Antipsychotic Agents

• What makes an antipsychotic conventional?
• D2 receptor antagonism makes an antipsychotic conventional
• Neurolepsis
• Extrapyramidal symptoms (EPS) and tardive dyskinesia
• Prolactin elevation
• The dilemma of blocking D2 dopamine receptors in all dopamine pathways
• Muscarinic cholinergic blocking properties of conventional antipsychotics
• Other pharmacological properties of conventional antipsychotic drugs
• Risks and benefits of long-term treatment with conventional antipsychotics
• What makes an antipsychotic atypical?
• Serotonergic neurotransmission and serotonin dopamine antagonism
• Serotonin synthesis and termination of action
• Serotonin receptors
• 5HT1A and 5HT2A receptors have opposite actions in regulating dopamine release
• 5HT2A antagonism makes an antipsychotic atypical
• Rapid dissociation of D2 antagonism makes an antipsychotic atypical
• D2 partial agonism (DPA) makes an antipsychotic atypical
• 5HT1A partial agonism (SPA) actions make an antipsychotic atypical
• Receptor binding properties and pharmacokinetics of antipsychotics
• Links between antipsychotic binding properties and clinical actions
• Cardiometabolic risk and antipsychotics
• Sedation and antipsychotics
• Antipsychotic pharmacokinetics
• Pharmacological properties of individual antipsychotics
• Antipsychotics in clinical practice
• Schizophrenia symptom pharmacies
• The art of switching antipsychotics
• Combos and polypharmacy
• Future treatments for schizophrenia
• Presymptomatic and prodromal treatments for schizophrenia: putting the cart before the horse or preventing disease progression?
• Glutamate-linked mechanisms and new treatments for schizophrenia
• Glutamate agonists or antagonists for schizophrenia?
• Novel serotonin- and dopamine-linked mechanisms
• Acetylcholine-linked mechanisms
• Peptide-linked mechanisms
• Future combination chemotherapies for schizophrenia and other psychotic disorders
• Summary

Antipsychotic Agents

This chapter explores antipsychotic drugs with an emphasis on treatments for schizophrenia. These treatments include not only conventional antipsychotic drugs but also the newer atypical antipsychotic drugs, which have largely replaced the older conventional agents in many countries. Atypical antipsychotics are also used as mood stabilizers for the manic, depressed, and maintenance phases of bipolar disorder in both adults and in children, but this is discussed in Chapter 13 on mood stabilizers. Atypical antipsychotics have many other “off-label” uses, from augmentation of antidepressants in treatment-resistant depression and of anxiolytics in treatment-resistant anxiety disorders to treatment of psychosis and behavioral disturbances in Alzheimer’s disease and other dementias. The use of atypical antipsychotics for indications other than the treatment of psychosis and schizophrenia is discussed in chapters dealing with those other disorders. Here we will discuss the use of conventional and atypical antipsychotics for the treatment of schizophrenia and also take a look into the future by discussing numerous new drugs under development for schizophrenia.

Antipsychotic drugs exhibit possibly the most complex pharmacological mechanisms of any drug class in the field of clinical psychopharmacology. To assist the reader in mastering this critical area of therapeutics in psychopharmacology, we have organized this chapter into five sections: first, the classic conventional antipsychotics; second, the contrasting pharmacological properties that make an antipsychotic atypical; third, a discussion of the multiple receptor actions of antipsychotics as well as their pharmacokinetics, comparing and contrasting the properties of the various individual atypical antipsychotics; fourth, a practical analysis of how these agents are put to use in clinical practice; and fifth, a discussion of new therapeutics for schizophrenia currently in development.

The reader is referred to standard reference manuals and textbooks for practical prescribing information, such as drug doses, because this chapter emphasizes basic pharmacological concepts regarding mechanisms of action and not practical issues such as how to prescribe these drugs (for that information, see, for example, S. M. Stahl, Essential Psychopharmacology: The Prescriber’s Guide, which is a companion to this book). The pharmacological concepts developed here should, however, help the reader understand the rationale for how to use antipsychotic agents based on their interactions with different neurotransmitter systems. Such interactions can often explain both the therapeutic actions and the side effects of antipsychotic medications and thus can provide very helpful background information for prescribers of these therapeutic agents.