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.
The chief function of the body is to carry the brain around.
▢ Recognize and differentiate the major cognitive domains of attention, memory, and executive function; appreciate how deficits in one or more of these areas can manifest across a range of psychiatric disorders
▢ Understand basic methods for objectively evaluating subjective cognitive complaints
▢ Recognize the relative impact of antidepressants, antipsychotics, and anticonvulsants on cognitive functioning
▢ Describe the relative effect of agents studied in RCTs to treat adult ADHD
▢ Describe management strategies for pharmacological tolerance to stimulants in adult ADHD
▢ Describe the evidence base to support the use of currently available pharmacotherapies targeting major cognitive impairment, including pro-cholinergics and NMDA receptor modulators
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).
Let us begin with some practical definitions regarding key components of cognition, as reviewed in Table 21.1 at the end of this chapter. Hierarchical models of cognitive functioning in general are often described as a pyramid (depicted in Figure 21.1) in which arousal and attention stand as prerequisite functions for target detection, comprehension, and sustained attention (vigilance); attention also depends on processing speed. Learning and memory are subservient to attentional processes, and all of these functions must precede planning, organizing, and logical reasoning.
|Cognitive domain||Practical definition||Bedside tests|
|Processing speed||The time it takes to perform a mental task and process information||Trail-making, digit symbol substitution (DSST)|
|Attention||The ability to concentrate on a discrete stimulus and ignore other perceivable stimuli; often divided into selective attention (focusing on one stimulus from among several), divided attention (processing responses to two or more stimuli), sustained attention (focusing on one stimulus for an extended period of time), and executive attention (e.g., choosing from among varied responses in a conflict situation)||Digit span; continuous performance tasks (e.g., detecting a specific letter or number when presented with a series); trail-making (captures visual attention and task-switching)|
|Working memory||A component of short-term memory that involves temporarily holding multiple pieces of information in mind at the same time. Examples would include keeping score while rolling the dice during a board game, or remembering a shopping list while scanning for items when walking down a supermarket aisle||Memory span (e.g., reciting up to seven random numbers forward and backward)|
|Verbal fluency||Measures vocabulary size, lexical access speed, and inhibition ability; abnormalities may be relevant to numerous brain disorders, including dementia, schizophrenia, traumatic brain injury, Parkinson’s disease, and developmental disorders, among others||Controlled oral word association tests (COWATs) are timed tests of category (semantic) fluency (e.g., “name as many animals as you can that are found in a zoo”), or letter (phonemic) fluency (“name as many things as you can that begin with the letter “f”)|
|Social cognition||A psychological function involving people’s capacity to encode, store, retrieve, and process information related to social interactions (e.g., emotion recognition, understanding etiquette, gestures, and inferences); may be impaired in schizophrenia, autism, and traumatic brain injury, among other disorders||Facial-affect recognition tasks, other normed tests of social inference (e.g., the Penn Emotional Acuity Test)|
|Disorder||Processing speed||Attention||Working memory||Verbal learning||Visual learning||Reasoning and problem-solving||Social cognition|
|Bipolar disorder||+/– Impaired||Impaired||Moderately impaired||Impaired||Intact||Intact||+/– Impaired|
|Major depressive disorder||Impaired||Impaired||Intact||+/– Impaired a||+/– Impaired||+/– Impaired b||+/– Impaired c|
a May be linked with slow processing speed (Zaremba et al., 2019)
b May be linked with slow processing speed (Mohn and Rund, 2016)
c May be linked with poor cognitive flexibility (Förster et al., 2018)
The concept of executive function involves higher-level processing and manipulation of complex information. Its elements are described in more detail in Box 21.1.
The term “executive function” broadly encompasses an array of “top-down” higher cognitive processes that includes attentional control, planning and logical reasoning, decision-making, impulse control and cognitive inhibition, working memory, verbal fluency, organizational skills, and cognitive flexibility/set-shifting. It is fundamental to problem-solving, creativity, self-regulation, and coping and resilience. Cognitive neuroscientists often conceptualize executive function as involving three core components: inhibition and interference control, working memory, and cognitive flexibility. As discussed in Chapter 1, the DLPFC is the primary seat of executive functioning which, along with the VMPFC (the prefrontal seat of emotional processing), is balanced by “bottom-up” or “hot” cognitive functions driven by limbic and paralimbic structures.
Memory involves the encoding and retrieval of information; it entails short- and long-term components, verbal and nonverbal elements, and emotional and nonemotional content. Like attention, it may be influenced by numerous psychiatric (e.g., anxiety/fear, distress, depression) and somatic (e.g., pain, fatigue, hunger) factors. Long-term memory is traditionally subdivided into the domains summarized in Figure 21.1.
For initial bedside assessments, the Montreal Cognitive Assessment (MoCA) is a quick (10–12 minute), easily administered brief neuropsychological performance test developed for assessment of dementia and mild cognitive impairment, capturing orientation, short-term/delayed recall, executive functioning/visuospatial processing, language, abstraction, and verbal fluency (Nasreddine et al., 2005). Scored from 0 to 30, scores >26 are considered normal; mild cognitive impairment subjects during field-testing had a mean score of 22.1, while those with Alzheimer’s dementia had a mean score of 16.2. The Screen for Cognitive Impairment for Psychiatry (SCIP) is another relatively brief (approximately 15 minute) tool to assess working memory, immediate and delayed verbal recall, verbal fluency, and psychomotor speed (Purdon et al., 2005). The Folstein Mini-Mental Status Exam (MMSE) is a commonly used tool that is better-suited to capturing gross cognitive deficits (as in dementia) but is nonstandardized, poorly captures mild cognitive impairment, may overestimate cognitive deficits in older adults without dementia, and may be influenced by education and IQ (Naugle et al., 1989). Formal neuropsychological testing may be useful to follow up abnormalities on initial screens or to tease out more complex diagnostic issues.
Even within a given psychiatric disorder, cognitive variations may be evident that define clinical subgroups. For example, in bipolar disorder, some subgroups can demonstrate social cognition that is superior to healthy controls, while other groups may show select deficits in processing speed, attention, verbal learning and social cognition, while still others manifest global cognitive impairment nearly as profound and extensive as seen in schizophrenia (Burdick et al., 2014). In major depression, only about one-fifth of patients manifest global impairment across most cognitive domains (Mohn and Rund, 2016). Table 21.2 at the end of this chapter provides a comparison of impairment across cognitive domains in schizophrenia and affective disorders.
Hierarchical models of cognitive functioning in general are often described as a pyramid (depicted in Figure 21.2) in which arousal and attention stand as prerequisite functions for target detection, comprehension, and sustained attention (vigilance); attention also depends on processing speed. Learning and memory are subservient to attentional processes, and all of these functions must precede planning, organizing, and logical reasoning.
In the parlance of cognitive neuroscience, general cognitive ability, often termed “g” or “g factor” broadly connotes general mental ability and is thought to account for about 40–50% of interindividual variability across diverse cognitive tasks that are thought to be inter-related. For clinicians, there are a number of implications for accurately defining cognitive domains:
Patients who complain of problems in a particular domain (such as “memory” or “attention”) may be identifying an altogether different kind of problem than they are perceiving (such as, performance anxiety or problems with set-shifting)
Patients with cognitive complaints such as executive dysfunction may seek treatment for “ADD” when in fact medications that can improve attentional processing may not necessarily help deficits in executive function, memory or other domains subservient to attention
Studies that assess “cognitive effects” of psychotropic drugs (either beneficial or adverse) may actually assess only narrow cognitive functions (such as processing speed) or broad constructs (such as “g”) without using validated measures. The digit symbol substitution test (DSST), a subcomponent of the Wechsler Adult Intelligence Scale, is among the more widely used measures of overall cognitive functioning inasmuch as it taps attention, processing speed, visuospatial motor skills, and correlates with everyday functional capabilities. For better or worse, it is considered more sensitive than specific in its ability to discern deficits in specific cognitive domains.
Self-reported cognitive function also may not reliably capture true functioning as accurately as can performance-based tasks (which may be more time-consuming or require more resources as a secondary outcome measure in a clinical trial than may be feasible). In other words, just because a patient reports that they are having subjective problems with attention or memory does not necessarily mean that they are having objective cognitive deficits.