General Principles
The science of psychopharmacotherapy continues to rapidly expand, creating both an opportunity and a challenge. As the neurosciences facilitate the development of new psychotropics, the art of applying these agents in clinical practice becomes increasingly more complex but no less important. For example, since the first edition of this book in 1993, several new antipsychotics and antidepressants have come into wide use clinically. Even while these agents are positively affecting the lives of countless patients, newer compounds with potentially novel mechanisms of action are poised to prove their worth in the broader clinical arena. In addition, these agents are effective for other conditions such as bipolar disorder, other treatment-refractory mood disorders, and anxiety-related disorders. Important subgroups such as children and adolescents, females of childbearing potential, the elderly, and the dual diagnosed (mental disorder plus alcohol/substance abuse) are now being carefully considered in clinical trials. Finally, large seminaturalistic clinical studies (e.g., Systematic Treatment Enhancement Program for Bipolar Disorder [STEP-BD]; Clinical Antipsychotic Treatment Intervention Effectiveness [CATIE] study; Sequenced Treatment Alternatives to Relieve Depression [STAR*D] study) are providing insight about existing therapeutic strategies in real world populations. In general, the need to know more about the differences in physiological processes, clinical presentation, treatment response, and safety in such patients has generated an increased appreciation of specific issues related to age, gender, psychiatric and medical comorbidities, concurrent medications, quality of life, and economic impact. Finally, the use of outcome assessments in the context of measurement-based care and encouragement of active patient participation in the diagnostic and treatment process may increase adherence and the chance for more effective strategies (1).
As a result, while improved therapies to ease a patient’s suffering are constantly emerging, the practitioner is required to continually assimilate and critically evaluate new information about recent advances, including novel agents targeted to affect specific components of various neurotransmitter systems, combination strategies (e.g., combined medications, psychotherapy plus pharmacotherapy), alternative uses of existing agents, and the specialized requirements of a growing number of identified diagnostic subgroups. Throughout this book, we provide a decision-making method that incorporates this growing database for the optimal use of drug and neuromodulation therapies in clinical practice.
Our model is grounded on a scholarly review and summation of the critical supporting research. Beginning with a discussion of the major principles underlying our approach, we follow with chapters on specific psychiatric disorders and their related therapies. There is an emphasis on the historical development of our present diagnostic system to underscore the fluid nature and increasing sophistication in defining various psychiatric disorders. The goal is to provide a logical treatment strategy that can be readily applied and easily adapted to an everincreasing body of relevant scientific data.
This approach is based on several underlying assumptions:
The medical model serves as the foundation for the treatment of psychiatric disorders.
A nontheoretical approach is advocated in considering etiology/pathogenesis.
An empirically based foundation derived from scientific investigation is used to guide diagnostic, treatment, and outcome decisions.
An increasing focus on prevention or preemption is advocated to minimize the long-term impact of psychiatric disorders and to improve prognosis (2).
The encouragement and facilitation of active of participation by the patient is ensured in the treatment planning process.
TABLE 1-1 PRINCIPLES OF PSYCHOPHARMACOTHERAPY | ||||||||||||||
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All modalities, from electroconvulsive therapy (ECT) to psychotherapy, can be incorporated into our approach when empirical data support their utility. When sufficient data are lacking, we offer suggestions based on our cumulative clinical and research experience.
Finally, a healthy skepticism about the aggressive use of drugs and the pressure to prescribe the newest agents is appropriate. Treatment strategies that attempt to balance “newer and more is better” versus “fewer and time-tested is best” are ultimately in our patients’ best interest (3).
TABLE 1-2 LEVELS OF DIAGNOSTIC SOPHISTICATION | ||||||||||||||||||||||||
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Principles of Psychopharmacotherapy
Seven major principles guide our approach to psychopharmacotherapy. They are summarized in Table 1-1.
PRINCIPLE 1
The diagnostic assessment subject to revisions is fundamental to our model.
Patients present with symptoms. The clinician’s goal is to formulate these problems within the context of the highest level of diagnostic sophistication (Table 1-2) based on both the subjective and the objective components of the evaluation. To accomplish this task, the clinician must realize that behavioral symptoms in psychiatry are analogous to localizing signs in neurology. Such symptoms as depressed mood or auditory hallucinations are mediated through the function or dysfunction of specific brain regions. Different disorders can cause dysfunction in the same brain region, leading to similar phenomenological presentations. For example, a brain tumor, stroke, or demyelinating
plaque can all affect the frontal lobe, culminating in similar behavioral symptoms.
plaque can all affect the frontal lobe, culminating in similar behavioral symptoms.
The increased specificity of a syndromic, as compared with a symptomatic, diagnosis comes from the use of both inclusion criteria (i.e., a constellation of symptoms and signs present for a set interval of time) and exclusion criteria (i.e., conditions that may mimic the syndrome under consideration but have a known pathophysiological or etiological basis) (4). Currently, most psychiatric diagnoses are at the syndromic level, with similar presentations often representing substantially different underlying disorders. Therefore, considerable variability is found in the treatment outcome of patients diagnosed with the same syndrome. Further, patients with the same pathophysiology may be erroneously differentially categorized because of alternate syndromic presentations. A classic example is tertiary syphilis, known as the “great mimic” due to its myriad clinical presentations. For this reason, clinicians must be ready to alter their diagnosis, as well as treatment plans, if dictated by changes in the course of illness.
Although criteria-based syndromic diagnoses have limitations, we emphasize their usefulness (e.g., enhance clinical decision making and improve clinical outcome) as a first step in developing an empirical approach to psychopharmacological and other therapies (5). Systematic studies of the effects of therapy on such syndromes permit investigators to
Conduct sequential investigations in different groups of patients with the same signs and symptoms with reasonable confidence that they are treating patients with similar syndromes
Clarify the effectiveness of a specific treatment (i.e., efficacy clearly outweighs safety and tolerability issues)
Compare the relative effectiveness of one treatment with another when assessing the outcome in patients with similar syndromic diagnoses
Clarify which particular symptoms may be critical in predicting an active treatment versus placebo difference (e.g., neurovegetative symptoms of depression)
Clarify atypical or specific subtypes of presentations that may not benefit from standard treatments (e.g., atypical or psychotic depressive disorders)
Perform replication studies as well as multisite clinical trials
Finally, diagnoses based on etiology or pathophysiology are superior to symptomatic or syndromic diagnoses in terms of their specificity and usefulness. With the completion of the Human Genome Project, the promise of greater homogeneity in diagnostic categories based on genetic information will increasingly guide treatment strategies (6,7,8,9 and 10). As in other areas of medicine, the likelihood of a successful outcome increases based on the level of diagnostic specificity because treatment can then be targeted to the underlying causative factors.
PRINCIPLE 2
Pharmacotherapy alone is generally insufficient for complete recovery.
Although drug therapy may be the cornerstone of recovery for many disorders, educational and psychosocial interventions are almost always helpful, as are more specialized forms of psychotherapy when indicated. Examples of the latter include the use of anxiolytic agents in combination with behavior modification for phobic disorders or the use of cognitivebehavioral or interpersonal psychotherapy plus antidepressants for depressive disorders. Further, because many of the psychotropics often have a delayed onset of action, early counseling may avoid premature discontinuation as well as provide hope and reassurance during this lag phase. In addition to communicating in an understandable fashion the nature of the symptoms and the disorder, and incorporating the patient and the family as active participants in the treatment plan, the clinician must generally be prepared to respond to these questions:
What is happening to me?
Will I get better?
What will it take?
How long will it take?
What are the limitations of my condition and of the proposed treatment?
How much will it cost?
Simple, straightforward explanations of a patient’s condition and the rationale for a specific course of action are generally well received. For those unable to benefit because of cognitive disruption, reassurance and expressions of empathy and concern are often therapeutic. A thorough, brief review of what is known about
the patient’s disorder should be communicated while dispelling common myths about his or her condition (e.g., the problem is related to a lack of moral strength). A patient’s prognosis should be realistically and, to the extent possible, optimistically explained. Various treatment options should also be discussed, as noted in “Informed Consent” in Chapter 3.
the patient’s disorder should be communicated while dispelling common myths about his or her condition (e.g., the problem is related to a lack of moral strength). A patient’s prognosis should be realistically and, to the extent possible, optimistically explained. Various treatment options should also be discussed, as noted in “Informed Consent” in Chapter 3.
Although the clinician can take the role of counselor and advisor, the ultimate course of action should be left to the patient, except in those few instances in which the patient cannot make a rational, prudent, and informed decision on his or her own behalf. Bringing the patient into the process as an active participant is beneficial to self-esteem and improves adherence. There are, however, two instances in which the clinician should not defer to the patient’s wishes: if the illness significantly affects the ability to make an informed decision and when a treatment is requested (e.g., a drug of abuse) that cannot be provided in good faith.
The educational process should continue throughout the entire treatment relationship and often involves clarifying issues as they arise. When a patient does not respond to the first line treatment, the next step is to discuss the possible reasons as well as the rationale for attempting second and subsequent treatment strategies. Finally, because many psychiatric disorders are recurrent, educating the patient and the family as to the early warning signs of a relapse may allow for earlier intervention and perhaps even prevention. In this way, a patient may suffer fewer adverse sequelae, often avoiding unnecessary hospitalizations and prolonged recovery phases from subsequent, repeated exacerbations.
In addition to adequate pharmacotherapy, specific forms of psychotherapy are often indicated. These may include cognitive or interpersonal psychotherapy or various behavior desensitization and biofeedback techniques. Some patients may benefit from insight-oriented psychotherapy; group, family, or marital counseling; or both. Finally, in more chronic disorders, patients often benefit from vocational rehabilitation. A knowledgeable clinician realizes that these disorders do not occur in a vacuum, and, regardless of diagnosis, each patient requires an individualized treatment plan to optimize outcome.
PRINCIPLE 3
The phase of an illness (e.g., acute, subchronic, chronic) and the timepoint of intervention (acute, maintenance, prophylaxis) are critically important in terms of the initial strategy and the duration of treatment.
Once an acute episode has been adequately controlled, ongoing extended treatment is often necessary to prevent relapse into the acute phase. Some patients with subchronic or chronic histories should also receive indefinite prophylaxis due to the higher likelihood of recurrence. Because it is difficult to accurately predict which patients will have subsequent episodes, however, clinicians may be reluctant to expose those who will not experience a recurrence to the adverse effects of long-term therapy.
The course of an illness also dictates the need for and the duration of maintenance and prophylactic therapy. In particular, prophylaxis may not be indicated for an uncomplicated first episode, depending on the specific disorder and the patient’s response to standard interventions. Conversely, patients with a history of multiple recurrences; with a family history of a psychiatric disorder; with prolonged durations of, or particularly severe, acute episodes; and with delayed rate of response to treatment intervention are candidates for ongoing prophylaxis.
Some medications are clearly appropriate during an acute phase of treatment but not for maintenance or prophylactic purposes. Other drugs may not be very useful for acute management but are exceptionally beneficial for maintenance or prophylaxis. For example, in an acute manic episode, adjunctive benzodiazepines may rapidly sedate a patient; however, these drugs are not ideal as a maintenance strategy once the acute symptoms are under control. With early signs of breakthrough and possible relapse, however, they may again play a role in preventing relapse into a full manic phase. Conversely, lithium is relatively ineffective for more severe, manic exacerbations but very effective for maintenance and prophylaxis once the acute symptoms are controlled with other interventions.
PRINCIPLE 4
The risk-to-benefit ratio must always be considered when developing atreatment strategy.
Determination of the overall effectiveness of a treatment should consider efficacy as well as safety and tolerability (11). Specific factors to consider are both psychiatric and physical contraindications. For example, bupropion is contraindicated in a depressed patient with a history of seizures or an eating disorder due to the increased risk of seizures while on this agent. Conversely, it may be an appropriate choice for a bipolar disorder with intermittent depressive episodes that is otherwise under good control with standard mood stabilizers. This consideration is based on the limited data suggesting that bupropion is less likely to induce a manic switch in comparison with first-generation antidepressants. Another example is the avoidance of benzodiazepines for the treatment of panic disorder in a patient with a history of alcohol or sedative-hypnotic abuse due to the increased risk of misuse or dependency. In this situation (and in general), selective serotonin reuptake inhibitors (SSRIs) are usually more appropriate.
Assessment of both the psychiatric and physical status is critically important. The presence of intercurrent medical disorders, as well as any medication used to manage them, increases the likelihood of an adverse outcome with an otherwise appropriate psychotropic medication. With a recent history of myocardial infarction, certain tricyclic antidepressants (TCAs) or lowpotency antipsychotics might be contraindicated due to potential adverse effects on cardiac function. Another example is the avoidance of carbamazepine (CBZ) in a bipolar patient with a persistently low white blood cell count. Finally, (β-blockers are typically contraindicated in a patient with asthma.
A related issue is the patient’s ability to metabolize and eliminate drugs adequately. For example, lithium is excreted entirely by the kidneys. If a patient suffers from significantly impaired renal function, high, potentially toxic levels could develop on standard doses. Although the dose could be adjusted to compensate for the decrease in drug clearance, it might be more appropriate to choose another mood stabilizer such as valproate or CBZ because they are primarily metabolized through the liver.
A final consideration is that of economics, which includes the procurement costs and myriad other factors that can increase the overall expense of treatment (see “Cost of Treatment” in Chapter 3).
PRINCIPLE 5
Prior personal (and possibly family) history of a good or a poor response to a specific agent often dictates the first-line choice for a subsequent episode.
Given the development of new drugs with more refined mechanisms of action, patients’ responses to therapeutic interventions increasingly become critical sources of data. Inadequate response or poor tolerability to a previous trial of a specific class of medication (e.g., an SSRI) would suggest the need to try a different pharmacological class (e.g., bupropion). Response (whether improvement or deterioration) also provides insight into the underlying pathophysiology. Therefore, the careful monitoring of outcome can generate information for modifying previously suboptimal therapies. If prior or initial response is inadequate, common issues to consider include
Appropriate diagnosis, including specific subtypes (e.g., delusional depression)
Adequacy of treatment (e.g., sufficient dose, duration, and blood concentration)
Nonadherence
Intercurrent substance or alcohol abuse; medical problems; or the concomitant use of natural remedies, prescription, or over-the-counter medications
Lack of adequate or appropriate social support
The presence of an Axis II diagnosis
PRINCIPLE 6
It is important to target specific symptoms and monitor their presence or absence over an entire course of treatment.
For example, in a bipolar patient, reduction of the amplitude of mood swings may be the focus of acute therapy. During the maintenance phase, however, the most sensitive predictor of an impending relapse might be a decreased need for sleep. Careful attention to the onset of such a symptom might lead to early treatment, preventing a full relapse or recurrence.
It is also important to recognize that certain symptoms may improve before others. In a depressive episode, vegetative symptoms such as sleep and appetite disturbances will often respond early in the course of treatment, whereas mood may take several weeks to improve.
The use of standard assessments (e.g., Beck Depression Inventory [BDI]) may help monitor and more accurately track changes in various symptoms. Cognizant of these different temporal patterns of response, the clinician may be encouraged to continue with a certain approach. Also, educating the patient regarding the differential time course to response for various symptoms may facilitate adherence. Subsequently, during the maintenance/prophylactic phase, the clinician should monitor how effectively a treatment prevents the reemergence of the acute symptoms.
The use of standard assessments (e.g., Beck Depression Inventory [BDI]) may help monitor and more accurately track changes in various symptoms. Cognizant of these different temporal patterns of response, the clinician may be encouraged to continue with a certain approach. Also, educating the patient regarding the differential time course to response for various symptoms may facilitate adherence. Subsequently, during the maintenance/prophylactic phase, the clinician should monitor how effectively a treatment prevents the reemergence of the acute symptoms.
PRINCIPLE 7
It is necessary to observe for the development of adverse effects throughout the entire course of treatment. Such monitoring often involves the use of the laboratory to ensure safety as well as optimal efficacy (12).
It is important to confirm that adverse effects are actually caused by a specific treatment. Because patients in clinical studies often experience a wide range of adverse effects while on placebo, one should not prematurely conclude that such events are due to active medication.
With the development of more specific agents, it is increasingly important to note and report undesirable behavioral effects as well as physical reactions. For example, if a patient becomes excessively passive, there is a chance that the behavior will be missed or attributed to the underlying psychiatric condition when it might be a previously unrecognized effect of a new medication. The identification of previously unknown adverse effects (while undesirable in themselves) can be the basis for the next round of serendipitous discoveries about the underlying pathophysiology of a given disorder.
In this context, the first role of the laboratory is to detect specific adverse effects to target organs (see “Role of the Laboratory” later in this chapter). Monitoring will generally be tailored to a specific therapy because of its known potential for causing certain problems. Examples include periodic blood counts with CBZ or clozapine and thyroid and renal function studies with long-term maintenance lithium.
Another use of the laboratory is therapeutic drug monitoring (TDM) of psychotropics with defined optimal ranges, narrow therapeutic indices, or both. Although TDM is not essential for many psychotropics, it is for others (e.g., lithium, several TCAs, valproate, CBZ). It may also be helpful to optimize the use of certain antipsychotics (e.g., haloperidol, olanzapine, clozapine) (13).
The same dose of many of these drugs produces substantially different concentrations among different patients due to multiple factors (e.g., elimination rates can vary to a clinically significant degree among patients). As a result, some patients will develop subtherapeutic, therapeutic, or toxic concentrations. TDM can provide necessary information on how rapidly a patient eliminates the drug, so the dose can be adjusted to maximize efficacy and safety (see Chapter 2). Alterations in drug concentrations can also be influenced by genetic factors. One example is CYP 2D6 poor metabolizers who cannot adequately convert tamoxifen to its active moiety (endoxifen), thereby compromising this agent’s ability to prevent breast cancer recurrence (14).
Diagnostic Assessment
Diagnosis is critical to understanding a patient’s presenting complaints as well as serving as the basis for developing treatment strategies. For this reason, each treatment section of this textbook is preceded by an introductory discussion of the relevant major psychiatric disorders, including a historical perspective to underscore the evolving nature of our nomenclature and the criteria used to define specific categories. We further refine this organization by incorporating factors that often affect presentation and response to treatment. Such variables include
Phase of the illness being treated (e.g., acute treatment, prevention or attenuation of relapse or recurrence)
Confounding issues such as other psychiatric or medical conditions
Psychosocial stressors, to the extent that they affect symptom presentation and effectiveness of treatment
Our model recognizes that the current understanding of pathophysiology and etiology is advancing but still at a rudimentary stage. Therefore, diagnostic assessment is an ongoing process that must be continuously updated throughout treatment. Such revisions are based on information acquired from the patient during follow-up, including response, partial response,
or lack of response to specific interventions as well as the emergence of new knowledge from subsequent scientific investigations.
or lack of response to specific interventions as well as the emergence of new knowledge from subsequent scientific investigations.
The diagnostic assessment consists of several stages:
A subjective account by the patient and collateral sources of the pertinent information, including personal and family histories
Objective parameters, including the mental status examination
The clinician’s initial impression, culminating in preliminary primary and differential diagnosis
Treatment planning, including further diagnostic workup, first-line treatment strategies, and education of the patient and the family
SUBJECTIVE COMPONENT
This aspect of a psychiatric evaluation incorporates several sources of information, including the individual’s own account, family and friends’ reports, the referral source, and any earlier database (e.g., the chart from a previous hospitalization). Basic identifying information such as age, sex, race, marital status, present family situation, living circumstances, work skills, present work situation, and sources of income is essential. The individual’s communication of the basic problems, or the “chief complaint,” will set the stage for an elucidation of the chronology of precipitating events that culminated in seeking help. Next is an exploration of any prior psychiatric history or treatment, or both, either personally or in other family members; serious past or ongoing medical problems, either personally or in family members; and the use or abuse of medications, illicit drugs, or alcohol.
Screening self-assessments, such as the BDI and Mood Disorders Questionnaire (MDQ), provide important additional information.
OBJECTIVE COMPONENT
Objective data include a thorough physical evaluation (including aneurological examination), supplemented by laboratory data such as routine blood work, urinalysis, chest X-ray, electrocardiogram, and drug screen (see “Role of the Laboratory” later in this chapter). All this information is routinely collected when a person first enters the hospital. On an outpatient basis, however, the clinician may select those tests deemed appropriate at the time.
The mental status examination is the most important aspect of this stage and scrutinizes how an individual is feeling, acting, and thinking at the time of the interview (i.e., a crosssectional vs. longitudinal evaluation). The clinician begins with a basic observation of appearance and motoric behavior, including affect (i.e., overt emotional reactions in terms of intensity, quality, appropriateness, and continuity) and mood (i.e., underlying feeling tone). It is important to note that affect and mood may not always be synonymous, and this discrepancy can complicate the diagnostic assessment.
Thought processes reflect one’s ability to assimilate and communicate ideas in a logical and coherent fashion. Thought content explores the substance of one’s ideation; and typical aberrations such as obsessions, phobias, illusions, delusions, or hallucinations may be elicited. Memory and orientation assessment is critical to the differentiation of a psychiatric versus a nonpsychiatric medical disorder. Memory for immediate, recent, and remote events can be readily tested, as well as orientation to time, place, person, space, and situation. Assuming the level of anxiety is not sufficient to impair responses to questions in these areas, deficits usually imply some impairment of brain functioning, which may (e.g., delirium) or may not (e.g., dementia) be reversible.
Intellectual capacity is considered in the context of an individual’s social, cultural, and educational opportunities. The presentation of problem-solving situations congruent with one’s life circumstances is an excellent way to determine intellect and capacity to make sound judgments. Insight has many levels of meaning. It may simply refer to a basic appreciation of how and why individuals find themselves in their present situation, or it can refer to an appreciation of a more complex set of causal relationships that have culminated in the present problem. Abstractive ability is the capacity to perceive a conceptual commonality in apparently distinct or separate entities. This ability can be tested by the patient’s understanding of proverbs and appreciation of humor.
To summarize, the mental status examination highlights several aspects of functioning. Each succeeding component requires that earlier aspects be intact for adequate reality testing, as
well as the optimal expression of one’s personality, as subjectively perceived and objectively observed in terms of emotions, thoughts, and behavior.
well as the optimal expression of one’s personality, as subjectively perceived and objectively observed in terms of emotions, thoughts, and behavior.
INITIAL IMPRESSION
Having obtained the necessary information from subjective and objective sources, the next step is to develop a preliminary diagnostic assessment, including commentary when possible on the five major axes (Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision [DSMIV-TR] (15)) as well as other differential diagnostic considerations. The diagnostic assessment serves many purposes:
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