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.

Younger readers may not appreciate that prior to DSM-IV, the phenomena that we today call “mood disorders” were identified more precisely as affective disorders, denoting a fundamental distinction between disturbances of mood (the subjective experience of emotion) and affect (the objective behavioral expression of mood). Given that problems with “mood” are ubiquitous throughout virtually all aspects of psychopathology, links between the signs and symptoms of “mood problems” are critical both to nosological classification and to identifying targets of pharmacotherapy interventions. Features associated with affective disorders encompass problems with energy, the sleep–wake cycle, thinking and perception, impulse control, cognition (e.g., attentional processing, problem-solving), motivation/arousal, and eating behaviors, among others.

In this chapter, we present information about the treatment of mood/affective disorders as a broad overarching category, with subdistinctions (such as polarity) highlighted as clinical descriptors, rather than as fundamentally different illnesses. This may trouble some readers. Yet, one could slice the affective pie innumerable ways.

Swiss psychiatrist Eugen Bleuler, who coined the term schizophrenia, identified affect, association, ambivalence and autism as the so-called “Four As” of negative symptom schizophrenia. Latter-day observers have sometimes added alogia, anergia, anhedonia, and apathy/amotivation to the original list.

Negative symptoms, as classically associated with schizophrenia, refer to the absence of normal function (hence, they are “deficit” states), as contrasted with positive symptoms (that is, the excess presentations of otherwise normal brain functions). In that sense, negative symptoms also differ fundamentally from depression insofar as the latter represents a kind of positive symptom, one characterized by the “feelingful” presence of emotions (anguish, despair) – quite different from the emotional vacancy of flat (rather than sad) affect. The schizophrenia literature often refers explicitly to “the deficit syndrome.”

When investigators report the findings from a clinical trial, the results require interpretation. Peer review is the process through which the structure and execution of a clinical study is judged to be coherent, linear, and logical. The procedure is not unlike conducting a mental status exam: the evaluator is trying to discern if the content is credible at face value, if any underlying factors that could be biasing the results are accounted for, if the observed phenomena are being interpreted accurately, and if the conclusions drawn are valid. With varying degrees of provisionality or certainty, clinical trials give information about the narrow impact of (usually) one intervention versus a comparator (a placebo; an active comparator; or treatment as usual (TAU)) for a circumscribed period of time, with efforts made to hold other relevant variables constant (so, no other treatments are begun or altered, adherence must be near-perfect, substance use is grounds for ejection, and major life disruptions could botch the findings).

Psychiatrist Thomas Szasz’s appraisal of the fundamental nature of psychosis underscores the magnitude of belief-conviction and cognitive rigidity with which false fixed beliefs and perceptions are espoused. Goals of pharmacological treatment for psychosis can target a number of domains: medications may loosen cognitive rigidity and dampen the intensity of false beliefs and perceptions (without necessarily rendering perceptions as conforming more accurately to objective reality); they may reduce the level of distress or agitation associated with psychosis (again without necessarily altering the inaccuracy that somehow sustains fixed false ideas and perceptions); they may improve social judgment (such that someone may acquire sufficient awareness, if not true insight, to recognize where and with whom psychotic phenomena should and should not be discussed); they may impose order on the form of thinking to allow a more linear (if not logical) process by which they reach conclusions; or, sometimes, medications may actually alter misperceptions and allow for greater concordance between external reality and one’s internal perception of it.

In this chapter we will focus on dimensional constructs of impulsive versus compulsive behaviors and their interface with aggression in relation to pharmacotherapy. Like so many other psychopathological states, impulsivity and compulsivity are not pathognomonic of any particular categorical diagnostic entity and may fit within the broader constellation of numerous conditions that affect mood, development, personality, addiction, cognition, and perception. Particular issues arise when considering trait versus state features of psychopathology and environmental factors that may exacerbate or otherwise contribute to an underlying diathesis.

We will begin with some definitions, followed by a quick review of pertinent neural circuitry that bears on relevant psychopathology and psychopharmacology (Box 14.1).

The relationship between food products and pharmacodynamically active agents traces at least to antiquity, even if Hippocrates never actually did say “let food be thy medicine and medicine be thy food” (Cardenas, 2013). In modern times the relationship between dietary supplements and medicine has come to pose a rather peculiar dichotomy between what might be called “legitimate” or “mainstream” medicine and nonstandard or “alternative” medicine. Interventions in the latter category suffer from issues of credibility due to an often less rigorous RCT database, at times poorly established rationales and/or mechanisms of action, and lack of regulatory agency product oversight for quality assurance purposes. Many patients obtain information about herbal products or dietary supplements simply from internet searches with little awareness of the scientific rigor or credibility behind advertising claims or consumer postings and testimonials, or cognizance of potential pharmacokinetic interactions.

In Chapter 5, we discussed the growing concept of precision medicine and its forerunner term, “personalized medicine,” as the initiative to craft individually tailored treatments. For psychiatry, precision medicine represents the goal of utilizing a given patient’s unique clinical and biological profile in order to broker the best fit with a particular drug regimen. That theme is woven throughout this book, as the means by which clinicians must interpret large-scale clinical trials and decide whether and how their findings apply to an individual case. In the minds of many psychopharmacologists, pharmacogenetics and pharmacogenomics represent a key component, if not the key component, of that endeavor, based on assumptions that everyone’s unique genetic architecture must figure critically in how they will respond to a drug – and that without such information, efforts toward devising an appropriate pharmacotherapy regimen are merely trial and error.

Attentional problems are among the most ubiquitous and nonpathognomonic of psychiatric complaints. Nearly all psychiatric disorders impact cognitive functioning in one form or another, and it can be a challenge for clinicians to differentiate free-standing disorders of cognition (e.g., adult ADHD or dementia) from those that are iatrogenic (due to psychotropic or nonpsychotropic medications) or the epiphenomena of other conditions (such as depression, mania, anxiety, or schizophrenia). Cognitive problems involve distinct domains that can form unique constellations and present differently from one psychiatric disorder to another (e.g., skip ahead to Table 21.2). Sometimes they may be just one facet of a more complex, heterogeneous phenotype. Consequently, pharmacotherapies for cognitive problems in one disorder (say, dementia) may not so neatly extrapolate to those of another (say, ADHD). Cognitive problems may be profound and all-encompassing (as in dementia, some developmental disorders, or schizophrenia), artifactual (as in depression-related cognitive dysfunction (formerly called pseudodementia)), or subtle (as might occur in anxiety disorders or high-functioning patients with mood disorders).

Previous chapters have described ways in which “real-world” patients usually present with a diversity of psychiatric, medical, psychosocial, and other features that make a “one-size-fits-all” approach to treatment problematic. Large-scale randomized trials typically favor diagnostic uniformity so that all enrolled subjects more or less display the same kinds of symptoms under study. Consequently, the controlled trials literature that informs evidence-based practice largely comes from rarified, homogeneous study groups with rigidly defined diagnostic criteria. As a result, such studies trade off optimal outcomes (“efficacy”) for generalizability (“effectiveness”) under more ordinary conditions. This is why so-called “effectiveness” studies such as the Clinical Antipsychotics Treatment Intervention Effectiveness trial (CATIE; see Chapter 15) strive to enroll representative patients with comorbidities, imperfect treatment adherence, and issues with drug tolerability, adopting “bottom line” primary outcome measures such as “all-cause dropout.” No matter how well a treatment can work, the pragmatic concern remains how well it actually does work in real-life settings.