and TCAs can produce dangerous cardiac arrhythmias. MAOIs can also produce serious blood pressure elevations if they are combined with certain other drugs or tyramine-rich foods such as aged cheese or meats. Patients on MAOIs must adhere to strict dietary guidelines in order to prevent problems.

The SSRI antidepressants produce a characteristic spectrum of adverse effects including nausea, diarrhea, weight loss, headache, insomnia, agitation, and fatigue. Many of these effects resolve within 2 to 3 weeks of treatment, and patients are generally advised to continue taking their medication to see if the unwanted effects dissipate over time. These compounds can also cause sexual side effects such as reduced sexual interest as well as difficulty in achieving orgasm. Other less common effects include tremor, rash, and easy bruising. Although they tend to be relatively safe in overdose, SSRIs can produce serious adverse effects if combined with other serotonin-containing drugs (i.e., serotonin syndrome). Serotonin syndrome is characterized by symptoms such as confusion, tremors, sweating, fever, and incoordination. It may become potentially life threatening if not recognized and appropriately treated.

Other non-SSRI antidepressants have somewhat unique side effects. The side effects of Effexor are similar to those of an SSRI at lower doses, and it causes an increase in blood pressure in a small percentage of patients. Serzone tends to be sedating and many patients prefer to take it at bedtime, especially if they have insomnia. It can interact with many commonly used medications including certain antihistamines, antibiotics, and anti-fungal agents, causing potentially dangerous cardiac arrhythmias. Wellbutrin is a stimulant-like agent that can produce agitation and insomnia in susceptible individuals. It has the potential to increase the risk for seizures in a small percentage of patients. It is the antidepressant least likely to cause weight gain and sexual dysfunction and has been successfully used to improve sexual function in some patients. Remeron is sedating and can also produce significant weight gain. It tends to be prescribed at bedtime for patients with insomnia.

Antianxiety agents

Antianxiety drugs are used to treat primary anxiety disorders such as panic attacks, phobias, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD), as well as anxiety that accompanies depression. In addition these medications are used to treat anxiety associated with various emergency medical conditions (e.g., myocardial infarction). Alcohol is the oldest antianxiety agent. Medical use of anxiolytics began with barbiturates and propanediols, drugs with sedative and anxiety-reducing effects, but these agents also slowed thinking and decreased alertness.

In the late 1960s, benzodiazepines were introduced as drugs that reduced anxiety but preserved cognitive function and physical activity. These drugs include diazepam (Valium), lorazepam (Ativan), and alprazolam (Xanax). Benzodiazepines are believed to stimulate another neurotransmitter, gamma aminobutyric acid (GABA), which plays an inhibitory role in brain function, lessening arousal and anxiety. Benzodiazepines are safer compared to the earlier antianxiety drugs. Nevertheless they do have significant cognitive and sedating effects that limit their use. Moreover benzodiazepines produce tolerance and withdrawal symptoms, which defines them as potential drugs of abuse. Their effects tend to dissipate over time, leading to the need for increases in dosage and increased potential for toxicity.

Scientists have searched for antianxiety drugs that do not produce tolerance or addiction. Currently the SSRI antidepressants are the preferred agents for treating anxiety disorders including panic attacks, phobias, and OCD. They have been found to reduce effectively symptoms of anxiety and do not lead to dependence syndromes. However these agents often require several weeks before beginning to exert therapeutic effects. They are not useful for emergency situations, but rather, for ongoing management and prevention of recurrent distressing symptoms. Buspirone (Buspar) is another agent that affects serotonin and was developed for the treatment of anxiety disorders. Like the SSRIs, it has a role in maintenance treatment rather than for acute intervention in anxiety disorders. Benzodiazepines continue to be the most frequently used agents for acute anxiety because of their immediate effects.

ADVERSE EFFECTS. The adverse effects of SSRIs have been described in the previous section. Regarding benzodiazepines, several side effects are generally extensions of their therapeutic effects: sedation, impaired cognitive or motor performance, tolerance, and physical dependency (addiction); the sedative effects impair driving and attention to mechanical tasks. However untreated anxiety or insomnia can produce serious problems in these same areas. Thus clinicians must carefully weigh the risks and benefits of prescribing benzodiazepines. Their safety profile is better compared to that of barbiturates. Nevertheless physical addiction can occur, and if abruptly discontinued, a withdrawal state can result.

Benzodiazepine withdrawal is rather similar to withdrawal from alcohol. It is characterized by anxiety, restlessness, agitation, and insomnia, as well as increased heart rate, sweating, tremors, and blood pressure elevation. An example of a withdrawal reaction is the so-called "rebound insomnia" associated with the discontinuation of short-acting benzodiazepines (e.g., triazolam) as a sleep-aid. In more severe cases, withdrawal from benzodiazepines can lead to a seizure. This syndrome typically develops two or three days after abrupt cessation of benzodiazepines, especially shorteracting agents such as Xanax. It is characterized by an acute confusional state with fluctuating level of consciousness, disorientation, hallucinations, paranoia, agitation, and often seizures. Without appropriate medical management, this syndrome can be life threatening. During short-term, low-dose therapy, the risk is low; however patients with prior drug abuse or alcoholism are at an increased risk for these problems as are patients who take higher doses over longer periods of time.

Mood Stabilizers

Mood stabilizing agents are primarily indicated for the treatment of bipolar disorder, previously known as manic-depressive illness. Bipolar disorder is typically characterized by alternating episodes of depression and mania. Whereas depression is a state of low mood, hopelessness, low motivation and energy, and slowed activity, mania is a state of elevated or euphoric mood, increased energy, inflated self-esteem, racing thoughts, and a tendency to become involved in excessive, often unrealistic, and even unnecessarily risky activities. Like other psychiatric disorders, there are various forms of bipolar disorder. Some patients experience primarily depressive episodes with only occasional manias, while other patients may experience almost continuous mania, with very little depression. Whatever form the disorder takes, mood stabilizing agents are intended to reduce the frequency and severity of the mood episodes, and thereby reduce functional impairment.

The first mood stabilizer was lithium carbonate, a naturally occurring salt introduced into clinical use in the 1960s. For many years it was the preferred treatment for bipolar disorder, although its mechanism of action has never been well understood. It is effective for both depression and mania and has been shown to reduce the risk of suicide in patients with bipolar disorder. It has a variety of toxic side effects that limit its tolerability (see below). In addition, lithium has a very narrow therapeutic range, in terms of blood levels, below which it may be ineffective and above which it causes toxic side effects. A number of commonly prescribed medications can interact with lithium and increase its serum level. Therefore any patient taking lithium requires regular monitoring of serum levels in order to maintain safety and efficacy with this drug.

Because of its side effects and safety issues, today fewer patients are being treated with lithium as other options have become available. Most of the other mood stabilizers are anticonvulsants initially developed for seizure control. Carbamazepine (Tegretol) and valproate (Depakote) were the earliest drugs of this class. Depakote has become the firstline medication for bipolar disorder, particularly for patients who have rapid cycling of moods or episodes with combined symptoms of depression and mania (i.e., mixed episodes). Although they have been well studied and demonstrated to be effective, similar to lithium, both of these agents have side effects and potential for toxicity (although not as narrow a margin for toxicity as that of lithium). Several newer anticonvulsants have therefore been studied and introduced for mood stabilization. These include gabapentin (Neurontin), lamotrigine (Lamictal), topiramate (Topamax), and oxcarbazepine (Trileptal). Although they appear to be better tolerated overall, the efficacy of these newer agents is not yet as well established as that of the older mood stabilizers.

ADVERSE EFFECTS. Lithium is associated with numerous side effects including cognitive slowing, gastrointestinal upset, weight gain, tremor, excessive thirst and urination, acne, and rash. Long-term use of lithium is known to be particularly toxic to the thyroid and kidneys. When the level of lithium in the serum becomes high, patients develop signs of neurological toxicity, such as slurred speech, impairment in gait and coordination, worsening tremor, and sedation. Lithium toxicity is considered a medical emergency requiring hospitalization, intravenous hydration, and often hemodialysis to prevent irreversible kidney failure.

The most common early side effects of Depakote are sedation and gastrointestinal upset, both of which tend to subside or decrease within a few weeks. Other reported side effects include weight gain, dizziness, tremor, and hair loss. Depakote frequently induces an elevation in the liver enzymes, which is usually benign, but requires monitoring because of the rare possibility of liver toxicity. Depakote may also lower serum platelets. Tegretol too can be toxic to the liver and bone marrow and therefore requires serum monitoring. It also produces sedation and dizziness, as well as cognitive slowing. In rare instances, it is associated with the development of a severe allergic reaction involving the skin. Elevation of Tegretol levels beyond a certain level can produce neurotoxicity with coordination and gait impairment, and abnormal eye movements. Tegretol has a tendency to reduce the levels of other medications, such as oral contraceptives.

Side effects of the newer anticonvulsants include sedation and dizziness. Lamictal is associated with the development of a life-threatening rash in rare cases. Topimax is associated with weight loss and cognitive slowing.

Ethical Dilemmas in Psychopharmacology

CONSENT TO TREATMENT. A principal ethical dilemma of treating people with mental illnesses is that many patients are impaired by their condition, but need to make an informed choice as to their treatment and its risks and benefits. For example, antipsychotic drugs may be prescribed to a psychotic patient who is paranoid, especially about drugs he is asked to take. The prescriber faces the dilemma of determining how reasonable the patient's ability is to accept or refuse treatment for an illness that impairs his ability to process reality, leading him to suspect all those who try to help him, and even to constitute a risk to self or others.

A basic tenant of medical care is that a competent patient has the right to refuse treatment of any kind. Unfortunately, determining competency can be difficult, and state laws have not clearly defined competency in regard to psychotic disorders. One study demonstrated that the most severely psychotic patients refused treatment more frequently than did patients who are less symptomatic (Marder et al.). For patients who are a danger to themselves(e.g., refusing to eat) or to others (e.g., attacking feared persecutors), both common sense and state statutes permit temporary involuntary medication treatment. However when a patient who is very ill and hospitalized for a mental illness refuses medications, but is not a danger to herself or others, it can be very difficult to provide optimal care. Many physicians involve the family in this decision, but this approach poses risks too. From the perspective of the paranoid patient, an alliance between a doctor and the family may make the patient even more suspicious of the physician. Often the psychiatrist is forced to involve the court system in determining whether a patient is competent to refuse treatment. Although a judge may allow involuntary treatment, these competency hearings may delay decision making for weeks, and are expensive for both the patient and the treating physician or facility.

CONSENT TO PARTICIPATE IN PSYCHOPHARMACOLOGIC RESEARCH. Conducting research on new psychopharmacologic treatments poses ethical dilemmas. For serious mental illnesses such as schizophrenia, current treatment is beneficial in reducing the symptoms, but many patients continue to have significant impairments. Improved treatments are needed, especially for the patients with the most severe psychopathology. In addition to knowing whether the new treatments will help those patients with the most severe symptoms, research into the new treatments needs to include the full range of patients. A critical component of conducting ethical research is obtaining informed consent from potential research subjects. Often those patients with the most severe psychopathology also have the greatest impairment in their ability to provide informed consent to be a research subject (Kim et al.).

Informed consent includes four key components: understanding, appreciating, reasoning, and expressing a choice. Patients with schizophrenia are more likely to have impairments with one or more of these four areas of decision making. At the same time, it is important to emphasize that having a psychiatric illness is by no means synonymous with having impaired decision-making capacity to consent for research. In studies of the decisional abilities of patients with schizophrenia, for example, the majority of non-hospitalized patients have not been found to be impaired on measures of their capacity to consent (Jeste et al., 2003).

Including patients with severe mental illness in studies of new medications, when the patient's ability to give informed consent to be a research volunteer is impaired due to the illness, is a major ethical challenge. In 1998, the National Bioethics Advisory Commission (NBAC) issued a report entitled "research involving persons with mental disorders that may affect decision making capacity." This report recommended additional special protections for research that involved persons with mental disorders. Critics of the NBAC report have expressed concern that the report's recommended additional special protections, specifically a proposed moratorium on research studies that posed greater than minimal risk until a new "special standing panel" or "national IRB" could review each study, which could impede important biomedical research, including neuroimagning and genetic linkage studies (Shore and Hyman). Another criticism of the NBAC report was that many medical illnesses, not just mental illnesses, can impair a person's decision-making capacity. By focusing on persons with psychiatric disorders, the NBAC report's recommendations risk increasing the stigma associated with mental illnesses (Appelbaum). One area of current research focuses on ways to enhance the process of informed consent so patients with more severe psychopathology can participate in research. As new potential treatments for schizophrenia become available, a key question will be finding ethical ways of determining whether these medications help the most severely ill patients.

SPECIAL POPULATIONS: ELDERLY PATIENTS. Certain segments of mentally ill populations are at a particularly high risk of problems with decisional capacity. These include children, elderly persons, and non-English speaking ethnic minority groups. Below one such group—that is, elderly patients with serious mental illnesses in need of pharmacotherapy—is considered.

It is anticipated that the numbers of older persons with psychiatric disorders will increase substantially within the next three decades (Jeste et al., 1999a). Yet most investigations of the efficacy and safety of pharmacologic treatments for these illnesses have focused on younger adults. Hence there will be a need for a marked growth of geriatric psychopharmacologic research in the immediate future. As mentioned above, an important issue in intervention research is ensuring that the patient has adequate decisionmaking capacity for participation in such research. Older psychiatric patients are at a risk of lacking decisional capacity by virtue of their aging-associated cognitive deficits and physical comorbidity, which are compounded by complex medication regimens. At the same time it is critical to stress that considerable heterogeneity exists among older persons with mental illnesses. Moreover the capacity to consent may vary from one protocol to another. It is clear that empirical research into assessing and possibly improving decisional capacity is needed in older people with severe mental illness.

One model of a multidisciplinary collaboration that is necessary for facilitating such research is the Bioethics Unit of an Intervention Research Center (Jeste et al., 2003). This Unit was developed in the last half of the 1990s. It includes geriatric psychiatrists, psychologists, bioethicists, lawyers, and most importantly, a Community Advisory Board comprised of patient participants in research, their family members, patient advocates, and mental health workers in the community not affiliated with the research team. The members of the Bioethics Unit have conducted several studies of decisional capacity and of ways to improve the process of giving information to the research participants by educational means (e.g., repeating the information) or by use of techniques such as PowerPoint slide presentation of the consent material (Dunn et al.; Palmer et al.). As of mid-2003, those investigations suggest that older individuals with psychotic disorders vary considerably in their decisional capacity, and many (but not all) subjects are fully capable of consenting to research projects. Additionally the patients's comprehension of the consent material can be improved significantly through repetition and user-friendly presentation of the information. It thus appears that, even in older seriously mentally ill individuals, decisional capacity for a given research protocol is not necessarily an unmodifiable trait, but can be enhanced with improvements in consenting procedures. Research at the Bioethics Unit has also demonstrated that the Community Advisory Board is very helpful in ensuring community equipoise—for example, the community's perspective of the relative risk: benefit ratio of a research protocol.

INVOLUNTARY TREATMENT. One of the most controversial areas in psychiatry is involuntary outpatient treatment. The field of psychiatry has long held that benevolent coercion is necessary to treat some people with serious mental illnesses such as schizophrenia and bipolar disorder, and most experts would agree that involuntary treatment for a person who is imminently suicidal or homicidal is justified. However it is much less clear whether a person with a serious mental illness who stops his medications and decompensates, becoming homeless or requiring rehospitalization, may be treated against his or her will to prevent this decompensation. In the early-twenty-first century, there are many people with serious mental illnesses who are unable or unwilling to receive outpatient mental health treatment, and some of these patients end up being homeless, incarcerated, or hospitalized multiple times. Involuntary outpatient treatment has been advocated as a means to improve the mental healthcare of these patients (Swartz et al.; Torrey and Zdanowicz).

Most states have provisions for involuntary outpatient treatment, which is usually court-ordered. This involuntary outpatient treatment is often used for patients who are being released from a psychiatric hospital and have a past record of stopping their medications, decompensating, and being rehospitalized. Depending on the particular state, this involuntary treatment may or may not include forced administration of medications. Proponents of involuntary outpatient treatment argue that it can help a patient to remain compliant with treatment (or face re-hospitalization), and at the same time, force the mental health systems to provide a patient with needed treatment. Opponents of involuntary outpatient treatment argue that it unnecessarily restricts the rights of people with mental illnesses, and that improved access to comprehensive outpatient services can accomplish the same goals as involuntary outpatient treatment (Allen and Smith).

DRUG THERAPY AND RESOURCE ALLOCATION. Since the mid-1990s the cost of pharmaceuticals has received increasing attention. Pharmaceutical costs are currently the fastest rising component of healthcare costs; between 1987 and 1996 per capita spending on psychotropic medications increased by 254 percent, while spending on all mental health and substance abuse treatments only increased by 30 percent (Zuvekas). This increase has many causes, including an increasing awareness and acceptance of treatment for mental illnesses, and a large number of newer psychiatric medications that have fewer side effects and may be more effective, but are significantly more expensive. For example there are five new atypical antipsychotic medications that have been introduced in the past decade. These medications have fewer short-term and long-term side effects, but cost much more than the older antipsychotic medications. The newer medications cost approximately $300 to $400 per month. This compares with about $15 to $50 per month for the older antipsychotic medications. There is some evidence that over one to two years the atypical antipsychotic medications are cost neutral due to lower rates of relapse and fewer psychiatric hospitalizations (Csernansky and Schuchart). Similarly the newer antidepressants are also more expensive (at $80 to $90 per month) than the older antidepressants ($10 to $15 per month). It should be kept in mind that the recent increase in cost of medications is not restricted to psychiatric medications; lipid lowering agents cost $70 to $90 per month, Viagra runs $8 to $9 per pill and common triple-drug treatments for HIV can cost $1000 to $1250 per month (drugstore.com).

Optimistically a balancing of the needs of the patient, the government's ability to pay, and market forces may provide the optimal solution. From a clinical and ethical perspective, it is necessary to ensure that patients who would benefit from a new psychotropic drug should not be denied that medication. However people without prescription drug benefits as part of their healthcare insurance are often unable to afford to pay for their medications and many state Medicaid plans and private insurance companies have created medication formularies that restrict the medications which a patient can receive. Many psychiatrists, patients, and patient advocates believe that these restrictions on which medications can be used to treat a serious mental illness could cause an exacerbation of symptoms and may require more intensive, institutional-based care in the future, ultimately resulting in greater cost. Among the important issues that arise in the debate over the cost of newer psychiatric medications include: Who decides whether a new medication, which is safer but more expensive, should be used: the patient, the physician, the insurance company, or the government?

Conclusion

Psychopharmacologic medications have undergone a major transformation since the mid-1990s. In 2003, medications have fewer side effects, are easier to take, and may be more effective. On the other hand, these medications are significantly more expensive. The development of these newer medications has highlighted the challenge of ethically studying new treatments for people with serious mental illness. In addition these new medications have not solved the longstanding dilemma of consent for psychotropic medication treatment or administering psychiatric treatment involuntarily. Finally weighing the cost versus benefit of these newer (more expensive) medications has been receiving growing attention.

david p. folsom

jeremy sable

dilip v. jeste

SEE ALSO: Behavior Control; Health Insurance; Life, Quality of; Mental Health; Mental Illness; Patients' Responsibilities; Pharmaceutics, Issues in Prescribing; Profit and Commercialism; Psychiatry, Abuses of

BIBLIOGRAPHY

Allen, M., and Smith, V. F. 2001. "Opening Pandora's Box: The Practical and Legal Dangers of Involuntary Outpatient Commitment." Psychiatric Services 52: 342–346.

Appelbaum, Paul S. 1999. "Competence to Consent to Research: A Critique of the Recommendation of the National Bioethics Advisory Commission." Accounts Res. 7(2–4): 265–276.

Csernansky, J. G., and Schuchart, E. K. 2002. "Relapse and Rehospitalisation Rates in Patients with Schizophrenia: Effects of Second Generation Antipsychotics." CNS Drugs 16: 473–484.

Dolder, C. R.; Lacro, J. P.; Dunn, L. B.; et al. 2002. "Medication Adherence: Is There a Difference Between Typical and Atypical Agents?" American Journal of Psychiatry 159: 103–108.

Dunn, L. B.; Lindamer, L. A.; Palmer B. W.; et al. 2002. "Improving Understanding of Research Consent in Middle-Aged and Elderly Patients with Psychotic Disorders." American Journal of Geriatric Psychiatry 10: 142–150.

Grob, G. 1994. The Mad among Us: A History of the Care of America's Mentally Ill. New York: Free Press.

Jeste, Dilip V.; Alexopoulos, G. S.; Bartels, S. J.; et al. 1999. "Consensus Statement: The Upcoming Crisis in Geriatric Mental Health: Challenges and Opportunities." Archives of General Psychiatry 56: 848–853.

Jeste, Dilip V.; Dunn, L. B.; Palmer, B. W.; et al. 2003. "A Collaborative Model for Research on Decision Capacity and Informed Consent in Older Patients with Schizophrenia: Bioethics Unit of a Geriatric Psychiatry Intervention Research Center." Psychopharmacology

Jeste, Dilip V.; Gilbert, P. L.; McAdams, L. A.; et al. 1995. "Considering Neuroleptic Maintenance and Taper on a Continuum: Need for Individual Rather than Dogmatic Approach." Archives of General Psychiatry 52: 209–212.

Jeste, Dilip V.; Rockwell, E.; Harris, M. J.; et al. 1999. "Conventional vs. Newer Antipsychotics in Elderly Patients." American Journal of Geriatric Psychiatry 7: 70–76.

Kim, S. Y. H.; Karlawish, J. H. T.; and Caine, E. D. 2002. "Current State of Research on Decision-Making Competence of Cognitively Impaired Elderly Persons." American Journal of Geriatric Psychiatry 10: 151–165.

Marder, S. R.; Mebane, A.; Chien, C. P.; et al. 1983. "A Comparison of Patients Who Refuse and Consent to Neuroleptic Treatment." American Journal of Psychiatry 140: 470–472.

Palmer, B. W.; Nayak, G. V.; Dunn, L. B.; et al. 2002. "Treatment-Related Decision-Making Capacity in Middle-Aged and Older Patients with Psychosis: A Preliminary Study Using the MacCAT-T and HCAT." American Journal of Geriatric Psychiatry 10: 207–211.

Shore, David, and Hyman Steven E. 1999. "An NIMH Commentary on the NBAC Report." Biological Psychiatry 46(8): 1013–1016.

Stahl, S. M. 1997. Psychopharmacology of Antidepressants. London: Martin Dunitz Ltd.

Swartz, M. S.; Swanson, J. W.; Wagner, H. R.; et al. 2001. "Effects of Involuntary Outpatient Commitment and Depot Antipsychotics on Treatment Adherence in Persons with Severe Mental Illness." Journal of Nervous and Mental Disease 189: 583–592.

Torrey, E. F., and Zdanowicz, M. 2001, "Outpatient Commitment: What, Why, and for Whom." Psychiatric Services 52: 337–341.

Zuvekas, S. H. 2001. "Trends in Mental Health Services Use and Spending, 1987–1996." Health Affairs 20: 214–221.

INTERNET RESOURCES

drugstore.com. 2003. Available from <www.drugstore.com>.

National Bioethics Advisory Commission. 1998. "Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity." Available from <http://www.georgetown.edu/research/nrcbl/nbac/capacity/TOC.htm>.

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Psychopharmacology

PSYCHOPHARMACOLOGY

Psychopharmacology is defined as the use of drugs to modify mental or behavioral performance. In general, psychopharmacology is used in the treatment of biologically based mental illnesses, although there has been increased interest in using drugs to enhance performance in healthy individuals.

Psychopharmacology assumes a strong mind-brain connection, if not a complete reduction of mind to brain. However, early theories about the relationship of brain chemistry to behavior were weak and post hoc. Most drugs were discovered accidentally and adopted because of their effects on symptoms (Valenstein 1998). Only later were theories of the ways drugs act on the brain developed, followed by theories of how mental states are related to brain chemistry. Although the mechanism of action on neuronal receptors has been elucidated for many drugs, the mechanisms by which drugs influence behavior at the whole-brain level are poorly understood. There are no definitive biological markers for diagnosing mental illness, and thus diagnosis relies on a clinical judgment of whether symptoms are present.

Although theories that mental illnesses result from a specific underlying chemical imbalance are not well substantiated, they have encouraged afflicted persons to seek treatment by reducing some of the stigma associated with psychological theories of mental illness. The discovery of drugs that alleviate some of the most debilitating symptoms of mental illness also allowed deinstitutionalization to occur, resulting in much more effective, community-based treatment programs

Psychopharmacologic Agents

The major classes of psychopharmacologic agents (Schatzberg and Nemeroff 1998) are antipsychotics (also known as neuroleptics), antidepressants, anxiolytics (antianxiety agents), and mood stabilizers. In addition, cognitive enhancing drugs are receiving increasing interest and use.


ANTIPSYCHOTICS. Antipsychotics, which are used primarily for the treatment of schizophrenia, reduce symptoms such as paranoia, visual and auditory hallucinations, and delusions. The first drugs of this type—phenothiazines—initially were produced as synthetic dyes. Later research in the 1940s showed that they act on the central nervous system as antihistamines. When administered to patients with allergies, they produced side effects that included decreased muscle tone, reduced nausea, and mild elation. That led to their use to relax patients before surgery, treat Parkinson's disease, and calm agitated and manic patients. In manic patients these drugs were also found to reduce the psychotic symptoms associated with the disorder. Antipsychotics are the most successful variety of psychopharmaceutical agents, reducing symptoms in 90 percent of patients in the acute phase of the disorder. Long-term use, however, may result in negative side effects that include tardive dyskinesia, which is characterized by involuntary motor movements such as those seen in Parksinson's patients, and neuroleptic malignant syndrome, which is a potentially fatal side effect. In contrast to the typical antipsychotics, the development of atypical antipsychotics has focused on not only reducing psychotic symptoms but also on improving negative symptoms (for example, loss of motivation, social withdrawal, and affective flattening) associated with schizophrenia and reducing adverse side effects.


ANTIDEPRESSANTS. Antidepressant pharmaceuticals also were discovered fortuitously. After World War II chemical companies had a surplus of the rocket fuel hydrazine, which they began modifying in an attempt to find new compounds with properties that might be useful for medical purposes. In the course of testing one of the new compounds against tuberculosis it was found to cause euphoria as a side effect. A derivative of hydrazine was synthesized as iproniazid, and after animal testing showed that the drug increased alertness, it became a treatment for depression.

There are three primary classes of antidepressants: selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and tricyclics. Common SSRIs include fluoxitine (Prozac) and paroxitine (Paxil), MAOIs are exemplified by phenylzine (Nardil) and isocarboxazid (Marplan), and tricyclics include amitriptyline (Elavil) and imipramine hydrochloride (Tofranil).

All these drugs are considered equally effective in reducing depressive symptoms. The typical response rate of patients with uncomplicated unipolar depression to antidepressants is about 65 percent, compared with a 30 percent response rate on placebo. In addition to reducing current symptoms of depression these drugs appear to reduce the 50 percent relapse rate of major depressive episodes by 50 percent over the course of one year. The observed response rate with pharmacologic agents has been found to be identical to that of cognitive-behavioral psychotherapy. Treatment for depression that combines pharmacologic treatment and psychotherapy is more effective than is either modality alone (Burns 1980).

Side effect profiles or counterindications usually influence which drugs are prescribed more frequently. Side effects of SSRIs include headache, tremor, nausea, diarrhea, insomnia, agitation, nervousness, and sexual dysfunction. More important, SSRIs were found to increase suicidal behavior among adolescents, prompting the U.S. Food and Drug Administration (FDA) to mandate "black box" warnings to that effect on prescription bottles. Side effects of MAOIs include weight gain, orthostatic hypotension (drop in blood pressure when standing up quickly), delayed ejaculation, insomnia, and cholinergic side effects such as blurred vision, constipation, dry mouth, speeded heart rate, and urinary retention; MAOIs also require a diet that avoids foods with tyramine as hypertension and cerebral hemorrhage or death (rare) may occur. Side effects of tricyclics include weight gain, sexual dysfunction, cholinergic side effects, and sedation.

ANXIOLYTICS. The first drugs for treating anxiety were discovered in 1945 during testing of drugs designed to combat infectious bacteria. Those early drugs were found to be extremely habit-forming and to produce drowsiness, and ultimately were replaced by a class of antianxiety drugs called benzodiazepines (for example, alprazolam [Xanax] and diazepam [Valium]) that were discovered after an unexpected chemical reaction occurred in a compound that originally had been developed for use as a dye.

Benzodiazepines are very effective in reducing anxiety. In fact, since their introduction in the 1960s anxiolytics have been referred to as "happy pills." Eighty-two percent of patients on alprazolam show improvement compared with 42 percent on placebo. These drugs are also effective in reducing the occurrence of panic attacks. Benzodiazepines are among the most frequently prescribed drugs; however, they are habit-forming, and many of the 7 million prescriptions written yearly in the United States are in response to simple stresses of everyday life rather than debilitating conditions.

MOOD STABILIZERS. Mood-stabilizing drugs are used in the treatment of bipolar (manic-depressive) illnesses, in which patients suffer from recurrent cycles of depressive moods followed by manic periods. Lithium is the primary treatment for manic-depressive illness. Its effectiveness was discovered in the course of testing the hypothesis that uric acid would increase mania. Uric acid was difficult to work with because it was not easily soluble, and so lithium urate was used instead and surprisingly reduced mania. The FDA approved lithium treatment for mania in 1970 after a double-blind study showed that all the manic patients on lithium remained well, whereas half the patients who were switched from lithium to a placebo relapsed.

Additional double-blind, placebo-controlled studies have found that 70 to 80 percent of patients show improvement on lithium. Lithium reduces the intensity of manic and depressive episodes and decreases the overall number of episodes. Major side effects include excessive thirst and volume of urine, memory problems, tremor, and weight gain. In addition, high doses can lead to endocrine and renal complications.


COGNITIVE ENHANCERS. Cognitive-enhancing drugs are designed to improve cognitive functions such as memory and attention. Pharmacological agents to improve memory function are particularly important in slowing the memory loss observed in patients with Alzheimer's disease. The focus of this research has been on drugs that influence the brain systems involved in learning and memory. More specifically, agents are being developed to help patients retain memories that may be lost as individuals age. In clinical trials, donepezil (Aricept), rivastigimine tartrate (Exelon), and galantamine (Reminyl) all have been shown to reduce cognitive decline in the early stages of Alzheimer's. However, the measures of performance used have been very general tests of cognitive functioning, and so the exact cognitive function that is affected by these drugs is unclear. Side effects of these medications usually occur at higher doses and include gastrointestinal problems, dizziness, and headaches.

Drugs that enhance attentional functioning have been developed for the treatment of attention deficit hyperactivity disorder (ADHD). These drugs help patients maintain attention on a task over an extended period and reduce impulsive motor behaviors. Treatment for ADHD has consisted primarily of psychostimulants, including methylphenidate (Ritalin), d-amphetamine (Dexedrin), and a mixture of amphetamine salts (Adderall). Although the idea of giving stimulants to reduce hyperactivity is counterintuitive, these drugs have been shown to reduce symptoms in 70 to 80 percent of children with ADHD and are much more effective than are psychological treatments. These drugs reduce psychomotor activity and restlessness and increase a patient's ability to pay attention. Some of the more frequently reported side effects of psychostimulants include weight loss, social withdrawal, irritability, and insomnia.

With the development of these drugs interest has increased in the possibility of creating cognitive enhancers for healthy adults. Early research investigating the effects of Alzheimer's drugs on memory in healthy adults showed little to no improvement in memory function. As a result of that failure pharmaceutical companies began to focus on drugs that influence the formation of new memories and the retention of memories. However, data showing clinical effectiveness of these drugs were not available in the first years of the twenty-first century. In contrast to memory enhancement, much research suggests that healthy individuals who take methylphenidate and other psychostimulants show improvements in working memory and sustained attention. Conflicting research not only failed to replicate those improvements but found impairments in other cognitive functions. Before these drugs are prescribed for cognitive enhancement, their effects on healthy adults must be confirmed in controlled clinical trials.

Ethical Considerations

The ethical issues surrounding psychopharmacology can be grouped into four categories: research on psychopharmacologic agents, use in clinical treatment of illness, use for performance enhancement, and prophylactic or preventive use.

RESEARCH. Ethical issues in psychopharmacological research are largely the same as those in research in general and include issues related to the ethical treatment of animals, the informed consent of participants, and the appropriate use of placebos in control groups (Roberts and Krystal 2003). Because of the high commercial value of these products conflicts of interest among scientists are also important.

CLINICAL TREATMENT. Ethical issues that arise in the treatment of mental illness include informed consent (whether treatment is taking place inside or outside a research study), weighing the risks of side effects against the benefits of treatment (particularly the increased risk of suicide among adolescents taking certain antidepressants and the risks to the fetus or child of a pregnant or nursing mother receiving treatment), and access to treatment (for example, whether financial ability should determine which patients get access to newer, more expensive antipsychotics and which get cheaper, older, and less effective generic medications).

However, there are also "big picture" issues concerning what is viewed as an illness and when treatment should be directed at the individual rather than the environment. With most prescriptions for antidepressants and anxiolytics being written by general physicians rather than mental health professionals, drugs often are prescribed for dispositional characteristics or problems that are not biological in nature (for example, for persons dealing with stressful life events, grieving from a loss, or pessimistic by nature) even though psychological interventions designed to enhance coping skills could be more effective. Further, environmental change may be more effective than individual interventions in reducing the prevalence of some mental illnesses.

For example, with suicide as a leading cause of death among college students, perhaps it would be more efficacious to think about rampant depression as a problem stemming from the environment rather than from the individual. This changes the focus of treatment to modifications of the environment, (such as transition programs, peer support resources, and so on) as opposed to treating the many individuals who are suffering as a result of that environment. This amounts to taking a human factors approach to society and asking how to take what is known about cognitive strengths and limitations and use it to redesign cultural institutions to maximize productivity and benefit the individual while minimizing stress.


COGNITIVE ENHANCEMENT AND PROPHYLAXIS. Ethical questions concerning cognitive performance enhancement and prophylactic use have begun to be addressed. (President's Council on Bioethics 2003). The use of enhancing drugs when deficits are present (for example, for patients with Alzheimer's or ADHD) is subject to the same ethical questions as is the use of other psychopharmaceuticals for the treatment of illness. New ethical concerns arise when drugs are used to enhance performance in patients in whom no deficits are present (Farah, Illes, Cook-Deegan, et al. 2004) or to prevent illness when no signs of illness are present. For example, the potential risks of taking a drug are much more important in risk-benefit calculations when the patient's quality of life is high in the absence of the drug.

Questions of access and coercion also arise: With the use of Ritalin as a study aid reportedly on the rise among high school and college students, does this constitute an unfair advantage to the users? Will nonusers feel pressured to use the drugs in order to compete with users? Will those who cannot afford the drugs be left behind? In addition, general questions of what it means to be a person have been asked: To what extent is character built by coping with the limitations and imperfections present in oneself and others? Should individuals be free to experiment on themselves with such drugs? Will achieving human perfection make people happier?

Finally, with the contemporary emphasis on genetic contributions to psychiatric disorders, individuals eventually may be able to take drugs prophylactically based on genetic tests that assign an increased probability of developing a disorder. This raises concerns about whether this information should be supplied to individuals and how they will interpret the risks. It also prompts questions about how likely an outcome should be before information is given or action is taken. In light of the relative lack of understanding of brain system dysfunctioning in disorders, prophylactic use of drugs likely will become an increasingly serious issue.


ELIZABETH J. MULLIGAN ERIC D. CLAUS

SEE ALSO Emotion; Neuroethics; Psychology.

BIBLIOGRAPHY

Burns, David D. (1980). Feeling Good: The New Mood Therapy. New York: Avon. Provides a comprehensive overview of pharmacologic and cognitive-behavioral treatments for depression.

Farah, Martha J.; Judy Illes; Robert Cook-Deegan; et al. (2004). "Neurocognitive Enhancement: What Can We Do and What Should We Do?" Nature Reviews Neuroscience 5: 421–425. A response to the President's Council on Bioethics (2003). Presents an argument in support of the development and use of cognitive enhancing drugs.

President's Council on Bioethics. (2003). Beyond Therapy: Biotechnology and the Pursuit of Happiness. Washington, DC: Author.

Roberts, Laura Weiss, and John Krystal, eds. (2003). Special issue on psychopharmacology and ethics. Psychopharmacology 171(1): 1–119.

Schatzberg, Alan F., and Charles B. Nemeroff, eds. (1998). The American Psychiatric Press Textbook of Psychopharmacology, 2nd edition. Washington, DC: American Psychiatric Press.

Valenstein, Elliot S. (1998). Blaming the Brain: The Truth about Drugs and Mental Health. New York: Free Press. Presents the historical development of drugs used to treat mental illness and critically analyzes the role of the pharmaceutical industry in promoting biological theories of mental illness.

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