Long established as the preeminent source in its field, the eagerly anticipated fifth edition of Dr Stahl's essential textbook of psychopharmacology is here! With its use of icons and figures that form Dr Stahl's unique 'visual language', the book is the single most readable source of information on disease and drug mechanisms for all students and mental health professionals seeking to understand and utilize current therapeutics, and to anticipate the future for novel medications. Every aspect of the book has been updated, with the clarity of explanation that only Dr Stahl can bring.
Targeting Dopamine and Serotonin Receptors for Psychosis, Mood, and Beyond: So-Called “Antipsychotics”
This chapter explores drugs that target dopamine receptors, serotonin receptors, or both, for the treatment of psychosis, mania, and depression. It also explores myriad additional neurotransmitter receptors that these agents engage. The drugs covered in this chapter have classically been called “antipsychotics,” but this terminology is now considered out of date and confusing since these same agents are used even more frequently for mood disorders than for psychosis, yet are not classified as “antidepressants.” As mentioned earlier, throughout this textbook we strive to utilize modern neuroscience-based nomenclature, where drugs are named for their pharmacological mechanism of action and not for their clinical indication. Thus, drugs discussed in this chapter have “antipsychotic action” but are not called “antipsychotics”; they also have “antidepressant action” but are not called “antidepressants.” Instead, this chapter reviews one of the most extensively prescribed classes of psychotropic agents in psychiatry today, namely, those that target dopamine and serotonin receptors, and that began as drugs for psychosis, and later extended their use even more frequently as drugs for mania, bipolar depression, and treatment-resistant unipolar depression. On the horizon is the use of at least some of these agents in PTSD (posttraumatic stress disorder), agitation in dementia, and beyond. We discuss how the pharmacological properties of these agents form not only a single large class of many agents, but in many ways, how each individual agent has binding properties that render every agent unique from all the others. The reader is referred to standard reference manuals and textbooks for practical prescribing information because this chapter on drugs for psychosis and mood emphasizes basic pharmacological concepts of mechanism of action and not practical issues such as how to prescribe these drugs (for that information, see, for example, Stahl’s Essential Psychopharmacology: the Prescriber’s Guide, which is a companion to this textbook).
The pharmacological concepts developed here should help the reader understand the rationale for how to use each of the different agents, based first and foremost upon their interactions with the dopamine and serotonin receptor systems, and secondarily with other neurotransmitter systems. Such interactions can often explain both the therapeutic actions and the side effects of the various drugs in this group. Understanding the full range of receptor interactions for each individual drug also sets the stage for differentiating one drug from another, and thus for tailoring the selection of a drug treatment by matching the pharmacological mechanisms of a specific drug to the therapeutic and tolerability needs of an individual patient.
How do the drugs approved for treating psychosis, especially in schizophrenia, work? The earliest effective treatments for schizophrenia and other psychotic illnesses arose from serendipitous clinical observations approximately 70 years ago, rather than from scientific knowledge of the neurobiological basis of psychosis, or of the mechanism of action of effective drugs that empirically treated psychosis. Thus, the first truly effective drugs for psychosis other than sedating tranquilizers were discovered by accident in the 1950s when a drug with antihistamine properties (chlorpromazine) was observed to improve psychosis when this putative antihistamine was tested in schizophrenia patients. Chlorpromazine indeed has antihistaminic activity, but its therapeutic actions in schizophrenia are not mediated by this property. Once chlorpromazine was observed to be an effective drug for treating psychosis out of proportion to its ability to cause sedation, it was tested experimentally to uncover its mechanism of antipsychotic action, which was identified as dopamine D2 receptor antagonism (Figures 5-1 and 5-2).
Early in the testing process, chlorpromazine and other drugs for psychosis of this era were all found to cause “neurolepsis,” known as an extreme form of slowness or absence of motor movements as well as behavioral indifference in experimental animals. The original drugs for psychosis in fact were first discovered largely by their ability to produce this effect in experimental animals, and thus sometimes drugs with antipsychotic properties are called “neuroleptics.” A human counterpart of neurolepsis is also caused by these drugs and is characterized by psychomotor slowing, emotional quieting, and affective indifference, sometimes also called “secondary” negative symptoms because they mimic the primary negative symptoms associated with the untreated illness itself (see Figures 4-56 through 4-59 and Tables 4-4 and 4-5). We know today that neurolepsis and secondary negative symptoms are likely caused at least in part by blocking D2 receptors that normally mediate motivation and reward (Figure 5-2B) as an undesired “cost of doing business” in order to simultaneously block D2 receptors that are thought to mediate the positive symptoms of psychosis due to excessive release of dopamine (see Figure 5-2A).
By the 1970s it was widely recognized that the key pharmacological property of all “neuroleptics” with antipsychotic properties was their ability to block D2 receptors (Figure 5-1 and Figure 5-2B), specifically those in the mesolimbic/mesostriatal dopamine pathway (Figure 5-2B; see also Figure 4-15). This pharmacological property has been retained by many of the newer agents, some of which add highly potent serotonin 2A (5HT2A) antagonism and/or 5HT1A partial agonism to D2 antagonism, others of which substitute D2 partial agonism for D2 antagonism, and, most recently, still others which only have 5HT2A antagonism and drop the D2 targeting entirely (Figure 5-1). The effects of serotonin-receptor-targeting of the newer agents and of partial agonism are discussed in detail below. Also explained in the following sections are how targeting serotonin and dopamine receptors in various brain circuits mediates not only therapeutic effects in psychosis and other conditions, but also side effects. These drugs are first classified into several general groups and then each individual drug is discussed.