Schizophrenia first-generation antipsychotics

The first generation antipsychotics, now known as typical drugs, were all D2 receptor blockers and, as such, very likely to produce Parkinsonian side effects. Because antipsychotic potency was associated with D2 receptor affinity, it was assumed that dopamine overactivity was the essential defect in schizophrenia and that a direct dopamine blockade was the definitive route to treatment. But these drugs affected both the target dopamine pathways of the mesolimbic projection and the uninvolved nigrostriatal projection. Unfortunately, that meant that movement disorders were the price that had to be paid for antipsychosis. 

Jones, P. B., Barnes, T. R., Davies, L., Dunn, G., Lloyd, H., Hayhurst, K. P., Murray, R. M., Markwick, A., Lewis, S. W. 2006, Randomized controlled trial of the effect on quality of Life of second- vs first-generation antipsychotic dmgs in schizophrenia Cost utility of the latest antipsychotic drugs in schizophrenia study (Cutlass 1), Arch.Gen.Psychiatry, vol. 63, no. 10, pp. 1079-1087. 

Clozapine has been found effective in patients who did not improve during treatment with first-generation antipsychotics, and since the hematological side effects permit only its restricted use, this dmg has a unique indication for treatment- resistanf schizophrenia. Another unique indication for clozapine is the reduction in the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorders. The indications of clozapine and its two analogues, olanzapine and quetiapine, are summarized in Tab. 13.5. The US labels of these drugs served as the data source [62-64]. Clozapine and olanzapine, but not quetiapine, are available in intramuscular form, which is helpful in the treatment of acutely agitated patients with diagnoses as defined in Tab. 13.5. 

With the widespread use of second-generation antipsychotics (SCAs) as first-line treatment, the management of schizophrenia has improved with regard to side-effects, adherence with medication, and, in many cases, efficacy in comparison with the first-generation antipsychotics. 

Observational studies In a retrospective comparison of risperidone with haloperidol or trifluoperazine in an Asian population with first-episode schizophrenia-spectrum disorders ( = 261), some 90% discontinued treatment before 18 months however, the median time to discontinuation of risperidone was 69 days compared with 27 days for the first-generation antipsychotic drugs [123 ]. Risperidone had a longer time to discontinuation owing to intolerable adverse reactions than haloperidol and trifluoperazine. Nevertheless, lack of comparability precluded firm conclusions. 

Liew A, Verma S, Poon LY, Edimansyah A, Subramaniam M, Vaingankar J, Chong SA. Comparing effectiveness of risperidone with first-generation antipsychotic medications in patients with schizophrenia-spectrum disorders. Ann Psy-chopharmacol 2010 24 973-80. 

The risks of diabetes with different antipsychotic drugs have been compared in a meta-analysis of 11 studies in people with schizophrenia or related disorders, including cross-sectional studies, case-control studies, cohort studies, and controlled trials [37 ]. The relative risk of diabetes in patients with schizophrenia taking one of the second-generation versus first-generation antipsychotic drugs was 1.3 (95% Cl = 1.1, 1.5). 

Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia a meta-analysis. Lancet... 

Chen JJ, Chan HY, Chen CH, Gau SS, Hwu HG. Risperidone and olanzapine versus another first generation antipsychotic in patients with schizophrenia inadequately responsive to first generation antipsychotics. Pharmacopsychiatry 2012 45(2) 64-71. 

Aripiprazole was formulated in the early 1980s to function as a potential dopamine modulator, with both antagonist and agonist activity at the D2 receptor. It is the first D2 partial agonist available for the treatment of schizophrenia and is sometimes referred to as a third-generation antipsychotic. This novel mechanism is... 

The first of the second-generation, or atypical, antipsychotics was clozapine. Clozapine (Clozaril) is relatively free of the movement disorders that characterize the first-generation drugs. This is true of, and defines, second-generation, atypical antipsychotics. It was a significant breakthrough for schizophrenia patients. 

An important leap in the treatment of schizophrenia occurred in the late 1980s with the introduction of the first of a number of medications that offered a wider spectrum of action and relatively improved tolerability. Some of these atypical antipsychotics, also called second-generation antipsychotics, are listed in Table 5.13. 

The CATIE project will evaluate the clinical effectiveness of atypical antipsychotics in the treatment of schizophrenia and of Alzheimer s disease. Although antipsychotics were first introduced for the treatment of schizophrenia, they are now used for many other disorders. It is unclear how effective they are and, most important, in view of their rather high cost, how favorably they compare to the first generation of antipsychotics, all of which are available in generic (and thus much less expensive) forms. The CATIE (Clinical Antipsychotic Trials in Intervention Effectiveness) study has specific aims, including the determination of long-term effectiveness and tolerability of the atypical antipsychotics, compared to each and to a typical or classic antipsychotic. At this... 

Second-generation antipsychotics (SGAs) (also known as atypical antipsy-chotics), except clozapine, are the agents of first choice in treatment of schizophrenia. Growing, but stiU controversial, evidence supports that the SGAs (e.g., clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole) have superior efficacy for treatment of negative symptoms, cognition, and mood. 

The primary treatment for schizophrenia involves use of antipsychotic medications. These are classified as typical or first generation, and atypical. The atypical antipsycho tics differ from the typical in having relatively less extrapyramidal side effects, such as rigidity, dystonia (muscle spasm), akathi-sia (motor restlessness), and pseudo-Parkinsonian symptoms. 

Systematic reviews First-generation and second-generation antipsychotic drugs in patients with schizophrenia have been compared in a meta-analysis [14= ] (for an in-depth review, see SEDA-27, 50). The study included 150 double-blind, mostly shortterm, randomized clinical trials with 21 533 participants. Four second-generation antipsychotic drugs (amisulpride, clozapine, olanzapine, and risperidone) were better than first-generation ones for overall... 

Sikich L, Frazier JA, McClellan J, Findling RL, Vitiello B, Ritz L, Ambler D, Puglia M, Maloney AE, Michael E, De Jong S, Slifka K, Noyes N, Hlastala S, Pierson L, McNamara NK, Delporto-Bedoya D, Anderson R, Hamer RM, Lieberman JA. Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry 2008 165(11) 1420-31. 

Smith M, Hopkins D, Peveler RC, Holt RI, Woodward M, Ismail K. First- v. second-generation antipsychotics and risk for diabetes in schizophrenia systematic review and meta-analysis. Br J Psychiatry 2008 192(6) 406-11. 

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