The therapeutic efficacy and target symptoms of maprotiline were tested by administering it in addition to conventional neuroleptic treatment for 10 weeks to a total of 32 chronic schizophrenic patients who showed no, or only partial, response to the neuroleptic medication. The final global improvement rating was 68.8% for all patients. Average therapeutic doses administered were 150 mg per day. Changes in psychotic symptoms were assessed by the Brief Psychiatric Rating Scale (BPRS), Psychiatric Evaluating scale (PES), and the Scale for the Assessment of Negative Symptoms (SANS). All mean improvement rates of these rating scales were observed at the 2nd week after the start of treatment, and maprotiline produced a marked amelioration in negative symptoms such as decreased spontaneity, blunted affect, emotional withdrawal, impaired work or recreation, etc. The incidence of side-effects was 37.5%. Constipation was the most frequently occurring side-effect. Neither side-effects nor laboratory test results were serious enough to discontinue the trial, except in the case of one chronic patient who showed acute exacerbation of symptoms due to maprotiline-induced insomnia, elation and hallucination. These results suggest that maprotiline improves the negative symptoms of schizophrenia by a noradrenaline potentiating action not demonstrated by dopaminergic or serotonergic reward systems.