Introduction Psychopharmacology is the scientific study of the effect of drugs on psychological processes. The field of psychopharmacology has two interrelated goals. The first is to understand the way that drugs interact in the brain and the effects that these interactions have on behavior, consciousness, cognition, emotion, and other psychological processes. The second goal is to use knowledge of the effects of drugs to improve human psychological welfare. In most cases, this involves studying drug effects in the hope of developing and improving drugs used to treat psychiatric disorders such as depression and schizophrenia. In other cases, drug effects may be studied in the hope of learning ways to prevent people from taking drugs in ways that cause harm to both individuals and society.
Although psychopharmacological research may involve any drug with the capacity to alter psychological experience (a psychotropic drug), most studies have focused on the examination of drugs that fall into two broad categories: those that are useful in the treatment of psychological disorders (therapeutic drugs) and those that have the capacity to produce compulsive patterns of use and abuse in the people who take them (drugs of abuse).
History Though psychopharmacology is a relatively new scientific field, archaeological evidence indicates that human beings have been using drugs to manipulate their psychological experiences and to treat disease since prehistory. Many psychotropic substances are naturally occurring or produced by natural processes, and early people were often adept at exploiting and, in many cases, cultivating the plants from which they came. Many of these psychotropic substances, including opium, cocaine, alcohol, and peyote (a hallucinogen), were used both for their ability to influence individual experience and in social, cultural, and ceremonial contexts. In some cases, they were used medicinally to treat a variety of physical and psychological ailments.
The ancient Greeks used a variety of drugs to treat mental illness and had formed a specific theory of illness and health that guided their use. Hippocrates theorized that mental and physical illnesses were caused by an imbalance in one or more of the four bodily fluids (humors): blood, bile, choler, and phlegm. Specific drugs and other treatments were used to increase or decrease these humors in an effort to reestablish the balance. For example, symptoms thought to be caused by an excess of blood, such as mania, might be treated by bleeding the patient. Bleeding would, indeed, often slow the patient down, and this would be taken as evidence of the validity of the underlying theory. Though modern medicine requires a different level of proof of efficacy, the strategy of treating symptoms by using remedies that produce opposite or counteracting effects to the symptoms of interest remains a mainstay of pharmacological approaches to treating psychological disorders.
The modern psychiatric drug era got its start in the 1950s. During this decade, early examples of virtually all major classes of psychiatric drugs were discovered, in many cases by accident. In 1949, John Cade was conducting a series of experiments involving injecting uric acid into guinea pigs. When he added
lithium in an effort to increase the water solubility of the solution, he noted that the animals were much calmer, so he tested the effects of lithium in people with mania. Lithium has become a commonly prescribed mood stabilizer, effective in the treatment of bipolar disorder. Though originally investigated as an antihistamine and surgical sedative, the first antipsychotic medication, chlorpromazine (Thorazine), was found to be useful in treating patients with schizophrenia in 1952. Iproniazid (Marsilid), an early antidepressant drug approved for use in 1958, was initially intended to treat tuberculosis. Meprobamate (Miltown, Equanil, Meprospan), an anxiolytic or antianxiety medication, became available about the same time.
These medications produced a revolution in the treatment of mental illness. Before the advent of modern medications, the available treatment options for patients with serious mental illnesses were rarely effective and in some cases were downright barbaric. Most patients with serious mental illness were confined in psychiatric hospitals and asylums. The new drugs dramatically reduced the number of institutionalized psychiatric patients and improved the quality of life of countless individuals. Nevertheless, none of these drugs were completely effective, and they all had a tendency to produce troubling side effects in a significant number of the people who took them.
In the decades that followed, many chemical modifications of these drugs were explored, occasionally creating minor improvements in effectiveness or reducing some of the side effects. By the late 1980s, a smaller breakthrough occurred with the successful reintroduction of clozapine (Clozaril), a new, atypical antipsychotic medication, and the development of fluoxetine (Prozac), an antidepressant. These drugs were somewhat novel in the way they acted in the brain. They offered distinct advantages in practice and stimulated new avenues for research. As understanding of the underlying causes of psychiatric disorders improves, researchers hope to develop safer and more effective medications for mental illness.
Drug Effects Before any drug can alter psychological experience, it must reach target receptors in the brain, typically from some other part of the body. Pharmacokinetics refers to the study of drug movements throughout the body over time. The speed of drug onset and the duration of drug effect are important variables in determining the qualitative experience of taking the drug. For example, drugs of abuse that are absorbed and distributed quickly tend to produce stronger rewarding properties than those with more gradual onsets. For this reason, drug abusers may try to change the way that drugs are administered in an effort to speed their onset.
Psychopharmacologists also need to understand specifically what drugs do once they reach their targets in the brain. This topic is referred to as pharmacodynamics. Psychotropic drugs produce their effects by interacting with proteins in the membranes of individual neurons in the brain. These proteins normally interact with naturally occurring chemicals in the brain called neurotransmitters, which serve as chemical bridges across the spaces between neurons, called synapses, so that signals can be transmitted from one neuron to another. There are many different neurotransmitters, and for each of these, there may be a number of different specific receptor proteins. The various receptor proteins are not evenly distributed throughout the brain; different regions of the brain vary in terms of the density of different types of receptors for different neurotransmitters. Membrane proteins on both sides of the synapse are involved in the process of releasing, receiving, and recycling these chemical messengers, and psychotropic drugs can interact at any point along the way.
Psychotropic drugs can interact with these proteins in a host of different ways, thereby altering the activity of naturally occurring neurotransmitters in various regions of the brain. In general, drug effects are classified as either agonist or antagonist effects. Agonists are drugs that increase the natural activity of the neurotransmitter in some way. An agonist drug might mimic the effects of the neurotransmitter at the receptor itself, or it might stimulate the release of a neurotransmitter or prolong its effectiveness by preventing the neuron’s normal process of eliminating the neurotransmitter once it is used. Because all these potential effects would ultimately enhance the function of the neurotransmitter, they would all be classified as agonist effects. In contrast, antagonist effects serve to reduce the functioning of the neurotransmitter. Sample antagonist effects include blocking receptor proteins or preventing the storage of neurotransmitters.
"Affinity" refers to the degree to which a drug interacts with membrane proteins. Drugs with high affinity interact strongly, readily, or for relatively long durations. Low-affinity drugs interact weakly, incompletely, or briefly. Thus, the effects of various drugs can be described in terms of how strongly they interact (affinity) and in what ways they interact (agonist or antagonist) with which specific receptors for which specific neurotransmitters. In principle, drugs can be designed to be quite specific, though in practice most drugs that are commonly used have multiple effects.
Classes of Psychiatric Medications The main classes of psychiatric medications are antipsychotics, antidepressants, mood stabilizers, and anxiolytics.
Antipsychotics Antipsychotics are used to treat symptoms of psychosis related to a range of conditions or disorders, including mania, delusional disorders, and psychotic depression. Most commonly, however, they are used in patients suffering from schizophrenia. There are many antipsychotic medications available, but they can be broadly classified into two groups: typical (first generation) and atypical (second generation). The typical antipsychotics, also called neuroleptics or major tranquilizers, are dopamine antagonists. They work primarily by blocking the D2 subclass of receptor proteins for the neurotransmitter dopamine. By blocking these receptors, typical antipsychotics reduce dopamine activity in specific circuits within the brain. The more strongly a typical antipsychotic binds or interacts with the D2 receptor, the more potent the drug. This, and other evidence, has suggested a dopamine hypothesis of schizophrenia—that is, that schizophrenia is caused by overactivity of dopamine circuits in the brain.
Though generally effective, the typical antipsychotics have important limitations. D2 receptors are concentrated in regions of the brain that are important to the regulation of movement, and blocking these receptors produces significant movement-related side effects. In addition, typical antipsychotics are effective in treating only the more overt, or positive, symptoms of schizophrenia, such as hallucinations; they do little to help with the negative symptoms, such as emotional flatness and social withdrawal. These drugs also are simply not effective in some patients.
Since the 1990s, a flurry of antipsychotic development has occurred, based largely on the finding that a specific antipsychotic drug, clozapine, can be effective in treating psychosis without producing the movement-related side effects. Clozapine and similar drugs that were developed later are referred to as atypical agents because although they are relatively weak D2 receptor blockers, they were thought to be at least equal to the typical drugs in treating the positive symptoms of schizophrenia and better at treating the negative symptoms, with a low risk of movement-related side effects. However, further study has shown that this may not necessarily be the case, and some scientists have questioned whether the distinction between typical and atypical antipsychotics is truly a meaningful one.
Antidepressants Antidepressants are a diverse class of drugs that are effective in the treatment of depression. Though different individuals may respond better or worse to any particular drug, overall the drugs are roughly equal in clinical effectiveness. They are not, however, equal in the side effects that they produce or in the effects that they have at the synapse. The oldest class of antidepressant drugs is the
monoamine oxidase (MAO) inhibitors, or MAOIs. Monoamine oxidase is an enzyme that usually functions to degrade three different neurotransmitters: dopamine, serotonin, and norepinephrine. The MAO inhibitors attach to this enzyme and prevent it from doing its work. Therefore, these drugs are ultimately agonists for the three neurotransmitters. This mechanism of action, however, has an inconvenient and potentially dangerous side effect. Monoamine oxidase is used not only in the brain but also in the human digestive system to metabolize tyramine, a substance found in aged cheeses and meats, some nuts and beans, and assorted other foods. People prescribed MAOI antidepressants need to be quite careful about what foods they eat to avoid those high in tyramine. If they do not, serious and potentially dangerous elevations in blood pressure can occur.
A second category of antidepressant drug is the tricyclic antidepressants. The tricyclics are also agonists for the neurotransmitters serotonin and norepinephrine, but they accomplish this in a different way. In addition to being degraded by MAO inside the cell, these neurotransmitters are also reabsorbed by the neuron once they have been released. The process is called reuptake. By blocking reuptake, the tricyclics allow these neurotransmitters to stay in the synapse for a longer period of time, enabling them to repeatedly interact with receptor proteins in adjacent cells. Like the MAOIs, the tricyclics have numerous side effects, but the most troubling is the fact that these drugs can be very toxic, indeed lethal, in overdose.
The second wave of drug development was led by the antidepressant fluoxetine (Prozac)—an example of a third category of antidepressant referred to as
selective serotonin reuptake inhibitors (SSRIs). Like the tricyclics, the SSRIs block reuptake. However, they are more specific to the neurotransmitter serotonin and have a much better safety profile than the other classes of antidepressants. The most troubling problems associated with the SSRIs are sexual side effects.
A fourth class of antidepressant is often simply referred to as atypicals. These drugs are quite varied in terms of their effects in the brain and do not fit neatly into any other category. Some drugs combine reuptake blocking with effects on postsynaptic receptors. Others are relatively specific to the neurotransmitter dopamine. Like the other antidepressants discussed, these drugs are roughly equal in effectiveness, although their side effects can differ considerably.
Mood Stabilizers Moodstabilizers are used in the treatment of bipolar spectrum disorders (formerly known as manic-depressive illnesses). These disorders are characterized by emotional volatility; the individual has some combination of periods of mania, depression, or both interspersed with more normal functioning. Therefore, there are three treatment issues: the treatment of mania, the treatment of depression, and the stabilization of mood over time.
The most common substance used to stabilize mood is lithium. Lithium is typically considered to be an effective treatment for stabilizing mood across time as well as an effective, if slow, treatment for reducing mania. Its effectiveness as an antidepressant is less clear. The precise mechanism of action that makes lithium effective is unclear, as it has many effects in the brain. A number of medications, including anticonvulsants, antipsychotics, and antidepressants, have been proposed to treat bipolar disorder either in place of or in addition to lithium. Combination therapy (prescribing multiple drugs from different categories to treat the disorder) is a common practice in treating bipolar disorder.
Anxiolytics Anxiolytic is another name for an anxiety-reducing drug, also known as a tranquilizer. Most of the typical or traditional anxiolytics are central nervous system depressants. These drugs operate by enhancing the effects of an inhibitory neurotransmitter called gamma-aminobutyric acid (GABA), which reduces the electrical activity of the brain. The most common anxiolytics, a class of drugs called the benzodiazepines, have a neuromodulatory effect at the GABA receptor. When these drugs interact with the receptor, naturally occurring GABA is more effective. The benzodiazepines are highly effective in treating symptoms of anxiety in the short term and are commonly used in treating anxiety associated with generalized anxiety disorder and panic attacks. They are less effective in dealing with some symptoms associated with other anxiety disorders, such as post-traumatic stress disorder and obsessive-compulsive disorders. An additional limitation is that the benzodiazepines, though generally safe to use as prescribed, can become a substance of abuse if taken inappropriately, for long periods of time, or in relatively high doses. In addition, when taken in high doses or with alcohol or other central nervous system depressants, these drugs can be quite dangerous.
Alternatives to the benzodiazepines include the novel antianxiety drug buspirone (BuSpar) and several of the antidepressant medications discussed earlier. These drugs have several important advantages over the benzodiazepines and one major drawback. They are not central nervous system depressants and therefore do not cause sedation or interact with alcohol or other central nervous system depressants. However, they are very slow to take effect in comparison to benzodiazepines. It typically takes a week before even the initial responses are observed and several weeks before the full clinical effect is reached.
Drugs of Abuse and Substance Dependence Although the majority of drugs used in the treatment of psychological disorders are not prone to abuse, a broad range of other drugs with differing therapeutic purposes and different synaptic functions are. In
substance dependence, the effects that a drug produces change across time in two ways. First, tolerance and withdrawal may occur. In this case, more and more of the drug is required to achieve the same intoxicating effect (tolerance), and negative effects occur when the drug is removed (withdrawal). Second, substance dependence is characterized by loss of control over use of the substance; dependent individuals will use the drug in greater quantity or frequency than they intend and will be unable to curtail their use.
The synaptic changes associated with drug tolerance and drug withdrawal depend on the particular type of drug that has been used. In the case of the opiate drugs, for example, receptors in a region of the brain called the locus coeruleus decrease their responding when the drugs are taken. However, over time and over repeated administrations of the drug, this region of the brain will begin to adapt. The cells become less responsive to the opiate drugs by altering the sensitivity of those receptors with which the drugs interact. Therefore, more of the drug is needed to produce the original effect, and the system becomes dysregulated if the drug is abruptly removed. Synaptic changes of this nature occur with dependence involving other drugs as well, though the precise details of these changes differ from drug to drug. Although important in the treatment of drug addictions, changes associated with tolerance and withdrawal are not complete descriptions of the common denominator that links diverse substances as drugs of abuse.
A feature that all drugs of abuse share is that they are potent reinforcers—they feel good to humans (and animals). All rewards, whether natural or drug, activate dopamine release in a region of the brain called the nucleus acumbens. Direct electrical stimulation of pathways related to the nucleus acumbens will also serve as a powerful reinforcer, and this system is activated with drugs of abuse. Drugs as diverse as amphetamines, cocaine, alcohol, opiates, nicotine, phencyclidine (PCP), and marijuana all trigger the release of dopamine in this reward circuit. Similar to the changes seen with tolerance and withdrawal, the sensitivity of dopamine receptors in this circuit changes when repeatedly activated by drugs of abuse. In time, the sensitivity of the reward system is adjusted; stronger rewards—that is, more drugs—become necessary to activate the system.
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