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 neurotic has problems. The psychotic has solutions.
▢ Understand the relationship between specific dopamine tracts and positive or negative symptoms in patients with psychosis, and their “higher” regulation by cortical glutamatergic circuitry
▢ Understand the interplay between 5HT2A and DA circuitry relevant to the pharmacotherapy of psychosis
▢ Discuss the potential utility of antipsychotic medications for cognitive rigidity, impaired set-shifting, and related components of executive dysfunction
▢ Describe the evidence base, and possible risks versus benefits, for using high-dose antipsychotic drugs
▢ Understand the use and logistics of short- and long-acting IM injectable antipsychotics
▢ Identify evidence-based augmentation strategies for antipsychotics and the database to inform pros and cons of combining multiple antipsychotic drugs
▢ Describe challenges in the pharmacotherapy of cognitive dysfunction in schizophrenia
▢ Identify issues and controversies regarding the safety, efficacy, and necessity of long-term pharmacotherapy with antipsychotic medications
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.
Taking a mainly neurocognitive approach to understanding these collective treatment goals, let us jump in by expanding on Figure 14.1, the “top-down/bottom-up” view of cognition described in the preceding chapter. If prefrontal/executive and limbic/emotional structures strive to maintain balance and homeostasis between “cold” and “hot” cognition, respectively (i.e., a functioning corticolimbic loop), we can envision this circuitry gone further awry when it frankly distorts perception and reality testing.
We all suspend reality testing, at least momentarily, when first viewing an optical illusion, or when bamboozled by a magic trick whose effect contradicts our internalized rules of physical reality. Something eventually jogs our internal capacity to realign our subjective perception with objective external reality, and then we usually are bemused (unless we are unable to find that internal affirmation). When we doubt our perceptions or our brains misperceive ideas or sensations we usually rely on others as a cross-check (“Did you hear that?” “Do you smell something burning?”). “Gaslighting” occurs when someone we trust as an external validator of our internal perception of reality deliberately (and usually malevolently) contradicts our internal experience of objective reality. At that point, the idealized equilibrium between “hot” and “cold” cognition becomes shaky and one or the other system tends to take charge.
“Cold” cognition allows logical reasoning to prevail by allowing us to vet evidence that can support or refute a hypothesis. This largely forms the basis of cognitive therapy. (“It’s certainly possible you didn’t get the job because they were biased against you, but are there other possible explanations?”) The same process comes into play when reality-testing frankly psychotic phenomena (“Is there a reason why the television would be talking about you?”). Or, for that matter, judging pharmacological cause-and-effect (see Chapter 1) – as when, say, deciding whether a physical sensation is a likely adverse drug effect. (“It’s certainly possible that acetaminophen could worsen a fever, but consider the perhaps more likely explanation that it may simply be ineffective against the ailment causing it.”)
“Gaslight” was a 1938 play and later film in which sinister Charles Boyer diabolically tried to drive his on-screen wife Ingrid Bergman insane by invalidating and undermining the reality of her day-to-day perceptions and experiences – all in an effort to gain legal control over her finances. So much for routinely assuming benevolent intentions on the part of family members as collateral historians.
By contrast, “hot” cognition hijacks the process by over-riding logic and plausibility. A threat to someone’s basic welfare and sense of fundamental well-being unavoidably engages hot cognitive circuitry, if only for evolutionary reasons and the sake of preserving both the self and the species. Whether through autonomic hyperarousal (activating the limbic fight-or-flight response, and a self-protective harm-avoidant stance) or simply through bottom-up emotional overdrive of a prefrontal executive process (loudly shouting “Stop! Thief!” in a crowd, or “Fire!” in a movie theater, typically bypasses “cold” cognitive deliberation), factual accuracy gives way to urgency when survival stakes are sufficiently high. This is evolutionarily adaptive; there is not enough time to thoroughly gauge the validity of a possible threat and still maintain survival of the species.
Fight-or-flight “hot” cognition is thought to derive from hyperdopaminergic activation of mesolimbic circuitry. In particular, the amygdala and hippocampus together are thought to play a key role in detecting novelty in the environment and forming memories with high emotional valence (Blackford et al., 2010). Overactivity of this circuitry, depicted in Figure 15.1 as an expanded view from Figure 14.1 in Chapter 14, can drive autonomic hyperarousal and be a proximal contributor to agitation, psychosis, mania, and related states of hypervigilance.
Paul Broca coined the term le grand lobe limbique (“limbus” meaning “border,” denoting the curved rim of the cortex). Its exact structural subcomponents have been debated over time. Its role in emotional processing was described by James Papez (sometimes called “the Papez circuit”).
Pharmacotherapies that aim mainly to reduce anxiety and agitation, such as sedative-hypnotics (e.g., benzodiazepines), might literally dampen down the autonomic output from hyperactive mesolimbic activity, but that may not be synonymous with reducing the sense of perceived threat. Box 15.1 addresses the distinction between “fear” and “anxiety” with regards to presumed underlying neural circuitry and pharmacotherapy.
Some authorities point out that fear (a primal, visceral response to immediate threat) operates on limbic dopaminergic circuitry, while anxiety (a less immediate state of threat to fundamental safety and well-being, and in some ways an overdeliberative process of weighing risks and implications) may reflect more serotonergic circuitry. Dopamine modulation may be more immediately relevant to fear circuitry than is the case for “just” anxiety and worry. DSM-5 also describes fear as “the emotional response to real or perceived imminent threat” while anxiety is “anticipation of future threat.” Fear is considered a basic, discrete cognitive reaction that involves visual processing, whereas worry tends to be a more complex cognitive phenomenon based on learned experiences and more verbal than visual processing.
Antipsychotic drugs may be particularly useful when antifear rather than antianxiety circuitry has gone awry. Pure D2 antagonists may offer a more direct method than benzodiazepines to down-regulate high dopamine tone emanating from hot cognitive circuitry, but pose the risk of also down-regulating other dopaminergic tracts that can sustain collateral damage (i.e., tuberoinfundibular or nigrostriatal) or may in themselves be hypotonic and in need of up-regulation (e.g., mesocortical DA circuitry in the setting of negative symptoms). D2/D3 partial agonists (i.e., aripiprazole, cariprazine, and brexpiprazole) represent a refinement over traditional pure D2 antagonists by functioning more as a rheostat that modulates dopaminergic tone based on ambient DA functional activity. The theory of DA partial agonism posits that D2/D3 partial agonists would selectively increase dopaminergic tone where is it low (i.e., mesocortical pathways) and decrease it where it is too high (i.e., mesolimbic pathways). Put another way, imagine administering a tight D2 antagonist (say, haloperidol) with a D2 full agonist (say, methylphenidate) and hoping that the D2 blocker will somehow show regional selectivity by binding to hyperactive mesolimbic brain circuitry (and not impede arousal and attention by blocking mesocortical DA tracts) while at the same time, hoping the DA agonist (methylphenidate) will selectively agonize mesocortical but not mesolimbic circuits. Partial agonism regulates this balance based on regionally ambient DA tone.
Figure 15.2 depicts the four main dopaminergic tracts in the brain: mesocortical and mesolimbic circuits, respectively, regulate attentional processing/executive function and emotional processing. Dopamine-blocking drugs can cause collateral damage to the tuberoinfundibular (prolactin-regulating) and nigrostriatal (extrapyramidal-regulating) tracts inasmuch as: (a) DA released from the hypothalamus tonically inhibits prolactin release from the anterior pituitary (hence, DA blockers often cause hyperprolactinemia) and (b) DA projections from the substantia nigra to the extrapyramidal system tonically inhibit the release of acetylcholine; pharmacological blockade of nigrostriatal DA projections mimics parkinsonism by allowing release of excess extrapyramidal acetylcholine (which we then treat rather crudely with anticholinergic drugs – which in turn pose problems of their own for arousal and attentional processing). D2 antagonists that (desirably) suppress mesolimbic DA hyperactivity in mania or psychosis unfortunately also (undesirably) suppress mesocortical DA activity, which in turn may exacerbate negative symptoms or otherwise lead to diminished arousal and attention, avolition, and apathy.
Recall from Chapter 1 Table 1.2 the varied functions of D1, D2, and D3 receptor subtypes in the CNS. While all traditional antipsychotics (cf., pimavanserin) antagonize mesolimbic D2 receptors, there is increasing interest in the role of D3 receptors (involved in reward-based behavior) and D1 receptor antagonism (relevant to antipsychotic and possible antidepressant effects). As an example of the latter, consider the novel antipsychotic drugs amisulpride and sulpiride (neither available orally in the USA), known for their potential value in depression at low doses (e.g., amisulpiride or sulpiride 50–300 mg/day), putatively attributed to blockade of presynaptic D2/D3 autoreceptors, in turn increasing dopamine release with increased postsynaptic binding at D1 receptors that richly populate the striatum. Higher doses (e.g., amisulpride 400–1200 mg/day; sulpiride 600–1600 mg/day) are associated with postsynaptic D2/D3 antagonism in limbic regions, and presumably consequent antipsychotic efficacy. Amisulpride has a tighter D2 receptor binding affinity (Ki ~ 3.0 nM) than does sulpiride (Ki ~ 9.8 nM).
One oft-cited definition of “atypicality” of antipsychotics involves a molecule exerting a 5HT2A:D2 receptor binding ratio >1 (Meltzer et al., 1989). 5HT2A receptors have a reciprocal relationship with DA binding in that antagonizing 5HT2A receptors increases DA release while 5HT2A agonism decreases DA release. You might ask, what’s so good about an antipsychotic increasing DA release? The answer lies in location. 5HT2A receptors are densely distributed in the PFC, where increased DA tone is a desirable phenomenon with respect to attentional processing. and perhaps the treatment of negative symptoms. (There is also substantial 5HT2A density in the nigrostriatal pathway. 5HT2A blockade there can reduce D2 antagonism in the dorsal striatum (caudate and putamen), effectively reducing, at least to some degree, the adverse iatrogenic motor effects caused by D2 antagonists.)
PET imaging studies reveal at least some degree of postsynaptic 5HT2A binding with some FGAs, including loxapine (Kapur et al., 1997a) and chlorpromazine (Trichard et al., 1998). The perphenazine metabolite N-dealkylperphenazine also has high 5HT2A binding affinity (Sweet et al., 2000). 5HT2A:D2 binding ratios of these FGAs do not exceed 1, technically making these antipsychotics (whose 5HT2A occupancy is <80%) novel but not “atypical.”
Another theory about atypicality arose when Kapur and Seeman (2001) proposed a hypothesis about the MOA of SGAs that became known as the “fast-on/fast-off” hypothesis. Briefly, it espoused that “atypicality” of an antipsychotic depended mainly on how rapidly a drug dissociated from the D2 receptor after initially binding to it. These authors suggested that 5HT2A blockade was less relevant (if at all relevant) to antipsychotic response than D2 binding and dissociation. Later work then challenged this hypothesis by suggesting that drug accumulation in the lipophilic environment of the cell interior may underestimate the speed of dissociation from the D2 receptor, showing wider variation in dissociation (Sahlholm et al., 2016).
The above notwithstanding, a key point of clinical relevance is the prospect that postsynaptic 5HT2A antagonism could directly produce an antipsychotic effect. This is the basis for the antipsychotic efficacy of pimavanserin, presently FDA-approved only for the treatment of psychosis in patients with Parkinson’s disease. Recall also from Chapter 13 Box 13.4 that the 5HT2A binding properties of pimavanserin make it a compelling candidate treatment not only for psychosis but also for depression – at least, based on its mechanistic rationale and initial proof-of-concept data. Similarly, the MOA of lumateperone – involving an approximate 60-fold greater binding affinity at 5HT2A than D2 receptors – should pique the interest of any psychopharmacologist wishing to minimize regionally undesired dopalytic effects (say, in the basal ganglia) when treating psychosis, and possible mood disorders as well.
Yet another consideration regarding antipsychotic pharmacodynamics involves nondopaminergic mechanisms altogether. The investigational drug SEP-363856 has no binding affinity at D2 (or any other DA) receptor but is instead believed to exert a possible antipsychotic effect (and spare dopaminergic motor tracts altogether) via agonizing the trace amine-associated receptor 1 (TAAR1), as well as 5HT1A receptors. The compound received FDA breakthrough status in 2019 and remains under study.