Antipsychotic medications are used to treat and manage symptoms for several psychiatric disorders and are commonly categorized into two classes. First-generation antipsychotics (FGAs), also known as "typical antipsychotics," were developed in the 1950s. Second-generation antipsychotics (SGAs), also known as "atypical antipsychotics," emerged in the 1980s. To date, FGAs have been classified according to their chemical structure, which includes serotonin-dopamine antagonists and multiacting receptor-targeted antipsychotics, whereas SGAs have been categorized according to their pharmacological properties as dopamine partial agonists. There is ongoing research testing the proposed mechanisms of action within each class with respect to the neurobiology of different psychiatric disorders. According to findings from the 2004-05 Medical Expenditure Panel Survey, an estimated 2 million adult patients in the U.S. were prescribed an antipsychotic medication, three quarters of whom were taking an SGA. In 2003, an estimated $2.82 billion were spent in the country on these medications, with SGAs accounting for 93% of this expenditure. Today, 20 FGAs and SGAs are commercially available in the U.S. and approved by the FDA. Individuals taking antipsychotics may stop taking their medication for a number of reasons, including adverse events (AEs) and a lack of improvement in their symptoms. As a result, ongoing evaluations of drug efficacy and models of patient decisionmaking are essential. This Review provides a comprehensive synthesis of the evidence examining the benefits and harms associated with the use of FDA-approved FGAs and SGAs. This CER focuses on comparisons of individual medications rather than drug classes. This topic is important and timely, given the ongoing debate about the comparative benefits and harms of FGAs and SGAs. The focus of this report complements other recent reviews investigating different SGAs, the off-label use of antipsychotics, and FGAs versus SGAs in the pediatric population. The focus of this report is adults age 18 to 64 years with schizophrenia, schizophrenia-related psychoses, and bipolar disorder. The following Key Questions were investigated in the report: 1. For adults (age 18 to 64 years) with schizophrenia, schizophrenia-related psychoses, or bipolar disorder, what are the comparative efficacy and effectiveness of FGAs versus SGAs for improving core illness symptoms? 2. For adults (age 18 to 64 years) with schizophrenia, schizophrenia-related psychoses, or bipolar disorder, what is the comparative effectiveness of FGAs versus SGAs for improving functional outcomes and decreasing health care system utilization? 3. For adults (age 18 to 64 years) with schizophrenia, schizophrenia-related psychoses, or bipolar disorder, do FGAs and SGAs differ in medication-associated AEs and safety? 4. For adults (age 18 to 64 years) with schizophrenia, schizophrenia-related psychoses, or bipolar disorder, what is the comparative effectiveness of FGAs versus SGAs for the following other outcomes: Relapse and remission rates, Medication adherence and persistent use, Patient insight into illness, Health-related quality of life, Patient satisfaction, Comorbidity: endpoints of victimization, homelessness, and substance abuse, Patient-reported outcomes, Ability to obtain and retain employment and succeed in job duties, Concomitant use of other medications, especially those used to treat EPS, and Patient preferences. 5. For adults (age 18 to 64 years) with schizophrenia, schizophrenia-related psychoses, or bipolar disorder, what are the comparative effectiveness and risks of FGAs versus SGAs in subgroups defined by the following variables? Disorder subtypes, Sex, Age group (18-35 years, 36-54 years, and 55-64 years), Race, Comorbidities, Drug dosage, Follow up period, Treatment of a first episode versus treatment in the context of previous episodes (previous exposure to antipsychotics), and Treatment resistance.