New Insights into Schizophrenia through Novel Antipsychotics / 대한정신약물학회지

ABSTRACT

This review serves as new insights into schizophrenia through novel antipsychotics. The observation that 'chlorpromazine' and other early neuroleptics all produced extrapyramidal side effects led patients to think that these were necessarily linked to the therapeutic response. This all reinforced the central role of dopamine(D2) in therories of schizophrenia. It is likely that the original dopamine hypothesis is too simplistic, however, the probable heterogeneity of schizophrenia makes it difficult to establish specific disease-related abnormalities in a single neurotransmitter system. The discovery of 'clozapine' and other novel antipsychotics has forever altered the conventional wisdom that held all antipsychotics to be equally efficacious and uniformly neurotoxic. The drugs that are more effective in the treatment of schizophrenia and that also have important effects on neurotransmitters other than dopamine has further widened both our understanding of the complexities of and our search for more effective and less damaging treatments. Although dopamine remains the key neurotransmitter of interest in research on the cause of schizophrenia, we have moved from a simple dopamine hypothesis to a multiple dopamine receptor hypothesis and on to a dysregulated dopamine system hypothesis, the latter emphasizing the loss of balance between dopamine and other neurotransmitters and the restoration of that balance of the neurotransmitters between different brain regions in the treatment of schizophrenia. The search is therefore on for more specific and 'cleaner' antipsychotics, with or without direct antidopaminergic effects. Unfortunately, when we study schizophrenia, we are studying a 'dirty disease' in the sense that it is undoubtedly the final common expression of many pathophysiologies. In addition, the antipsychotics we use for treatment are 'dirty drugs'; they have multiple effects on multiple systems. Therefore, previous research efforts on understanding the pathophysiologies of schizophrenia through the mechanism of action of antipsychotics(symptoms --> [symptomatic] diagnosis --> [symptomatic] treatment --> causes) are 'diagnosis-targeted' psychopharmacology and merely on the road toward the causative diagnosis and treatments. Now, I propose carefully the following alternative approaches for the 'causative diagnosis and treatment'. 1) 'Modified diagnosis-targeted' psychopharmacology The likelihood of drugs increasingly tailored to different 'causative subtypes' of schizophrenia within present diagnostic systems(symptoms --> [symptomatic] diagnosis --> causative subtypes --> [causative] treatment) is not far beyond the horizon. 2) 'Symptom-targeted' psychopharmacology New treatment for schizophrenia may actually be targeted at 'specific aspects or symptoms' of the illness, such as hallucinations or delusions, rather than at the illness as a whole(symptoms --> causes --> [causative] diagnosis --> [causative] treatments). Schizophrenia will eventually be treated with combinations of different drugs(rational polypharmacy). In order for combined treatment to be used for schizophrenic patients, however, symptoms have to be defined correctly and identified accurately. Only recently, owing to the many scientific developments in understanding the biology of schizophrenia, has there been a potential benefit to making specific subdivisions among the symptoms of schizophrenia and relating them to specific biological processes. 3) 'Cause-targeted' psychopharmacology For the possibilities of different causes relating similar symptoms, pharmacological tailoring according to causes that are detected by biological tests performed firstly in patients showing psychiatric symptoms is recommended(causes --> [causative] treatments --> [causative] symptoms --> [causative] diagnosis). This review represent a major shift of traditional thinking influenced by the recent obstacles in our understanding of schizophrenia, the developments in methodology which have influenced scientifically informed notions of our clinical practice, and the introductions of antischizophrenic drugs, antidelusional drugs, antihallucinatory drugs and antideficit drugs which are likely to develop in future. Also this changing concepts about diagnosis and treatments are applied to other psychiatric disorders.