All patient subpopulations are inherently “special” based on their unique constellations of clinical and demographic features that moderate and mediate treatment outcomes. This chapter will focus on diversity across distinct clinical subpopulations for which moderating or mediating factors do not simply provide information about the likelihood of a favorable drug response, but more specifically identify the need to adjust medication dosages or regimens, or favor certain medications over others based on evidence for safe and effective use in a particular patient group. Chronological age and biological sex assignment rarely in themselves signal the need for dosage adjustments, although associated features (e.g., diminished hepatic or renal function; pregnancy, premenstrual mood disturbances) may bear on a select evidence base for a given subpopulation. Metabolic (e.g., CYP450) enzymes also can vary by race, gender, age, and genetic polymorphisms, as noted in Chapter 8.

If the placebo effect is not the bane of every psychopharmacologist’s existence, it probably should be. Placebo responses largely negate all rules of pharmacodynamics, undermine theories about drug mechanisms of action, ruin clinical trials by causing failed (rather than negative) findings that mask the true potential for otherwise promising compounds, inflate costs for drug research and development, and generally give a black eye to neuroscience-based explanations for psychopathology. They also lend humility to clinicians’ assumptions that psychopharmacology reliably holds the upper hand when dealing with any and all matters of mental illness. In this chapter we will review known clinical features and correlates (if not actual predictors) of placebo responsivity across major psychiatric conditions, and offer guidance about how clinicians can anticipate, recognize and manage placebo effects – rather than ignore, dismiss, or otherwise struggle against them.

We have, we hope, covered a large but not unwieldy swath of territory of practical relevance for the everyday clinician trying to make pharmacological decisions informed by evidence. As illustrated throughout the preceding pages, the availability of empirical data to guide treatment decisions varies greatly within and across disorders. It probably matters more that clinicians know how to think empirically – that is, knowing when, where, and how to look up information pertinent to a given case – rather than try to tackle the impossible task of comprehensively knowing the ever-changing clinical trials database for all disorders. Wisdom equally involves recognizing when evidence is lacking, prompting reliance on opinion, extrapolation, and plausible rationales – but not conflating those guideposts with an empirical database.

It is time now to cull the principles we have tried to illustrate and summarize what we would consider to be basic maxims for practical psychopharmacology.

Psychiatrists probably are not so unusual among health care professionals in their desire to measure things. But compared to practitioners in most other areas of medicine, they may be the newest entrants to the world of the quantitative versus qualitative. Measurement-based care (MBC) and laboratory testing have become increasing focal points of clinical practice. Perhaps this comes in response to decades (if not centuries) of an often impressionistic and sometimes sluggishly qualitative way of recording clinical observations; perhaps it is backlash against a psychoanalytic heritage that for too long eschewed quantitative measures and formal outcome tracking; it also reflects the promulgation of research tools (semi-structured interviews, questionnaires, rating scales) into nonresearch clinical settings; and no doubt, MBC has arisen in response to a health care system that has come to link service reimbursement with quantifiable parameters.

Addictions are, fundamentally, disorders of the reward pathway. Clinicians, patients or family members are sometimes dissatisfied with the pronouncement that an addiction is its own diagnosis, preferring instead to search for additional psychiatric conditions (such as mood or anxiety disorders) from which addiction behaviors might be secondary offshoots – perhaps in part because of the more extensive range of pharmacotherapy options available to treat mood and anxiety disorders than addictions. True dual diagnoses certainly exist, in which mood or thinking problems occur as free-standing entities, but unless they chronologically antecede an addiction it becomes difficult if not impossible to discriminate them from the symptoms caused by repeated intoxication and withdrawal states. Still, intrinsic disorders of the reward pathway can be complex and often inherently involve problems with mood, thinking, perception, impulse control, self-regulation, compulsivity, and a host of psychopathology dimensions described in earlier chapters.

Diagnostic systems such as the DSM have long struggled over whether to organize psychiatric disorders as black-and-white categories defined by operational criteria (where “casehood” is unambiguously either present or absent) versus dimensions of psychopathology (where certain clinical elements are present but insufficient in number or duration to meet minimum criteria that define a particular clinical condition). Clinicians, meanwhile, often tend to identify and treat prominent symptoms, with varying degrees of awareness and concern about their broader context for defining the presence or absence of a distinct syndrome. In this chapter we will examine when pharmacological treatment targets can or should be thought of as unambiguous disease categories as opposed to dimensions of psychopathology that may not always be so clear-cut.

Diagnoses are clusters of signs and symptoms that should form a coherent constellation based on their inter-relationships.

When someone takes a medication for depression, anxiety, or any other psychiatric problem, how do they or the prescriber know for certain if they are actually better or worse? And in either instance, whether to credit (or blame) the drug? If depression gets better 4–6 weeks after taking an antidepressant, how confidently should we attribute improvement to the drug rather than to serendipity? What if the patient gets better only after 14–16 weeks – is that too far in time to distinguish a plausible drug effect from spontaneous remission? Or, when can we assume the outcome was still a likely drug effect, given that an adequate trial may take longer in some people than others? If they felt better in just a few days, is that evidence of a placebo effect?

Trauma and dissociation are together often thought of as falling more within the treatment realm of cognitive-behavioral psychotherapy than psychopharmacology. Indeed, in the case of PTSD, trauma-focused psychotherapies collectively exert larger effect sizes than seen with pharmacotherapies (Watts et al., 2013; Lee et al., 2016), which in the aggregate yield response rates only of about 20–30%. Yet, in order to understand the potential relevance of pharmacotherapy to psychological trauma, one must first appreciate the interplay between trauma’s psychological and neurobiological corollaries. Traumatic events form durable, emotionally based memories consolidated through limbic circuitry – in turn affecting emotional regulation and broad cognitive domains (attentional processing and vigilance, executive function, and impulse control). Environmental cues that become associated with threats to one’s physical and/or emotional well-being become aversive and can elicit fear responses, involving autonomic hyperarousal and vigilance, and can prompt intrusive, repetitive thought patterns laced with negative affect states.

“Necessary clinical adjustments,” as noted in Chapter 1, come with the pharmacological territory for most patients with complex psychiatric disorders – partly because symptoms often can be protean and nonstatic, partly because illness severity can wax and wane, partly because of the impact of cotherapies, and partly from other factors such as pharmacokinetic interactions, treatment nonadherence, loss of efficacy, or other events in the natural evolution of illness. The mechanics and logistics of changing from one pharmacotherapy to another, or deciding when and how to deprescribe an ineffective or otherwise unhelpful medication, are seldom discussed in textbooks or practice guidelines. From an evidence-based perspective, there are few controlled trials designed to compare tolerability and outcomes across various methods and timeframes for stopping and starting or cross-tapering one drug in exchange for another.

No psychotropic drug has ever been developed specifically to treat any personality disorder, and the extent to which personality in all its developmental and biopsychosocial complexity even lends itself to the “disease” model – for which pharmacotherapy can be “reparative” – remains an open and debated issue. Personality represents the confluence of temperament, genetic predispositions, cohesion of identity, moral compass, interpersonal responsivity, and coping patterns that are shaped and developed over the course of early life experiences. Personality traits often reflect the interpersonally driven behavioral characteristics described in earlier chapters such as introversion/extroversion, internalizing/externalizing, aggression, harm avoidance/novelty-seeking, empathy and social cognition, antisocial behavior and interpersonal exploitativeness, and the use of developmentally primitive versus mature defense mechanisms. To the extent that personality traits may be maladaptive (e.g., impairing interpersonal effectiveness, leading to self-sabotage or self-harm) and are ego-dystonic, they represent targets for modification and change.

We hope that things have changed for the better since the time of Sir Francis Bacon’s seventeenth-century appraisal of medical treatment risks and benefits. Drugs themselves may not know the differences between the beneficial versus adverse effects they may exert, but prescribers should. All substances, even placebos, can cause negative effects in the minds and bodies of those who consume them, depending on expectations (e.g., past experiences, perceptions of help versus harm), underlying psychopathology (e.g., anxiety, somatization, paranoia), psychological dimensions (e.g., an external locus of control, suggestibility) as well as pharmacokinetics (e.g., delayed metabolic clearance) and, last but not least, pharmacodynamics.

Ostensibly innocuous, yet deceptively so, like Monty Python’s fabled Killer Rabbit of Caerbannog (but with no Holy Hand Grenade of Antioch to lob as a countermeasure), anxiety often stands underappreciated for its pernicious and often devastating ill effects. Less profound and baffling than the perceptual and ideational anomalies of psychosis, less emotionally wrenching or blatantly lethal than suicidal melancholy, and less relentlessly haunting than the psychic sequelae of trauma, anxiety may be the prime example of a normal human emotion gone awry. While “normal” anxiety cues vigilance to environmental threats, demands, and rewards, aberrant anxiety paralyzes cognitive function, over-rides judgment, subverts harm appraisal, drives impulsive action, and generally worsens the prognosis and treatment responsiveness of any coexisting psychiatric problem. It is also easily mistaken for other forms of psychopathology that involve autonomic hyperarousal and psychomotor activation, potentially driving wrong pharmacotherapy decisions.