Psychopharmacology has provided powerful tools for reducing severe psychiatric symptoms. The perception is that psychopharmacology is a means for treating illnesses. To understand how psychopharmacology can treat an illness, we must consider two ideas: that of treatment, and that of illness. Illness implies a physiologic disturbance, and treatment implies a specific corrective action. To what extent do these apply to psychopharmacology?
Pharmacologic interventions directly alter brain function. Brain function also is altered by experience. The ultimate mechanisms of the effects of experience and of pharmacologic treatments may be similar, because they involve the same neurons, but they may differ in ways that make one strategy or the other more practical or lasting. For example, treatment with serotonin reuptake inhibitors and psychotherapy had similar normalizing effects on cerebral blood flow in obsessive-compulsive disorder.1 However, increased orbitofrontal glucose metabolism, as measured by positron emission tomography (PET), differentially predicted response to psychotherapy or pharmacotherapy in obsessive-compulsive disorder.2
Experience and expectation alter both subjective and cerebral metabolic effects of stimulants.3 Treatment effects can be influenced by either positive (placebo)4 or negative (“nocebo”)5 expectations. Pharmacology may alter the manner in which the brain responds to other experiences, as may be the case with behavioral cross-sensitization between repeated stimulant administration and stressors,6–8 persistent neurochemical effects of stressors and catecholaminergic systems,9 and the phenomenon of conditioned nonresponse to potentially effective treatments.10 Usually, experience and pharmacology have combined effects, whether intended or not.
This article addresses interactions between pharmacology and other aspects of experience in terms of the model of a social brain. Discussions will include relationships between psychopharmacology and communication, targets of psychopharmacology, including models of psychiatric illnesses and target symptoms, potential synergisms between pharmacology and other treatment modalities, and directions for the future.
Transference and Psychopharmacology
Psychopharmacology is a powerful intervention. Its perception by the patient depends on the manner in which previous experience has prepared him for the idea that someone might prescribe an intervention that would change his brain function and perhaps the way he lived.11 One person might see such a treatment as a liberating mechanism by which she regained control of her life and responsibility for her own well-being. Another might see it as a means by which external people and forces controlled his life or as something to be passively complied with or, to resist this passivity, rebelled against. Others might feel a need to compete with the prescriber by not taking the medicine or not attributing favorable effects to it, others to please her by taking medicine faithfully and attributing miraculous benefit to it.
It is unlikely that any of these fictitious people consciously plan their reactions to pharmacology. It is up to the clinician to determine what the patient's attitude toward pharmacologic treatment is likely to be, and to use communication skills and personality to assure that the patient learns to use treatment adaptively.
For this to happen, the prescribing physician must have significant self-awareness. The clinician must be resourceful in finding clues about the patient's attitudes toward treatment, despite substantial time constraints, and must be able to communicate effectively with a wide range of people. At least as important, the prescriber must be aware of his own attitudes toward patients' autonomy or passivity, and able to avoid interference from his personal characteristics. Countertransference can ruin an otherwise elegant treatment plan.12
Treatments can elicit changes in brain function that are not related directly to their known physiological effects. This is the powerful but controversial placebo effect.13,14 Placebo and “nocebo” effects can be real physiological effects, even if they are mediated indirectly through conditioning and expectations about treatment.13,15 Susceptibility to placebo effects depends on the interaction between prescriber and patient.16
Conditioned drug effects, apparently analogous to placebo effects, can be demonstrated in animals.17 Depending on context and previous drug administration history, an animal can respond to a compound in a manner that is inconsistent with its pharmacology.18 Placebo effects are associated with side effects and physiological characteristics that in treatment trials resemble those of the active drug.19 For example, placebo-associated analgesia is blocked by opiate antagonists.20 Response to placebo in treatment of parkinsonism is associated with PET evidence (displacement of 11C-raclopride binding) for increased dopamine release.21
Expectations, negative or positive, also determine neural and motor responses to subthalamic nucleus stimulation,22 subjective and cerebral metabolic (PET) responses to stimulants3 and cognitive responses to sweet solutions.23 The placebo effect is an elegant demonstration of the social brain in action. Interestingly, until recently, physicians used placebos intentionally as treatments. Only since the modern pharmacologic era has the idea of placebo as “dummy treatment” come into being.4
It is now considered deceptive and generally unethical to treat a patient with a placebo intentionally, but the placebo effect mobilizes physiological forces that enhance or complement mechanisms of specific treatments.4 This effect is based in part on a belief, deeper than intellectual, that treatment will have good results. It is the responsibility of the physician to develop a strategy that has the maximum possibility of good results and to conduct this treatment in a manner that optimizes the patient's positive expectations. The placebo effect can be viewed as part of the patient's contribution to his or her own health.
The placebo effect initially may appear nonspecific, but it has both clinical and biological specificity. It may not be surprising that effects of placebo, good or bad, resemble those of active treatment.19 It is impressive, however, that placebo has important physiological effects that can also resemble those of the so-called active drug. As Constance Holden wrote, “Drugs and placebos look alike in the brain.”24
Placebo effects may represent an interaction between specific effects and a more general “salutogenic mechanism” based on expectations.25 Brain imaging studies have shown that placebo effects can have neural correlates involving brain areas that are important in reinforcement and motivation, such as the nucleus accumbens and amygdala.26,27 Both imaging and pharmacologic studies implicate opioid systems in placebo effects, at least on affect and pain.20,28
In general, the interaction between expectation and physiology exemplified by the placebo effect has led to suggestions of the term “meaning response” and underscores the importance of communication in the physiology of treatment response.29 Rather than ignoring or minimizing the so-called placebo effect, future pharmacologic research will do well to identify and harness its mechanisms.
Target Symptoms of Drugs
Specificity of Pharmacologic Effects
We often speak of drug actions as if they were specific. The specificity of a drug can be defined clinically or physiologically — as an antidote to a symptom, a treatment for a disease syndrome, or an agent acting on a physiological process that defines an aspect of brain function. We may know of many well-defined effects of a pharmacologic agent, but rarely do we understand the relationships between the effects of a drug and its mechanisms of action.
Regulatory approval of a drug requires that it be “specific” for a defined disease entity, such as depression. However, there is arguably no drug that is specific for any entity defined in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition: no specific antidepressant, no specific antipsychotic, no specific antimanic, no specific anxiolytic treatment. That is because all of these entities are descriptively defined syndromes (like dropsy) rather than physiologically defined illnesses. Treatments defined in this way can be valuable, but we must not have the illusion that they are specific for the problem we are trying to treat. Based on their preclinical data, for example, “antidepressants” appear to be anti-stress drugs, with alleviation of depression as a useful side effect.30,31
Treatments that are useful in psychiatry are likely to work by altering basic neurobehavioral processes that underlie, but cut across, our descriptive psychiatric syndromes.32 Most pharmacologic treatments focus on syndromal symptoms. Identification of mechanisms that underlie them, such as initiation of behavior33 or motivation/reward,34 is promising. For our purposes, interventions would focus on mechanisms underlying the course of illness and the interaction between context and brain function.
One promising example is behavioral sensitization, whereby the repeated administration of a drug leads to a progressive enhancement of its behavioral effects.35 The most-studied example is sensitization to motor effects of stimulants, but sensitization to reinforcing effects also occurs.36 Cross-sensitization occurs among different stimulants.37,38 This phenomenon may be relevant to overlapping psychiatric disorders such as substance use and recurrent affective disorders. Perhaps most important is the manner in which pharmacology and experience overlap in behavioral sensitization: sensitization often is context dependent,37,39 and there is cross-sensitization between stimulants and stressors,7,9,40 including prenatal stress.41
Behavioral sensitization to stimulants also results in a marked impairment of cellular immune responses.42 Drugs that are effective in treating bipolar disorder in humans prevent behavioral sensitization.43 Behavioral sensitization to amphetamine has been demonstrated in humans.44,45
Measurement and Monitoring of Drug Effects
We have no reliable or valid physiological measure of any therapeutic pharmacologic effect in psychiatry. Therefore, we must rely on clinical observation. Attempts to increase the reliability of clinical observation have resulted in development of rating scales. These are potentially useful ways to monitor severity of symptoms and their response to treatment and can also be used to anticipate relapse.46
Rating scales can be based on observations by a clinician in an interview, by the patient, or by a clinician or other observer based on observation of behavior. Each of these methods measures different aspects of treatment response.47
It is important that we understand certain limitations of rating scales. First, they are not truly quantitative. Reduction of a depression score by one-half does not mean a patient is half as depressed. Also, depending on the distribution of the total score across individual items, patients with the same score may differ substantially in their experience of the illness. Rating scales also tend to focus on psychiatric symptoms, rather than adaptation, satisfaction, or other more patient-centered aspects of illness (although there are exceptions).46 Compared with quantitative physiologically based measures, rating scales also have advantages, including the possibility of direct input from the patient, results that are available immediately, low cost, and the potential of being incorporated into the interview by a skillful clinician.
Alternatives — or, more likely, supplements — to behavior and symptom scales exist but have not been studied adequately. Their development and use will depend on better understanding of mechanisms underlying basic treatment actions. One potential practical alternative is human behavioral laboratory tests measuring constructs such as impulsivity,48 motivation/reward sensitivity,49 or aggression.50 Another option may be peripheral measures of physiological systems affected by a specific treatment. Development of these measures would require substantial improvement in the ability to determine relationships between measurable effects of drugs and their effects on psychiatric syndromes. Finally, neurophysiological measures such as sensory gating associated with psychosis may be an option.51 Practical use of these measures would require improvement in the reliability and portability of these procedures.
Whether through standard rating scales or other means, the clinician must develop some measure of target symptoms that the patient will recognize as signs of treatment effectiveness and must monitor these over an appropriate time course. There is substantial evidence that, if a drug at an adequate dose is not beginning to have a clinically visible effect by a certain time, it is probably not going to work and must be augmented or changed.52,53 This strategy should be discussed with the patient in advance, increasing the patient's involvement in treatment and responsibility for her own health.
Effects of Pharmacotherapy on Participation in Treatment
For treatment to be successful, the patient must participate, at least by such actions as taking medicine properly and cooperating with monitoring of response and medical effects.54 One could argue that passive participation is not optimal but is better than no participation at all. This may be true, but passive participation has substantial disadvantages. As discussed previously, the patient is likely to view treatment as something imposed by another person and is unlikely to experience his illness and its treatment in a manner that enhances maturity or adaptive abilities.
Nonpharmacologic treatments can enhance responsible participation in overall treatment. For example, in the difficult field of combined substance abuse and bipolar disorder, cognitive-behavior relapse prevention techniques increase the likelihood that a patient will keep appointments and take medicine.55 In other studies, identifying prodromal affective symptoms and developing behavioral strategies for them reduced the rate of relapse of bipolar disorder during pharmacologic treatment.56,57 Results like these suggest at least two broad mechanisms by which nonpharmacologic treatments enhance participation in and results of pharmacologic treatment, increasing structure in the treatment relationship and in the patient's life in general and increasing the patient's responsible role as an active agent in his treatment.
Nonpharmacologic treatment can be an elaborate, manual-based therapy, an insight-oriented treatment, or a manner of conducting psychopharmacologic treatment that emphasizes collaboration and responsibility to the extent that these are possible for a specific patient.58 When time is limited, the effectiveness of treatment can be optimized by using several procedures that maximize the efficiency of the clinical interaction and the responsibility of the patient's role. These include patient-centered rating scales or life-charting methods,59 identification of prodromal symptoms and development of proactive strategies for them,56 and involvement of the patient in advocacy groups such as the Alliance for the Mentally Ill or the Depression and Bipolar Support Alliance.
Synergy Between Pharmacologic and Nonpharmacologic Therapies
Many forms of experience can alter brain function. Studies of physiological effects of placebo and of psychotherapies point to two ways in which pharmacologic and nonpharmacologic treatments can interact: by sharing the same mechanism, or by complementary mechanisms. Such interactions may contribute to situations where response to combined pharmacologic treatment and specific psychotherapy was better than response to either alone.60
When pharmacologic and nonpharmacologic treatment modalities have similar mechanisms, the effects may not be synergistic; they may be undermined by adaptive effects such as tolerance and may be subject to ceiling effects. It is potentially more interesting when mechanisms are different; for example, with effects of psychotherapy and antidepressant treatment on carbon dioxide sensitivity in panic disorder. Such potentially synergistic effects would be less readily susceptible to adaptations like tolerance and would be more likely to produce additive effects.
Two Models for Treatment
We have arrived at our current pharmacologic age serendipitously. We use potentially effective treatments whose mechanisms we do not know and whose effects we cannot measure to treat syndromes whose underlying physiology we do not understand. Better understanding of the genetics and physiology of brain function has made it possible to view treatment of major psychiatric illnesses in the manner that one might view the treatment of a nonpsychiatric medical illness such as pneumonia or congestive heart failure. We use objective tests to determine the presence and severity of an illness, then specific treatments that reverse the pathophysiology of the illness and make the patient well. The fact that relatively effective treatments became available before there were objective tests or definitions for psychiatric illnesses did not weaken this model; after all, the value of digitalis was appreciated before its inotropic effects were identified.
This model, however, does not hold even for nonpsychiatric illness. Aspects of a patient's way of life, such as activity, diet, or smoking, have decisive effects on health and on response to treatments. Depression after a myocardial infarction can be a grave prognostic sign.61 Further, the placebo effect extends to nonpharmacologic treatments and to a wide range of medical conditions.4
Our increasing understanding of the physiology of neural adaptation and of the course of psychiatric illnesses leads to a different idea of treatment. This model retains an emphasis on understanding the physiology of brain function and its relationship to psychiatric illness. It visualizes pharmacologic treatment in the context of adaptive communication, realizing that pharmacology and experience can have complementary effects on brain function. In this manner, reduction of symptoms is associated with an increase in the patient's ability to take responsibility for his or her own health.
Despite large increases in our information about brain function, there have been only modest improvements in effectiveness of treatments for major psychiatric illnesses since the introduction of antipsychotic and antidepressive medicines during the 1950s. This is not surprising, as current treatments tend to be based on variations of models based on effects of the original drugs.30 Proposed strategies for the current pharmacological impasse include reductionistic measures based on detailed understanding of the human genome, or brain imaging. As we have discussed, however, real pharmacologic improvement can be derived from strategies that are much more low-tech, although still challenging. They include:
- Identifying neurobehavioral mechanisms underlying psychiatric syndromes and, especially, their recurrence;
- Developing quantitative, unbiased methods for measuring behavior change associated with treatment, to correct current over-reliance on clinician-administered behavior and symptom scales; and
- Improving understanding of interactions between pharmacological and nonpharmacological treatments.
A substantial but variable fraction of treatment effect, negative or positive, results from the relationship between patient and clinician and the patient's previous experience. Despite these limitations, pharmacologic treatments can substantially improve function and reduce suicide and other illness-related morbidity and mortality.62 This bodes well for increasingly effective treatments as we understand psychiatric illness and therapeutic mechanisms better, and learn to use pharmacological and nonpharmacological measures, synergistically and systematically, to produce specific and lasting adaptive change.
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