Patients with comorbid major depression and generalized anxiety disorder (GAD) tend to have a more severe and prolonged course of illness and greater functional impairment. GAD is one of the most common mental disorders in primary medical-care settings, and is associated with increased use of health services. Current theories on pathological anxiety fit a multifactorial epigenetic model that integrates early stressors, inherited and acquired vulnerabilities, and the risks of developing interrelated or coincidental somatic diseases. The tolerability profile of prescribed medication is an important consideration, particularly when long-term treatment is recommended. Distressing symptoms on stopping treatment are common with many classes of psychotropic drug, including selective serotonin reuptake inhibitor (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and benzodiazepines. There is clearly room for improvement in the development of more efficacious and more acceptable pharmacological approaches to the management of this common, distressing, typically disabling, and often persistent anxiety disorder.

This chapter focuses on drug development for psychiatric as opposed to other central nervous system (CNS) indications such as neurological conditions, pain, and sleep. It provides an overview of how CNS drug development has evolved over its relatively short history of perhaps 50-100 years as well as to provide some sense of how it might evolve in the not-too-distant future. Chlorpromazine and other phenothiazine molecules were synthesized around the turn of the last century and some were initially used to treat pinworm infestation. However, chlorpromazine over the last 50 years has come to play a pivotal role in the modern era of clinical psychopharmacology. CNS drug development principally focused on serotonin selective reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors SNRIs, atypical antipsychotics, and cholinesterase inhibitors. The current development of drugs for Alzheimer's and other neurodegenerative diseases could be a model for how future CNS drug development might proceed.