JOURNAL OF

PSYCHIATRIC

RESEARCHJournal of Psychiatric Research 40 (2006) 577–578

www.elsevier.com/locate/jpsychires

Editorial

Solving the puzzle of schizophrenia: Piece by piece

Approximately 1% of the world population will developschizophrenia during their lifetime. It is a severe andchronic disease affecting all spheres of functioning. Causesof schizophrenia are still largely unknown. To date, threefactors appear to play an important roles in the occurrenceof the disease: first, the hereditary part showing that schizo-phrenia is more likely to occur in families where a first-degree relative has the disease; second, brain structureabnormalities, especially in the frontal lobe and parieto-occipital regions; and third, chemical imbalance in thebrain neurotransmitters.

When studying brain structure abnormalities, it is diffi-cult to distinguish causes from effects and to evaluate towhat extent an anomaly is related to the disease itself orto a symptom. Whether schizophrenia involves a neurode-generative or a neurodevelopmental process is still unclear.Brain abnormalities are, however, present in the early stagesof the disease. In their article, Premkumar et al. (2006)examined the effects of illness stage and duration on the vol-ume of brain regions. To do that, they used first-episodeschizophrenia patients, chronic schizophrenia patients andhealthy matched controls. This design allowed them to ver-ify if structural abnormalities observed at the early stage ofthe disease remained the same or were modified in chronicschizophrenia. After correcting for age and duration of ill-ness, they found that the whole brain volume decreasedmore rapidly during the first years of the disease and sloweddown in the later years. More specifically, they observed anexponential association between the duration of illness andthe reduction of the prefrontal cortex, parieto-occipital cor-tex gray matter and total cortical gray matter.

The work of Schneider-Axmann et al. (2006) presentedin this issue, investigated the relationship between cerebro-spinal fluid, gray and white matter volumes in schizophre-nia patients and non-schizophrenic first-degree relatives.They found that gray matter volume was significantlyreduced while cerebrospinal fluid and lateral ventricle vol-umes were significantly increased compared to healthy con-trols and to non-affected first-degree relatives. Familymembers were comparable to healthy controls.

How much are these abnormalities specific to schizo-phrenia? Most of studies that examined structural brainabnormalities limited comparisons to healthy subjects.

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doi:10.1016/j.jpsychires.2006.08.001

However, some of the brain modifications observed inschizophrenia are also present in other psychiatric disor-ders. For example, decreases in the regional prefrontal cor-tex volumes have been also observed in individuals withpanic disorder (Protopopescu et al., 2006) and bipolar dis-order (Blumberg et al., 2006). Similarly, bilateral hippo-campal volume reduction, frequently observed inschizophrenia patients, was also found in patients withneurodegenerative disorders such as Alzheimer’s disease(Uotani et al., 2006) or temporal lobe epilepsy (Garcia-Finana et al., 2006) and in stress-associated psychopathol-ogies such as posttraumatic stress disorder (Karl et al.,2006), anorexia nervosa (Connan et al., 2006), or unipolardepression (Videbech and Ravnkilde, 2004).

There are few studies that attempted to link neurologicaldeficits observed in schizophrenia with structural brainabnormalities. In this issue of the Journal, Schulze et al.(2006) have examined the relationship between eye move-ments (smooth pursuit and antisaccade) and brain abnor-malities in schizophrenia patients and non-schizophrenicfirst-degree relatives. They found no association betweensmooth pursuit tasks and brain volume measures (wholebrain volume, prefrontal lobe, lateral ventricles, hippocam-pus, third ventricle and cerebellum). They did find, however,an association between the prefrontal lobe volume and themean latency of antisaccade as a whole; i.e., unrelated togroup membership, smaller prefrontal lobe volume predict-ing longer antisaccade latency. As the authors stressed, thiswould suggest a role of the prefrontal areas in the normalantisaccade production. Another article in this issue(Tu et al., 2006) also explored antisaccade deficits in schizo-phrenia using fMRI technology. They were interested instudying neural circuits involved in antisaccade tasks anddetermining if some deficits could be identified. In normalsubjects, antisaccade tasks activated the medial frontal gyrus(corresponding to the supplemental eye fields) and the ante-rior cingulate cortex. There were also bilateral activations ofinferior frontal gyrus, superior and inferior parietal lobules,and primary visual cortex. At the subcortical level, therewere activations in the bilateral lentiform nucleus, thalamusand cerebellum. In schizophrenia patients, there were nosignificant activations of the bilateral lentiform nucleusand thalamus, left inferior frontal gyrus, and left inferior

578 Editorial / Journal of Psychiatric Research 40 (2006) 577–578

parietal lobule. Dysfunctions in the fronto-striatal-thalamo-cortical circuits and fronto-parietal circuits could explainantisaccade deficits observed in schizophrenia.

Another study (Huang and Lee, 2006) has explored theassociation between serum brain-derived neurotrophic factor(BDNF) protein levels and clinical phenotypes in schizophre-nia and healthy subjects. They found that lower serumBDNF protein levels were associated with catatonic schizo-phrenia but not with the other studied clinical phenotypes(paranoid, residual, age at onset of the disease, suicideattempt and positive family history). In animals, BDNF isinvolved in the regulation of hippocampal plasticity andlearning process related to that brain region. In healthyhumans, the met-BDNF allele has been associated with areduction in the hippocampal volume (Bueller et al., 2006).A similar finding was also found in schizophrenia patients(Szeszko et al., 2005): the val66 met polymorphism inthe BDNF gene explained 44% of the variance in the hippo-campal volume of schizophrenia patients (Szeszko et al.,2005).

Altogether, these recent findings open new perspectivesof research in schizophrenia. Future research needs to focuson the association between brain structural abnormalitiesand specific deficits in schizophrenia. For example, thereis enough evidence to support the idea that cognitive deficitsin schizophrenia might be related to reduction in hippocam-pal volume and, most likely with the BDNF val66 met allele.However, such studies are yet to be done. On the otherhand, comparisons between schizophrenia and other psy-chopathologies that share common symptoms need to bedone in order to identify brain structural abnormalitiesand genetic factors that are specific to schizophrenia. Asfor now, scientific evidence tends to demonstrate that brainstructural abnormalities could be symptom-related insteadof disease-related. But to demonstrate either way, experi-mental groups need to be defined differently.

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Maurice M. OhayonDepartment of Psychiatry and Behavioral Sciences,

School of Medicine, Stanford University, CA, USAE-mail address: mohayon@stanford.edu