Clinical and biological outcomes of prolonged treatment with haloperidol in schizophrenia.

Paranoid schizophrenia with long-term course is a challenge for the clinical and therapeutic research, particularly because chronic course is difficult to identify due to the high rate of mortality in this category of patients. The therapeutic stability on an antipsychotic molecule (haloperidol) is indeed an exception, since the current trend in the case of unfavorable course is based on therapeutic versatility and polypharmacy. Haloperidol is the first-generation antipsychotic that is referred in the therapeutic guidelines as the "golden standard" regarding its efficacy on positive symptoms. The research in fundamental and molecular psychopharmacology has shown the aggressivity of this molecule on the secondary and tertiary signaling chains, including mitochondrial alterations. On male patients with paranoid schizophrenia (positive symptoms) and a chronic course of more than 35 years who received exclusively haloperidol, our study demonstrated an negative outcome with the loss of social functioning, persistence of positive symptoms, chronic extrapyramidal symptoms and mild cognitive impairment. The neuroimaging evaluations have shown atrophy in the temporal poles, posterior ventriculomegaly, cerebellar atrophy and calcification on choroid plexus and pineal gland. The difference between the histological changes induced by haloperidol on animal model and the ones on the patients in our study is located in the frontal cortex, thus suggesting the presence of two neurobiological models of schizophrenia in men: fronto-striatal and temporal-limbic-striatal. The persistence of extrapyramidal symptoms during the treatment with haloperidol may be considered as a clinical marker of the risk for negative outcome and a potential indication for the therapeutic switch.

The microvascular alterations in frontal cortex during treatment with antipsychotics: a post-mortem study.

INTRODUCTION: Schizophrenia is the most severe psychiatric illness, with a biological support in the brain. There is evidence that the adequate dopamine balance in the frontal cortex is associated with a better outcome of the disorder, while the alteration of dopamine mechanism at this level may affect the vascular system leading to secondary neuronal alterations. Our study was conducted post-mortem and its objective was to identify the alterations in the neuronal architecture, in the integrity of the microvascular unit in the frontal cortex of patients treated with potent and excessive D2-blocking antipsychotics. MATERIALS AND METHODS: We studied post-mortem sections of the frontal cortex of three patients (two women and one man) diagnosed with schizophrenia or schizophrenia-spectrum disorders and treated with antipsychotics for the last 24 months. The slides were prepared according to the classical histopathological protocols. RESULTS: Various alterations were found at the neural and vascular levels in the frontal cortex. The most significant was the neural loss as the result of severe changes in the microvessels (diameter reduction, hyaline and collagen deposits, edema, pinocytosis and vacuolization). DISCUSSION: The evidences shown in our study highlight the fact that antipsychotics with potent antagonist action on D2 receptors may affect the neurovascular unit and small vessels in frontal cortex by altering the balance vasoconstriction-vasodilatation, thus reducing the blood flow and metabolism and generating structural microvascular changes proportional with the level of apoptosis at this level. The functional integrity of the dopaminergic system in frontal cortex depends on the vascular support and the capabilities of the neurovascular unit and any dysfunction increases the neuronal loss with clinically significant changes. CONCLUSIONS: The pathological data of our study raises the hypothesis for the pathogenic stages at the level of microvessels in the frontal cortex of the patients with schizophrenia or schizophrenia-spectrum disorders treated with D2-blocking antipsychotics: a stage with functional, reversible alterations that may be correlated with the impairments of working memory and presence of extrapyramidal symptoms and a lesional, irreversible stage with significant deterioration of cognition and global functioning. Further studies are needed to verify this hypothesis.