Striatal metabolic rate and clinical response to neuroleptics in schizophrenia

Department of Psychiatry, University of California, Irvine.
Archives of General Psychiatry (Impact Factor: 14.48). 01/1993; 49(12):966-74.
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A low metabolic rate in the caudate nucleus and putamen in schizophrenic patients while they were not receiving medication was found to predict a favorable clinical response to haloperidol. Twenty-five patients (21 men and four women) entered a double-blind crossover trial of haloperidol and placebo; to our knowledge, this is the first such trial with positron emission tomography to be reported. Patients received either placebo or medication for the first 5 weeks, and they received the other treatment for the second 5 weeks. Positron emission tomographic scans were obtained at weeks 5 and 10. Patients with low relative metabolic rates in the caudate nucleus and putamen while they were receiving placebo were more likely to show decreases in their Brief Psychiatric Rating Scale scores with haloperidol treatment than individuals with normal or high metabolic rates. Among responders, haloperidol treatment had a "normalizing" effect on metabolic activity in the striatum, with the metabolic rate while they were receiving haloperidol being higher than that while they were receiving placebo. Nonresponders were more likely to show a worsening of hypofrontality while they were receiving medication and an absence of change in the striatum.

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    • "The caudate and putamen nuclei are involved in motor and cognitive functions (DeLong and Georgopoulos, 1981; DeLong et al., 1984; Middleton and Strick, 1994). Disruptions in the afferent and efferent connections and alterations within the nuclei themselves have been linked to motor disorders such as Parkinson’s and Huntington’s disease (DeLong and Georgopoulos, 1981; DeLong et al., 1984; Marsden, 1986), and psychiatric disorders such as schizophrenia (Buchsbaum et al., 1992; Hietala et al., 1995; Roberts et al., 1996, 2005; Howes et al., 2009; see also as reviews Perez-Costas et al., 2010; Simpson et al., 2010), bipolar disorder (Amsterdam and Newberg, 2007; Cousins et al., 2009), and major depression (Matsuo et al., 2008; Butters et al., 2009; Khundakar et al., 2011). Although some aspects of these diseases can be studied in postmortem human tissue, the use of animal models is also necessary. "
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    ABSTRACT: The striatum is a major component of the basal ganglia and is associated with motor and cognitive functions. Striatal pathologies have been linked to several disorders, including Huntington's, Tourette's syndrome, obsessive-compulsive disorders, and schizophrenia. For the study of these striatal pathologies different animal models have been used, including rodents and non-human primates. Rodents lack on morphological complexity (for example, the lack of well defined caudate and putamen nuclei), which makes it difficult to translate data to the human paradigm. Primates, and especially higher primates, are the closest model to humans, but there are ever-increasing restrictions to the use of these animals for research. In our search for a non-primate animal model with a striatum that anatomically (and perhaps functionally) can resemble that of humans, we turned our attention to the tree shrew. Evolutionary genetic studies have provided strong data supporting that the tree shrews (Scadentia) are one of the closest groups to primates, although their brain anatomy has only been studied in detail for specific brain areas. Morphologically, the tree shrew striatum resembles the primate striatum with the presence of an internal capsule separating the caudate and putamen, but little is known about its neurochemical composition. Here we analyzed the expression of calcium-binding proteins, the presence and distribution of the striosome and matrix compartments (by the use of calbindin, tyrosine hydroxylase, and acetylcholinesterase immunohistochemistry), and the GABAergic system by immunohistochemistry against glutamic acid decarboxylase and Golgi impregnation. In summary, our results show that when compared to primates, the tree shrew dorsal striatum presents striking similarities in the distribution of most of the markers studied, while presenting some marked divergences when compared to the rodent striatum.
    Frontiers in Neuroanatomy 08/2011; 5:53. DOI:10.3389/fnana.2011.00053 · 3.54 Impact Factor
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    • " ; Bilder et al . 1994 ; Beerpoot et al . 1996 ; Sheitman and Lieberman 1998 ; Staal et al . 2001 ; Arango et al . 2003 ; Altamura et al . 2005 ; Mitelman et al . 2005 ) . Lower pre - treatment metabolic rate in the striatum is predictive of good treatment outcome , and good responders showed greater striatal response compared to poor responders ( Buchsbaum et al . 1992 ) . Enhanced dopamine release upon amphetamine stimulation has been reported in treatment responsive subjects versus controls and treatment resistant subjects ( Abi - Dargham et al . 2000 ) . In other words , schizophrenia subjects with high striatal dopa - mine release are far more responsive to anti - psychotic drugs than those patien"
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    ABSTRACT: Schizophrenia is a severe mental illness that affects 1% of the world population. The disease usually manifests itself in early adulthood with hallucinations, delusions, cognitive and emotional disturbances and disorganized thought and behavior. Dopamine was the first neurotransmitter to be implicated in the disease, and though no longer the only suspect in schizophrenia pathophysiology, it obviously plays an important role. The basal ganglia are the site of most of the dopamine neurons in the brain and the target of anti-psychotic drugs. In this review, we will start with an overview of basal ganglia anatomy emphasizing dopamine circuitry. Then, we will review the major deficits in dopamine function in schizophrenia, emphasizing the role of excessive dopamine in the basal ganglia and the link to psychosis.
    Journal of Neurochemistry 04/2010; 113(2):287-302. DOI:10.1111/j.1471-4159.2010.06604.x · 4.28 Impact Factor
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    • "Severalgroupshaveemployedpositronemissiontomography (PET)andSPECTtostudybloodflowandbrainmetabolism intreatmentresistantpatients.Onegroupusing[18F]FDG PETreportedlowerrelativestriatalmetabolicratesinthe striatumofresponderscomparedwithnon-responders (Buchsbaumetal.,1992).Whentreatedwithhaloperidol, therelativemetabolicrateincreased,withalargerincreasein responders.AnothergroupusingSPECTimagingfoundthat poorresponderstoclozapinehadsignificantlylowerperfusion inthalamus,leftbasalgangliaandrightprefrontalregions priortotreatment(MolinaRodriguez,etal.,1996).Afurther SPECTstudyinnon-responderstorisperidonewhoweresub- sequentlysuccessfullytreatedusingclozapinefoundthatclin- icalresponsecorrelatedwithanincreaseinthalamicperfusion (Molinaetal.,2008).AnearlierSPECTstudyhadnotshown anydifferenceinperfusionbetweengoodandpoorresponders toantipsychoticdrugs,althoughitdidfindthatnon-respondershadlowervolumesofmostbrainstructures,andperformedworseonepisodicmemorytests(Lawrieetal .,1995). "
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    ABSTRACT: Schizophrenia is a severe mental illness affecting approximately 1% of the population worldwide. Antipsychotic drugs are effective in symptom control in up to two-thirds of patients, but in at least one-third of patients the response is poor. The reason for this is not clear, but one possibility is that good and poor responders have different neurochemical pathologies, and may therefore benefit from different treatment approaches. In this selective review we summarise research findings investigating the biological differences between patients with schizophrenia who show a good or a poor response to treatment with antipsychotic drugs.
    Journal of Psychopharmacology 11/2009; 24(7):953-64. DOI:10.1177/0269881109106959 · 3.59 Impact Factor
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