Patients experiencing a first episode of schizophrenia who also use marijuana or other cannabis products appear to have greater loss of brain volume over five years, along with other significant brain changes, compared with nonusing patients and healthy comparison subjects.

Moreover, the cannabis-using patients showed a less-pronounced improvement in positive and negative symptoms compared with nonusing patients, according to Dutch researchers. Their report was posted on AJP in Advance on February 15 and will appear in the April print edition of the journal.

The results suggest a neuroanatomical explanation for previous studies that have found a poorer outcome among cannabis-using patients.

"Cannabis use has been reported in up to 50 percent of the patients with schizophrenia, and cannabis-using patients, including those with a recent onset, seem to be clinically different from those not using cannabis," lead investigator Monica Rais, M.D., told Psychiatric News." They are reported to have more positive symptoms but fewer negative symptoms, an earlier onset, and an increased number of psychotic relapses or exacerbations.

"We hypothesized that the reported outcome differences between these two patient populations could be reflected in peculiar patterns of brain volume changes over time," Rais said.

She is with the Department of Psychiatry at the University Medical Center Utrecht in the Netherlands.

Though the cannabis-using patients did experience less-pronounced improvement in symptoms, in this study the researchers did not find statistically significant differences in global functioning outcome measures or in the number of days hospitalized; this may be due to the relatively small number of subjects in the study, Rais and colleagues wrote.

However, the longitudinal study advances the understanding of cannabis and its relationship to brain changes and underscores the importance of drug counseling for patients with schizophrenia. Previous links between brain volume and cannabis use in schizophrenia patients either have been indirect or have relied on measurements at only one point.

"Our results underline the importance of making a maximal effort to persuade patients with schizophrenia to stop using cannabis and warn young people in general for the possible risks associated with its use," Rais said.

In the study, 51 patients with first-episode schizophrenia and 31 comparison subjects without schizophrenia were recruited from the First-Episode Schizophrenia Research Program at the University Medical Center Utrecht. The comparison subjects did not use any illicit substances before or during the study.

The cohort was followed for five years to examine the relationship between brain morphology, the use of cannabis, and outcome. Patients with a lifetime diagnosis of abuse or dependence of a substance other than cannabis or nicotine were excluded.

At baseline, severity of illness was measured with the Positive and Negative Syndrome Scale. Drug use was assessed with the Composite International Diagnostic Interview, and the information provided by the patient was confirmed by a relative. Random urine toxicology tests were performed throughout the study.

The researchers also assessed the number of days spent in the hospital over the five-year period for all patients, and every patient was monitored carefully for the amount and type of medication prescribed.

During the study, 19 patients used only cannabis and no other illicit drugs, and 32 patients did not use any illicit drugs.

At the end of the five years, schizophrenia patients showed a larger decrease in gray matter volume over time than healthy subjects, and this decrement in gray matter volume was significantly more pronounced in the patients who continued to use cannabis. Moreover, the differences could not be attributed to outcome or baseline characteristics, the researchers wrote.

The cannabis-using group also showed less improvement in positive and negative symptoms over the five-year period, though this slower improvement did not translate into a statistically significant difference in functional outcome.

The cannabis-using group also showed more pronounced increases in lateral and third ventricle volumes than healthy subjects and patients who did not use cannabis.

Among all patients in the study—whether they used cannabis or not—the increase in lateral and third ventricle volumes was related to a higher score on the Camberwell Assessment of Needs (CAN), and an increase in lateral ventricle volume was related to a lower Global Assessment of Functioning score. (The CAN is a measure of the help patients need in daily life functioning.)

However, no significant correlations between increase in ventricular size and the clinical variables could be found between the cannabis-using and nonusing groups. So it would appear that brain volume loss may not wholly account for poorer functional outcome, the researchers concluded.

Similarly, the precise nature of the relationship between cannabis and brain volume loss remains to be elucidated. Excessive neuronal damage in drug-using patients with schizophrenia could either be a direct consequence of cannabis intake or occur as a consequence of psychotic symptoms in schizophrenia associated with cannabis use. Or it could be related to the possibility that cannabis-using patients may be more likely to be noncompliant with antipsychotic medication, which is believed to attenuate the progressive brain changes in schizophrenia.

"Although further studies need to be conducted to confirm whether the brain volume loss is a direct or an indirect effect of cannabis in schizophrenia, this study suggests that some of the detrimental effects of cannabis on the course of illness may be explained by its effect on the progression of brain changes in schizophrenia," Rais and colleagues wrote.

"Excessive Brain Volume Loss Over Time in Cannabis-Using First-Episode Schizophrenia Patients" is posted at<http://ajp.psychiatryonline.org/cgi/reprint/appi.ajp.2007.07071110v1>.▪