Negative, cognitive and residual positive symptoms are a frequent concern in schizophrenia patients despite optimal management with current medication. Also, adverse effects induced by antipsychotics prevent them to be used in the so called high risk patients. Until new drugs specifically designed to address these symptoms are developed, several drugs used in different conditions have been tested.

To assess the evidence regarding the use of non-antipsychotic, alternative drugs, to treat or prevent schizophrenia.

To broaden available pharmaceutical options in the management of unremitting symptoms in schizophrenia patients, beyond commonly used antipsychotics.

A survey of the literature regarding alternative drugs to treat schizophrenia symptoms. Studies available in MEDLINE and published after year 2000 were surveyed. Only drugs assessed in at least one randomized and controlled clinical trial were included.

Several drugs have been studied in the management of resistant symptoms in schizophrenia, mainly negative symptoms and cognitive dysfunction. Also, the management of high risk patients is controversial and raises many ethical concerns. Such alternatives, namely those with a suitable safety profile are appealing.

Omega-3, memantine, acetylcysteine, d-cicloserine, estrogens, psychostimulants and acetylcholinesterase inhibitors have been assessed but only some of these have shown promising results, each for a specific group of symptoms, in different stages of the disease and with a diverse safety profile.

There exist a few alternative drugs with promising efficacy in the management of non-remitting symptoms in schizophrenia. Also, due to its safety profile some may be interesting options to high risk patients.