Overview of Treatment

Introduction to Range of Treatments

Mental disorders are treatable, contrary to what many think.¹² An armamentarium of efficacious treatments is available to ameliorate symptoms. In fact, for most mental disorders, there is generally not just one but a range of treatments of proven efficacy. Most treatments fall under two general categories, psychosocial and pharmacological.¹³ Moreover, the combination of the two—known as multimodal therapy—can sometimes be even more effective than each individually (see Chapter 3).

The evidence for treatment being more effective than placebo is overwhelming, as documented in the main chapters of this report (Chapters 3 through 5). The degree of effectiveness tends to vary, depending on the disorder and the target population (e.g., older adults with depression). What is optimal for one disorder and/or age group may not be optimal for another. Further, treatments generally need to be tailored to the client and to client preferences.

The inescapable point is that studies demonstrate conclusively that treatment is more effective than placebo. Placebo (an inactive form of treatment) in both pharmacological and psychotherapy studies has a powerful effect in its own right, as this section later explains. Placebo is more effective than no treatment. Therefore, to capitalize on the placebo response, people are encouraged to seek treatment, even if the treatment is not as optimal as that described in this report.

If treatment is so effective, then why are so few people receiving it? Studies reveal that less than one-third of adults with a diagnosable mental disorder, and even a smaller proportion of children, receive any mental health services in a given year. This section of the chapter strives to explain why by examining the types of barriers that prevent people from seeking help. But the chapter first covers some general points about psychological and pharmacological therapies. It also discusses why therapies that work so well in research settings do not work as well in practice.

Psychotherapy

Psychotherapy is a learning process in which mental health professionals seek to help individuals who have mental disorders and mental health problems. It is a process that is accomplished largely by the exchange of verbal communication, hence it often is referred to as “talk therapy.” Many of the theories undergirding each orientation to psychotherapy were summarized earlier in this chapter.

Participants in psychotherapy can vary in age from the very young to the very old, and problems can vary from mental health problems to disabling and catastrophic mental disorders. Although people often are seen individually, psychotherapy also can be done with couples, families, and groups. In each case, participants present their problems and then work with the psychotherapist to develop a more effective means of understanding and handling their problems. This report focuses on individual psychotherapy and also mentions couples therapy and various forms of family interventions, particularly psycho-educational approaches. Although not discussed in the report, group psychotherapy is effective for selected individuals with some mood disorders, anxiety disorders, schizophrenia, personality disorders, and for mental health problems seen in somatic illness (Yalom, 1995; Kanas, in press).

Estimates of the number of orientations to psychotherapy vary from a very small number to well over 400. The larger estimate generally refers to all the variations of the three major orientations, that is, psychodynamic, behavioral, and humanistic. Each orientation falls under the more general conceptual category of either action or reflection.

Psychodynamic orientations are the oldest. They place a premium on self-understanding, with the implicit (or sometimes explicit) assumption that increased self-understanding will produce salutary changes in the participant. Behavioral orientations are geared toward action, with a clear attempt to mobilize the resources of the patient in the direction of change, whether or not there is any understanding of the etiology of the problem. Humanistic orientations aim toward increased self-understanding, often in the direction of personal growth, but use treatment techniques that often are much more active than are likely to be employed by the psychodynamic clinician.

While the following paragraphs focus on psychodynamic, behavioral, and humanistic orientations, they also discuss interpersonal therapy and cognitive-behavioral therapy as outgrowths of psychodynamic and behavioral therapy, respectively. Psychodynamic, interpersonal, and cognitive-behavioral therapy are most commonly the focus of treatment research reported throughout this report.

Psychodynamic Therapy

The first major approach to psychotherapy was developed by Sigmund Freud and is called psychoanalysis (Horowitz, 1988). Since its origin more than a century ago, psychoanalysis has undergone many changes. Today, Freudian (or classical) psychoanalysis is still practiced, but other variations have been developed—ego psychology, object relations theory, interpersonal psychology, and self-psychology, each of which can be grouped under the general term “psychodynamic” (Horowitz, 1988). The psychodynamic therapies, even though they differ somewhat in theory and approach, all have some concepts in common. With each, the role of the past in shaping the present is emphasized, so it is important, in understanding behavior, to understand its origins and how people come to act and feel as they do. A second critical concept common to all psychodynamic approaches is the belief in the unconscious, so that there is much that influences our behavior of which we are not aware. This makes the process of understanding more difficult, as we often act for reasons that we cannot state, and these reasons often are linked to previous experiences. Thus, an important part of psychodynamic psychotherapy is to make the unconscious conscious or to help the patient understand the origin of actions that are troubling so that they can be corrected.

For some psychodynamic approaches, such as the classical Freudian approach, the focus is on the individual and the experiences the person had in the early years that give shape to current behavior, even beyond the awareness of the patient. For other, more contemporary approaches, such as interpersonal therapy, the focus is on the relationship between the person and others. First developed as a time-limited treatment for midlife depression, interpersonal therapy focuses on grief, role disputes, role transitions, and interpersonal deficits (Klerman et al., 1984). The goal of interpersonal therapy is to improve current interpersonal skills. The therapist takes an active role in teaching patients to evaluate their interactions with others and to become aware of self-isolation and interpersonal difficulties. The therapist also offers advice and helps the patient to make decisions.

Behavior Therapy

A second major approach to psychotherapy is known as behavior modification or behavior therapy (Kazdin, 1996, 1997). It focuses on current behavior rather than on early patterns of the patient. In its earlier form, behavior therapy dealt exclusively with what people did rather than what they thought or felt. The general principles of learning were applied to the learning of maladaptive as well as adaptive behaviors. Thus, if a person could be conditioned to act in a functional way, there was no reason why the same principles of conditioning could not be employed to help the person unlearn dysfunctional behavior and learn to replace it with more functional behavior. The role of the environment was very important for behavior therapists, because it provided the positive and negative reinforcements that sustained or eliminated various behaviors. Therefore, ways of shaping that environment to make it more responsive to the needs of the individual were important in behavior therapy.

More recently, there has been a significant addition to the interests and activities of behavior therapists. Although behavior continued to be important in relation to reinforcements, cognitions—what the person thought about, perceived, or interpreted what was transpiring—were also seen as important. This combined emphasis led to a therapeutic variant known as cognitive-behavioral therapy, an approach that incorporates cognition with behavior in understanding and altering the problems that patients present (Kazdin, 1996).

Cognitive-behavioral therapy draws on behaviorism as well as cognitive psychology, a field devoted to the scientific study of mental processes, such as perceiving, remembering, reasoning, decision making, and problem solving. The use of cognition in cognitive-behavioral therapy varies from attending to the role of the environment in providing a model for behavior, to the close study of irrational beliefs, to the importance of individual thought processes in constructing a vision of the surrounding world. In each case, it is critical to study what the individual in therapy thinks and does and less important to understand the past events that led to that pattern of thinking and doing. Cognitive-behavioral therapy strives to alter faulty cognitions and replace them with thoughts and self-statements that promote adaptive behavior (Beck et al., 1979). For instance, cognitive-behavioral therapy tries to replace self-defeatist expectations (“I can’t do anything right”) with positive expectations (“I can do this right”). Cognitive-behavioral therapy has gained such ascendancy as a means of integrating cognitive and behavioral views of human functioning that the field is more frequently referred to as cognitive-behavioral therapy rather than behavior therapy (Kazdin, 1996).

Humanistic Therapy

The third wave of psychotherapy is referred to variously as humanistic (Rogers, 1961), existential (Yalom, 1980), experiential, or Gestalt therapy. It owes its origins as a treatment to the client-centered therapy that was originated by Carl Rogers, and the theory can be traced to philosophical roots beginning with the 19th century philosopher, Soren Kierkegaard. The central focus of humanistic therapy is the immediate experience of the client. The emphasis is on the present and the potential for future development rather than on the past, and on immediate feelings rather than on thoughts or behaviors. It is rooted in the everyday subjective experience of the person seeking assistance and is much less concerned with mental illness than it is with human growth.

One critical aspect of humanistic treatment is the relationship that is forged between the therapist, who in some ways serves as a guide in an exploration of self-discovery, and the client, who is seeking greater knowledge of the self and an expansion of inherent human potential. The focus on the self and the search for self-awareness is akin to psychodynamic psychotherapy, while the emphasis on the present is more similar to behavior therapy.

Although it is possible to describe distinctive orientations to psychotherapy, as has been done above, most psychotherapists describe themselves as eclectic in their practice, rather than as adherents to any single approach to treatment. As a result, there is a growing development referred to as “psychotherapy integration” (Wolfe & Goldfried, 1988). It strives to capture what is best about each of the individual approaches. Psychotherapy integration includes various attempts to look beyond the confines of any single orientation but rather to see what can be learned from other perspectives. It is characterized by an openness to various ways of integrating diverse theories and techniques. Psychotherapy also should be modified to be culturally sensitive to the needs of racial and ethnic minorities (Acosta et al., 1982; Sue et al., 1994; Lopez, in press).

The scientific evidence on efficacy presented in this report, however, is focused primarily on specific, standardized forms of psychotherapy.

Pharmacological Therapies

The past decade has seen an outpouring of new drugs introduced for the treatment of mental disorders (Nemeroff, 1998). New medications for the treatment of depression and schizophrenia are among the achievements stoked by research advances in both neuroscience and molecular biology. Through the process known as rational drug design, researchers have become increasingly sophisticated at designing drugs by manipulating their chemical structures. Their goal is to create more effective therapeutic agents, with fewer side effects, exquisitely targeted to correct the biochemical alterations that accompany mental disorders.

The process was not always so rational. Many of the older pharmacotherapies (drug treatments) that had been introduced by 1960 had been discovered largely by accident. Researchers studying drugs for completely different purposes serendipitously found them to be useful for treating mental disorders (Barondes, 1993). Thanks to their willingness to follow up on unexpected leads, drugs such as chlorpromazine (for psychosis), lithium (for bipolar disorder), and imipramine (for depression) became available. The advent of chlorpromazine in 1952 and other neuroleptic drugs was so revolutionary that it was one of the major historical forces behind the deinstitutionalization movement that is discussed later in this chapter.

The past generation of pharmacotherapies, once shown to be safe and effective, was introduced to the market generally before their mechanism of action was understood. Years of research after their introduction revealed how many of them work therapeutically. Knowledge about their actions has had two cardinal consequences: it helped probe the etiology of mental disorders, and it ushered in the next generation of pharmacotherapies that are more selective in their mechanism of action.

Mechanisms of Action

The mechanism of action refers to how a pharmacotherapy interacts with its target in the body to produce therapeutic effects. Pharmacotherapies that act in similar ways are grouped together into broad categories (e.g., stimulants, antidepressants). Within each category are several chemical classes. The individual pharmacotherapies within a chemical class share similar chemical structures. Table 2-9 presents several common categories and classes, along with their indication, that is, their clinical use.

Many pharmacotherapies for mental disorders have as their initial action the alteration—either increase or decrease—in the amount of a neurotransmitter. Neurotransmitter levels can be altered by pharmacotherapies in myriad ways: pharmacotherapies can mimic the action of the neurotransmitter in cell-to-cell signaling; they can block the action of the neurotransmitter; or they can alter its synthesis, breakdown (degradation), release, or reuptake, among other possibilities (Cooper et al., 1996).

Neurotransmitters generally are concentrated in separate brain regions and circuits. Within the cells that form a circuit, each neurotransmitter has its own biochemical pathway for synthesis, degradation, and reuptake, as well as its own specialized molecules known as receptors. At the time of neurotransmission, when a traveling signal reaches the tip (terminal) of the presynaptic cell, the neurotransmitter is released from the cell into the synaptic cleft. It migrates across the synaptic cleft in less than a millisecond and then binds to receptors situated on the membrane of the postsynaptic cell. The neurotransmitter’s binding to the receptor alters the shape of the receptor in such a way that the neurotransmitter can either excite the postsynaptic cell, and thereby transmit the signal to this next cell, or inhibit the receptor, and thereby block signal transmission. The neurotransmitter’s action is terminated either by enzymes that degrade it right there, in the synaptic cleft, or by transporter proteins that return unused neurotransmitter back to the presynaptic neuron for reuse, a “recycling” process known as reuptake. The widely prescribed class of antidepressants referred to as the selective serotonin reuptake inhibitors primarily block the action of the transporter protein for serotonin, thus leaving more serotonin to remain at the synapse (Schloss & Williams, 1998). Depression is thought to be reflected in decreased serotonin transmission, so one rationale for this class of antidepressants is to boost the level of serotonin (see Chapter 4).

Table 2-9. Selected types of pharmacotherapies

* Also known as first-generation antipsychotics, they include these chemical classes: phenothiazines (e.g., chlorpromazine), butyrophenones (e.g., haloperidol), and thioxanthenes (Dixon et al., 1995).
** Also known as second-generation antipsychotics, they include these chemical classes: dibenzoxazepine (e.g., clozapine), thienobenzodiazepine (e.g., olanzapine), and benzisoxazole (e.g., risperidone).
*** Include imipramine and amitriptyline.

Source: Perry et al., 1997

Although the effects of reuptake inhibitors on neurotransmitter concentrations in the synapse occur with the first dose, therapeutic benefit typically lags behind by days or weeks. This observation has spurred considerable recent research on chronic and “downstream” actions of psychotropics, particularly antidepressants. For example, in animal models the repeated administration of nearly all antidepressants is associated with a reduction in the number of postsynaptic 12/7/99 receptors, so-called down-regulation that parallels the time course of clinical effect in patients (Schatzberg & Nemeroff, 1998). Some of the secondary effects of reuptake inhibitors may be mediated by the activation of intraneuronal “second messenger” proteins which result from the stimulation of postsynaptic receptors (Schatzberg & Nemeroff, 1998).

Receptors for each transmitter come in numerous varieties. Not only are there several types of receptor for each neurotransmitter, but there may be many subtypes. For serotonin, for example, there are seven types of receptors, designated 5-HT₁ –5-HT₇, and seven receptor subtypes, totaling 14 separate receptors (Schatzberg & Nemeroff, 1998). The pace at which receptors are identified has become so dizzying that these figures are likely to be obsolete by the time this paragraph is read.

A pharmacotherapy typically interacts with a receptor in either one of two ways—as an agonist or as an antagonist.¹⁴ When a pharmacotherapy acts as an agonist, it mimics the action of the natural neurotransmitter. When a pharmacotherapy acts as an antagonist, it inhibits, or blocks, the neuro-transmitter’s action, often by binding to the receptor and preventing the natural transmitter from binding there. An antagonist disrupts the action of the neurotransmitter.

The diversity of receptors presents vast opportunities for drug development. Through rational drug design, pharmacotherapies have become increasingly selective in their actions. Generally speaking, the more selective the pharmacotherapy’s action, the more targeted it is to one receptor rather than another, the narrower its spectrum of action, and the fewer the side effects. Conversely, the broader the pharmacotherapy’s action, the less targeted to a receptor type or subtype, the broader the effects, and the broader the side effects (Minneman, 1994). However, the interaction among neurotransmitter systems in the brain renders some of the apparent distinctions among medications more apparent than real. Thus, despite differential initial actions on neurotransmitters, both serotonin and norepinephrine reuptake blockers have similar biochemical effects after chronic dosing (Potter et al., 1985).

Complementary and Alternative Treatment

Recent interest in the health benefits of a plethora of natural products has engendered claims related to putative effects on mental health. These have ranged from reports of enhanced memory in people taking the herb, ginseng, to the use of the St. John’s wort flowers as an antidepressant (see Chapter 4).

There are major challenges to evaluating the role of complementary and alternative treatments in maintaining mental health or treating mental disorders. In many cases, preparations are not standardized and consist of a variable mixture of substances, any of which may be the active ingredient(s). Purity, bioavailability, amount and timing of doses, and other factors that are standardized for traditional pharmaceutical agents prior to testing cannot be taken for granted with natural products. Current regulations in the United States classify most complementary and alternative treatments as “food supplements,” which are not subject to premarketing approval of the Food and Drug Administration.

At present, no conclusions about the role, if any, of complementary and alternative treatments in mental health or illness can be accepted with certainty, as very few claims or studies meet acceptable scientific standards. With funding from government and private industry, controlled clinical trials are under way, including the use of St. John’s wort (Hypericum perforatum) as a treatment for depression, and omega-3 fatty acids (fish oils) as a mood stabilizer in bipolar depression. In addition, it is important for clinicians and investigators to account for any herbs or natural products being taken by their patients or research subjects that might interact with traditional treatments.

Issues in Treatment

The foregoing section has furnished an overview of the types and nature of mental health treatment. The resounding message, which is echoed throughout this report, is that a range of efficacious treatments is available. The following material deals with four issues surrounding treatment—the placebo response, benefits and risks, the gap between how well treatments work in clinical trials versus in the real world, and the constellation of barriers that hinder people from seeking mental health treatment.

Placebo Response

Recognized since antiquity, the placebo effect refers to the powerful role of patients’ attitudes and perceptions that help them improve and recover from health problems. Hippocrates established the therapeutic principle of physicians laying their hands in a reassuring manner to draw on the inner resources of the patient to fight disease. Technically speaking, the placebo effect refers to treatment responses in the placebo group, responses that cannot be explained on the basis of active treatment (Friedman et al., 1996a). A placebo is an inactive treatment, either in the form of an inert pill for studying a new drug treatment or an inactive procedure for studying a psychological therapy. The effects of active treatment are often compared with a control group that receives a pharmacological or psychological placebo.

It is not unusual for a placebo effect to be found in up to 50 percent of patients in any study of a medical treatment (Schatzberg & Nemeroff, 1998). For example, about 30 percent of patients typically respond to a placebo in a clinical trial of a new antidepressant (see Chapter 4). The rate is even higher for an antianxiety agent (an anxiolytic) (Schweizer & Rickels, 1997). The placebo effect is of such import that a placebo group or other control group¹⁵ is mandated by the Food and Drug Administration in clinical trials of a new pharmacotherapy to establish its efficacy prior to marketing (Friedman et al., 1996a). If the pharmacotherapy is not statistically superior to the control, efficacy cannot be established. It is somewhat more difficult to fashion an analog of an inert pill in the testing of new and experimental psychological therapies. Psychological studies can employ a “psychological” placebo in the form of a treatment known to be ineffectual. Or they can employ a comparison group, which receives an alternative psychological therapy. Some treatment studies employ both a “psychological” placebo, as well as a comparison group.¹⁶

The basis of the placebo response is not fully known, but there are thought to be many possible reasons. These reasons, which relate to attributes of the disorder or the disease, the patient, and the treatment setting, include spontaneous remission, personality variables (e.g., social acquiescence), patient expectations, attitudes of and compassion by clinicians, and receiving treatment in a specialized setting (Schweizer & Rickels, 1997). In studies of postoperative pain, the placebo response is mediated by patients’ production of endogenous pain-killing substances known as endorphins (Levine et al., 1978).

Benefits and Risks

Throughout this report, currently accepted treatments for mental disorders will be described. Except where otherwise indicated, the efficacy of these interventions has been documented in multiple controlled, clinical trials published in the peer-reviewed literature. In some cases, these have been supplemented by expert consensus reports or practice guidelines.

Most studies of efficacy of specific treatments for mental disorders have been highly structured clinical trials, performed on individuals with a single disorder, in good physical health. While necessary and important, these trials do not always generalize easily to the wider population, which includes many individuals whose mental disorder is accompanied by another mental or somatic disorder and/or alcohol or substance abuse, and who may be taking other medications. Moreover, children, adolescents, and the elderly are excluded from many clinical trials,¹⁷ as are those in certain settings, such as nursing homes. Newer, more generalizable studies are being undertaken to address these shortcomings of the scientific literature (Lebowitz & Rudorfer, 1998).

Pending the results of these newer studies, it is important for clinical decisionmakers to review the current best evidence for the efficacy of treatments. People with mental disorders and their health providers should consider all possible options and carefully weigh the pros and cons of each, as well as the possibility of no treatment at all, before deciding upon a course of action. Such an informed consent process entails the calculation of a benefit-to-risk ratio" for each available treatment option. Most medications or somatic treatments have side effects, for example, but a likelihood of significant clinical benefit often overrides side effects in support of a treatment recommendation.

Gap Between Efficacy and Effectiveness

Mental health professionals have long observed that treatments work better in the clinical research trial setting as opposed to typical clinical practice settings. The diminished level of treatment effectiveness in real-world settings is so perceptible that it even has a name, the “efficacy-effectiveness gap.” Efficacy is the term for what works in the clinical trial setting, and effectiveness is the term for what works in typical clinical practice settings. The efficacy-effectiveness gap applies to both pharmacological therapies and to psychotherapies (Munoz et al., 1994; Seligman, 1995). The gap is not unique to mental health, for it is found with somatic disorders too.

The magnitude of the gap can be surprisingly high. With schizophrenia medications, one review article found that, in clinical trials, the use of traditional antipsychotic medications for schizophrenia was associated with an average annual relapse rate of about 23 percent, whereas the same medications used in clinical practice carried a relapse rate of about 50 percent (Dixon et al., 1995). The magnitude of the gap found in this study may not apply to other medications and other disorders, much less to psychological therapies. Studies of real-world effectiveness are scarce. Yet some degree of gap is widely recognized. The question is, why?

Efficacy studies test whether treatment works under ideal circumstances. They typically exclude patients with other mental or somatic disorders. In the past, they typically have examined relatively homogeneous populations, usually white males. Furthermore, efficacy studies are carried out by highly trained specialists following strict protocols that require frequent patient monitoring. Finally, participation in efficacy studies is often free of charge to patients.

It is not surprising that the reasons commonly cited to explain the discrepancy between efficacy and effectiveness focus on the practicalities and constraints imposed by the real world. In real-world settings, patients often are more heterogeneous and ethnically diverse, are beset by comorbidity (more than one mental or somatic disorder),¹⁸ are often less compliant, and are seen more often in general medical rather than specialty settings; providers are less inclined to adequately monitor and standardize treatment; and cost pressures exist on both patients and providers, depending on the nature of the financing of care (Dixon et al., 1995; Wells & Sturm, 1996). This constellation of real-world constraints appears to explain the gap.

Barriers to Seeking Help

Most people with mental disorders do not seek treatment, according to figures presented in the next section of this chapter and in Chapter 6. This general statement applies to adults and older adults and to parents and guardians who make treatment decisions for children with mental disorders. There is a multiplicity of reasons why people fail to seek treatment for mental disorders but few detailed studies. The barriers to treatment fall under several umbrella categories: demographic factors, patient attitudes toward a service system that often neglects the special needs of racial and ethnic minorities, financial, and organizational.

Several demographic factors predispose people against seeking treatment. African Americans, Hispanics (Sussman et al., 1987; Gallo et al., 1995), and poor women (Miranda & Green, 1999) are less inclined than non-Hispanic whites—particularly females—to seek treatment. Common patient attitudes that deter people from seeking treatment are not having the time, fear of being hospitalized, thinking that they could handle it alone, thinking that no one could help, and stigma (being too embarrassed to discuss the problem) (Sussman et al., 1987). Above all, the cost of treatment is the most prevalent deterrent to seeking care, according to a large study of community residents (Sussman et al., 1987). Cost is a major determinant of seeking treatment even among people with health insurance because of inferior coverage of mental health as compared with health care in general. Finally, the organizational barriers include fragmentation of services and lack of availability of services (Horwitz, 1987). Members of racial and ethnic minority groups often perceive that services offered by the existing system do not or will not meet their needs, for example, by taking into account their cultural or linguistic practices. These particular barriers are discussed in greater depth with respect to minority groups (later in this chapter) and with respect to different ages (Chapters 3 to 5).

Demographic, attitudinal, financial, and organizational barriers operate at various points and to various degrees. Seeking treatment is conceived of as a complex process that begins with an individual or parent recognizing that thinking, mood, or behaviors are unusual and severe enough to require treatment; interpreting symptoms as a “medical” or mental health problem; deciding whether or not to seek help and from whom; receiving care; and, lastly, evaluating whether continuation of treatment is warranted (Sussman et al., 1987)

¹² About 40 percent of those surveyed thought that they “didn’t think anyone could help” as a reason for not seeking mental health treatment (Sussman et al., 1987).

¹³ Other treatments are electroconvulsive therapy (Chapters 4 and 5) and some types of surgery.

¹⁴ There are certainly exceptions to this general rule. Some pharmacotherapies work as partial agonists and partial antagonists simultaneously.

¹⁵ When it is unethical to deprive patients of treatment, such as the case with AIDS, conventional treatment is given as the control.

¹⁶ The criteria developed by a division of the American Psychological Association for establishing treatment efficacy call for the experimental treatment to be statistically superior to “pill or psychological placebo or to another treatment” (Chambless et al., 1998).

¹⁷ In March 1998, the NIH issued a policy guideline stating that NIH-funded investigators will be expected to include children in clinical trials, which normally would involve adults only, when there is sound scientific rationale and in the absence of a strong justification to the contrary.

¹⁸ Having a second disorder increases the possibility of drug interactions, which may translate into reduced dosing. Comorbidity is discussed throughout this report.