Despite the lack of guidance available for practitioners, extensive polypharmacy has become the primary method of treating patients with severe and chronic mood, anxiety, psychotic or behavioral disorders. This ground-breaking new book provides an overview of psychopharmacology knowledge and decision-making strategies, integrating findings from evidence-based trials with real-world clinical presentations. It adopts the approach and mind-set of a clinical investigator and reveals how prescribers can practice 'bespoke psychopharmacology', tailoring care to the individualized needs of patients.
Complex Regimens and Rationale-Based Combination Drug Therapies
Out of intense complexities, intense simplicities emerge.
▢ Understand the three pillars of rational polypharmacy
▢ Recognize the signs of serotonin syndrome and its high- versus low-plausibility risks among various serotonergic agents
▢ Know when to deprescribe ineffective, redundant, or otherwise inappropriate medications and recognize common obstacles to practicing pharmacological hygiene
▢ Recognize medications that have multiple psychotropic properties which can facilitate parsimonious polypharmacy
▢ Beware the potential hazards of overaggressive polypharmacy and dosing
Many patients with complicated psychiatric disorders – which we will define here as conditions involving multiple comorbidities, atypical or protracted symptoms, persistent functional impairment, and poor treatment response – often find themselves taking multidrug therapy regimens. Sometimes, combination therapies reflect wise, thoughtful, and even elegant amalgams crafted with careful deliberation. Such handiwork might capitalize on pharmacodynamic synergies and complementary, nonredundant mechanisms of action, or specific medications may make unique contributions to an overall regimen (such as drugs thought to exert anti-impulsivity, antisuicide, pro-cognitive, or anxiolytic effects). In a well-devised multidrug treatment plan, each component ideally has a well-defined job description and fills a particular role, much the way each player on a sports team covers a unique position, or every instrument in an orchestra makes its own distinct contribution to form a cohesive whole. In that sense, every drug within a psychopharmacology regimen should serve an identifiable and unambiguous function. While patients and clinicians alike sometimes scoff at the sheer number of medications that may be in an extensive treatment regimen, as partners they may neglect to periodically inventory the ensemble drug by drug, reaffirming each component’s relevance, purpose, and performance.
The term “polypharmacy” is sometimes used with a pejorative connotation to mean the use of drugs that are nonessential, duplicative, or ineffective. “Complex combination therapy” is sometimes a preferred designation to connote purposeful multidrug regimens.
We would contrast purposeful polypharmacy with more haphazard assemblages of multiple drugs. Given the frankly modest effect sizes for many psychotropic drugs (see Chapter 3, Box 3.6), clinicians may sometimes feel compelled to “throw everything” they can at significant symptoms in hopes of achieving better outcomes, regardless of whether such approaches are evidence-based.
According to the cross-sectional National Ambulatory Medical Care Survey, prescribing of three or more psychotropic drugs occurs in fully one-third of psychiatric outpatient visits seen in US office-based practice settings (Rojtabai and Olfson, 2010). Observed trends from the mid-1990s to the mid-2000s included within-class duplications (e.g., two or more antidepressants, antipsychotics, or sedative-hypnotics), but not mood stabilizer combinations, and a significant rise in antidepressant–antipsychotic combination therapies. A longitudinal study of nearly 3000 bipolar disorder patients found that 21% took four or more psychotropic drugs, a status found more often among patients with psychosis, trauma histories, or comorbid anxiety of borderline personality disorders (Golden et al., 2017). National survey data of children and adolescents from the mid-1990s to the mid-2000s showed a nearly twofold increase in multiclass psychotropic prescribing, particularly in the coprescription of ADHD medications with antipsychotics, and antipsychotics with antidepressants (Comer et al., 2010).
One in five bipolar patients takes four or more psychotropic drugs.
There has been remarkably little formal study of very extensive polypharmacy regimens, and virtually no published systematic observations on the use of four or more coprescribed psychotropic agents. This deficit in the literature stands in contrast to the established and commonplace use of multidrug regimens elsewhere in medicine, such as for treatment-resistant infectious diseases, malignancies, or hypertension. Industry-sponsored clinical trials will likely never have incentive to demonstrate the value or safety of adding competitors’ drugs to those they manufacture. Nor is there commercial incentive to study complex combinations simply because they reflect community practices. The use of highly complex and extensive drug regimens in routine practice has far outpaced the evidence base and is among the most glaring of real-world unmet needs within psychiatry.
Palliative care patients take an average of 11.5 medications (McNeil et al., 2016); about two-thirds of oncology patients take ≥5 drugs in an antineoplastic regimen (Murphy et al., 2018); in hypertension, monotherapy is effective in only about one-third of cases, making dual or triple pharmacotherapy more common than rare (Frank, 2008).