Schizophrenia disrupts social and family relationships, resulting severe educational and occupational impairment, lost productivity, physical illness, and premature mortality. A wide range of non-psychiatric medical conditions and a variety of substances can induce symptoms of psychotic disorders and catatonia. These are medical and neurological disease which consist of substance induced, epilepsy, neoplasm, cerebrovascular disease or trauma, AIDS, B12 deficiency, carbon monoxide poisoning, Creutzfeldt-Jakob disease, heavy metal poisoning, herpes encephalitis, homocystinuria, Huntington’s disease, neurosyphilis, pellagra, systemic lupus erythematosus, Wernicke-Korsakoff syndrome, Wilson’s disease etc. When evaluating a patient with psychosis, clinicians should follow the general guidelines for assessing non-psychiatric conditions. First, psychiatrists should aggressively pursue undiagnosed non-psychiatric medical condition when a patient exhibits any unusual or rare symptoms or any variation in the level of consciousness. Second, psychiatrists should attempt to obtain a complete family history, including a history of medical, neurological and other psychiatric disorders. Third, psychiatrists should consider the possibility of a non-psychiatric medical condition, even in patients with previous diagnoses of schizophrenia. A patient with schizophrenia is just as likely to have a brain tumor that produces psychotic symptoms. Differential diagnosis of schizophrenia symptoms should be considered other psychotic disorders. The psychotic symptoms of schizophrenia can be identical with those of schizophreniform disorder, brief psychotic disorder, schizoaffective disorder, and delusional disorders. There is a precipitating traumatic event in brief psychotic disorder. When a manic or depressive syndrome develops concurrently with the major symptoms of schizophrenia, schizoaffective disorder is the appropriate diagnosis. Non-bizarre delusions present for at least one month without other symptoms of schizophrenia or a mood disorder warrant the diagnosis of delusional disorder. In this presentation, differential diagnosis of first episode psychosis will be reviewed based on the existing studies and general principles.