Psychiatric symptoms correlate with metabolic indices in the hippocampus and cingulate in patients with mitochondrial disorders.

There is increasing recognition that mitochondrial dysfunction may have a critical role in the pathophysiology of major psychiatric illnesses. Patients with mitochondrial disorders offer a unique window through which we can begin to understand the association between psychiatric symptoms and mitochondrial dysfunction in vivo. Using proton magnetic resonance spectroscopy ((1)H-MRS), we investigated metabolic indices in mitochondrial patients in regions of the brain that have been implicated in psychiatric illness: the caudate, cingulate cortex and hippocampus. In all, 15 patients with mitochondrial disorders and 15 age- and sex-matched controls underwent a comprehensive psychiatric assessment, including the administration of standardized psychiatric rating scales, followed by single voxel (1)H-MRS of the caudate, cingulate cortex and hippocampus to measure N-acetyl aspartate (NAA), creatine (Cr), glycerophosphocholine (GPC), myoinositol and glutamate+glutamine (Glx). Pearson's correlation coefficients were used to determine correlations between metabolites and the psychiatric rating scales. Anxiety symptoms in these patients correlated with higher GPC, Glx, myoinositol and Cr in the hippocampus. Impaired level of function as a result of psychiatric symptoms correlated with higher Glx and GPC in the cingulate cortex. In summary, we found remarkably consistent, and statistically significant, correlations between anxiety and metabolic indices in the hippocampus in patients with mitochondrial disorders, while overall impairment of functioning due to psychiatric symptoms correlated with metabolic markers in the cingulate cortex. These findings lend support to the notion that mitochondrial dysfunction in specific brain regions can give rise to psychiatric symptoms. In particular, they suggest that metabolic processes in the hippocampus may have an important role in the neurobiology of anxiety.

Inhibition of the serotonin transporter induces microglial activation and downregulation of dopaminergic neurons in the substantia nigra.

Drugs that selectively inhibit the serotonin transporter (SERT) are widely used in the treatment of depression and anxiety disorders. These agents are associated with a range of extrapyramidal syndromes such as akathisia, dystonia, dyskinesia and parkinsonism, suggesting an effect on dopaminergic transmission. We studied the time course of changes in dopaminergic neurons in the substantia nigra (SN) after initiation of two different SERT inhibitors, citalopram and fluoxetine. In the first experiment, groups of Sprague-Dawley rats received daily meals of rice pudding either alone (N = 9) or mixed with citalopram 5 mg/kg/day (N = 27). Rats were sacrificed after 24 h, 7 days or 28 days of treatment. Sections of SN were processed for tyrosine hydroxylase (TH) immunohistochemistry. Citalopram induced a significant decrease in TH-positive cell counts at 24 h (44%), 7 days (38%) and 28 days (33%). No significant differences among the citalopram treatment groups were observed in the SN. To determine whether these changes would occur with other SERT inhibitors, we conducted a second experiment, this time with a 28 day course of fluoxetine. As was observed with citalopram, fluoxetine induced a significant 21% reduction of TH cell counts in the SN. Immunoblot analysis showed that fluoxetine also induced a 45% reduction of striatal TH. To investigate a possible role for the innate immune system in mediating these changes, we also studied the microglial marker OX42 after administration of fluoxetine and noted a significant 63% increase in the SN of fluoxtine-treated animals. These results indicate that SERT inhibition can activate microglia and alter the regulation of TH, the rate limiting enzyme for dopamine biosynthesis. These changes may play a role in mediating the extrapyramidal side effects associated with SERT inhibitors.

Role of the dopamine transporter in mediating the neuroleptic-induced reduction of tyrosine hydroxylase-immunoreactive midbrain neurons.

We have previously reported a long-term downregulation of midbrain dopaminergic neurons following treatment with neuroleptic medications. The mechanism of this effect is not clear. The dopamine transporter (DAT) has been shown to play a role in the behavioural and biochemical action of neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We postulated a role for the DAT in mediating the changes induced by neuroleptic (i.e., antipsychotic) drugs. In the first experiment, Sprague-Dawley rats simultaneously received twice daily sub-cutaneous injections of either saline or the DAT inhibitor GBR 12909 (GBR; 5 mg/kg/day) and haloperidol (HAL; 2 mg/kg/day) or vehicle. In the second experiment, the animals were treated with daily sub-cutaneous injections of saline or the DAT inhibitor GBR 129091 plus oral risperidone (RISP; 1.5 mg/kg/day) or vehicle. In a third experiment, animals were given normal drinking water or water with clozapine (CLZ, 20 mg/kg/day). Animals were sacrificed immediately after the last treatment. Sections of the substantia nigra (SN) and ventral tegmental area (VTA) were processed for tyrosine hydroxylase (TH) immunoreactivity. Cell counts were analyzed by one-way analysis of variance followed by post-hoc Tukey tests, with significance set at p<0.05. Treatment with HAL or RISP resulted in a significant reduction (HAL 27%; RISP 25%) in the number of TH-immunoreactive cells present in the medial SN pars compacta. This effect was in both cases completely blocked by administration of the DAT inhibitor. In the VTA, TH-positive cell counts were significantly decreased with RISP, but not with HAL. Once again, the RISP-induced changes were blocked by co-administration of the DAT inhibitor. CLZ treatment did not significantly affect TH-positive cell counts in the SN. These results indicate a role for the active dopamine transporter in mediating the suppression of TH expression in midbrain dopaminergic neurons by antipsychotic drugs. DAT inhibitors may prove useful in ameliorating the neurological side effects of antipsychotic medication.

Role of serotonin transporter inhibition in the regulation of tryptophan hydroxylase in brainstem raphe nuclei: time course and regional specificity.

Drugs that selectively inhibit the serotonin transporter (SERT) are widely prescribed for treatment of depression and a range of anxiety disorders. We studied the time course of changes in tryptophan hydroxylase (TPH) in four raphe nuclei after initiation of two different SERT inhibitors, citalopram and fluoxetine. In the first experiment, groups of Sprague-Dawley rats received daily meals of rice pudding either alone (n=9) or mixed with citalopram 5 mg/kg/day (n=27). Rats were sacrificed after 24 h, 7 days or 28 days of treatment. Sections of dorsal raphe nucleus (DRN), median raphe nucleus (MRN), raphe magnus nucleus (RMN) and caudal linear nucleus (CLN) were processed for TPH immunohistochemistry. Citalopram induced a significant reduction in DRN TPH-positive cell counts at 24 h (41%), 7 days (38%) and 28 days (52%). Similar reductions in TPH-positive cell counts were also observed at each timepoint in the MRN and in the RMN. In the MRN, citalopram resulted in significant reductions at 24 h (26%), 7 days (16%) and 28 days (23%). In the RMN, citalopram induced significant reductions of TPH-positive cell counts at 24 h (45%), 7 days (34%) and 28 days (43%). By contrast, no significant differences between control and treatment groups were observed in the CLN at any of the time points that we studied. To investigate whether these changes would occur with other SERT inhibitors, we conducted a second experiment, this time with a 28-day course of fluoxetine. As was observed with citalopram, fluoxetine induced significant reductions of TPH cell counts in the DRN (39%), MRN (38%) and RMN (41%), with no significant differences in the CLN. These results indicate that SERT inhibition can alter the regulation of TPH, the rate limiting enzyme for serotonin biosynthesis. This persistent and regionally specific downregulation of serotonin biosynthesis may account for some of the clinical withdrawal symptoms associated with drugs that inhibit SERT.

The neuropsychiatry of adult-onset adrenoleukodystrophy.

Adrenoleukodystrophy is an inherited X-linked peroxisomal disorder that preferentially affects the adrenal cortex, testes, and brain and may occur at almost any age. Psychiatric symptomatology is present in many of the adult-onset cases reported in the literature and may be one of the earliest manifestations of the disease. The majority of patients with psychiatric disturbances have signs and symptoms typical of mania. Psychosis and cognitive impairment may also be prominent. Metabolic diseases such as adrenoleukodystrophy are probably underrecognized as a cause of psychiatric illness. Increased awareness of these disorders will lead to accurate diagnosis, appropriate treatment selection, and genetic counseling.

Late-onset adrenoleukodystrophy associated with long-standing psychiatric symptoms.

BACKGROUND: It is not commonly appreciated that patients with adrenoleukodystrophy (ALD) can first present in adulthood with psychiatric symptoms. METHOD: This case study involved a 31-year-old man who was referred for a neuropsychiatric assessment of tardive dyskinesia and treatment-resistant psychosis. Upon neurologic examination, he was found to have spasticity, marked hyperreflexia with clonus, and bilateral Babinski signs. T2-weighted magnetic resonance imaging demonstrated severe white matter disease. Metabolic screening revealed abnormalities of very long chain fatty acids consistent with the diagnosis of ALD. These results prompted us to review the literature on late-onset ALD with attention to (1) the nature of the associated psychiatric and neurologic symptoms, (2) the neuroimaging abnormalities associated with this disorder, and (3) treatment considerations. RESULTS: Individuals with adult-onset ALD may initially present with psychiatric symptomatology. Most commonly, these patients manifest signs of mania including disinhibition, impulsivity, increased spending, hypersexuality, loudness, and perseveration. ALD patients will often have upper motor neuron findings on neurologic examination. Despite the name of the disease, patients with ALD may not have clinical evidence of adrenal dysfunction. Neuroimaging reveals diffuse, confluent white matter lesions that typically originate in the parieto-occipital region. Both neuroleptic and anticholinergic medications may result in significant side effects with little resolution of the underlying psychiatric symptoms. CONCLUSION: This case study and review of the literature illustrate the importance of performing neurologic and radiological examinations on all psychiatric patients with chronic illnesses. We emphasize the importance of reexamining and reimaging patients who are not responding to standard treatment. The clinical problem of "treatment resistance" should be seen as an indication that other diagnoses, such as an underlying metabolic disorder, need to be considered.

Neurologic side effects in neuroleptic-naive patients treated with haloperidol or risperidone.

OBJECTIVE: To compare the side effect profile of risperidone with that of oral haloperidol in patients with no previous exposure to antipsychotic drugs (APDs). BACKGROUND: Early studies suggested that the APD risperidone may have a side effect profile comparable with that of placebo. These early studies involved patients with chronic schizophrenia and a long history of APD use. Very little information is available regarding the neurologic side effects of risperidone in patients without previous APD exposure. METHODS: The authors prospectively studied 350 consecutive neuroleptic-naive patients admitted to their acute-care psychiatry service; 34 of these were treated with risperidone (mean dose, 3.2 mg/d) and 212 were treated with low-dose haloperidol (mean dose 3.7 mg/d). All patients were assessed on admission and twice weekly thereafter using rating scales for dystonia, parkinsonism, akathisia, and dyskinesia. RESULTS: The incidence and severity of dystonic reactions, akathisia, parkinsonism, and dyskinesia were comparable in the risperidone- and haloperidol-treated groups. CONCLUSIONS: The neurologic side effect profile of low-dose risperidone is comparable with that of haloperidol in patients receiving APDs for the first time. Risperidone may not be a useful alternative to typical APDs for patients with PD and psychosis.

Persistent loss of tyrosine hydroxylase immunoreactivity in the substantia nigra after neuroleptic withdrawal.

A 37 year woman developed neuroleptic induced parkinsonism that persisted long after the drug had been discontinued. This prompted a study of the effect of an eight week course of haloperidol (HAL) followed by two week withdrawal, on dopaminergic neurons of the substantia nigra in rats. Animals treated with HAL showed a highly significant 32%-46% loss of tyrosine hydroxylase (TH) immunoreactive neurons in the substantia nigra, and 20% contraction of the TH stained dendritic arbour. Neuroleptic drug induced downregulation of nigral dopaminergic neurons may help to explain the persistent parkinsonism found in many patients after withdrawal of medication.

Neuropsychiatric aspects of the adult variant of Tay-Sachs disease.

Tay-Sachs disease (a GM2 gangliosidosis) is an inherited neuronal storage disease that can affect individuals across the age spectrum. Psychosis is reported in 30% to 50% of adult-onset patients, and many are misdiagnosed with schizophrenia. Mood disorders are present in more than 25% and cognitive impairment in more than 20%. Treatment of psychosis with neuroleptics may not have a favorable risk/benefit ratio, but treatment with benzodiazepines or electroconvulsive therapy may be efficacious. Metabolic diseases such as gangliosidosis are probably under-recognized as causes of neuropsychiatric illness. Increased awareness of these disorders will lead to accurate diagnosis, appropriate treatment selection, and genetic counseling.

Haloperidol induces persistent down-regulation of tyrosine hydroxylase immunoreactivity in substantia nigra but not ventral tegmental area in the rat.

The dopamine antagonist haloperidol can cause tardive side-effects that may persist after the drug is withdrawn. We studied the time course of changes in dopaminergic neurons of the substantia nigra and ventral tegmental area following withdrawal of haloperidol. Rats received daily intraperitoneal injections of saline or haloperidol for eight weeks and were killed at two, four or 12 weeks after the final injection. Sections of substantia nigra and ventral tegmental area were processed for tyrosine hydroxylase immunohistochemistry. Quantitative morphometric analysis was carried out blinded in order to determine the number, cell body size and topography of tyrosine hydroxylase-positive cells, and the immunoreactive area of the substantia nigra and ventral tegmental area. In haloperidol-treated rats, tyrosine hydroxylase-positive cell counts were normal in ventral tegmental area but were decreased in substantia nigra by 34% at two weeks withdrawal and by 52% at four weeks withdrawal; cell counts were almost fully recovered by 12 weeks withdrawal. Cross-sectional area of tyrosine hydroxylase immunoreactivity within the substantia nigra demonstrated a similar pattern of reduction, with full recovery by 12 weeks withdrawal. Mean cell size, by contrast, was essentially unchanged at two and four weeks withdrawal, but was significantly decreased in sub-regions of substantia nigra at 12 weeks withdrawal. These results indicate that haloperidol can produce selective changes in midbrain dopamine neurons that persist long after discontinuation of the drug. This decrease in tyrosine hydroxylase-immunoreactive cell counts may play a role in the neurobiology of the persistent tardive syndromes associated with the use of neuroleptics.

Role of glutamate receptor subtypes in the differential release of somatostatin, neuropeptide Y, and substance P in primary serum-free cultures of striatal neurons.

The spiny and aspiny neuronal populations of the striatum display differential vulnerability to the toxic effects of glutamatergic agonists. Substance P-containing spiny neurons appear to be more vulnerable to NMDA-receptor-mediated toxicity and less susceptible to kainate toxicity than the somatostatin- and neuropeptide Y (NPY)-containing aspiny population. We studied whether selective glutamatergic agonists might have similar differential effects on neuropeptide release from the substance P- and somatostatin/NPY-containing neuronal populations. After collection of a baseline sample, striatal neurons in primary culture were treated with one of the following: phosphate-buffered saline, 56 mM potassium chloride (KCl), 100 microM N-methyl-D-aspartate (NMDA), 100 microM quisqualate, 100 microM kainate, or 100 microM glutamate. Baseline and treatment samples were measured by radioimmunoassay for somatostatin, NPY, and substance P. KCl and kainate provoked a selective release of somatostatin and NPY, whereas substance P measured in the same samples showed no response. By contrast, NMDA elicited a selective release of substance P without a similar increase of either somatostatin or NPY. Quisqualate evoked comparable responses in the three peptides. These results indicate that the glutamatergic regulation of somatostatin and NPY release from aspiny striatal neurons in primary culture is preferentially mediated by the kainate receptor, whereas substance P release is selectively mediated by the NMDA receptor. These findings suggest a preferential expression of functional kainate receptors on the aspiny somatostatin/NPY neurons and of NMDA receptors on the substance-P-containing spiny neurons.

The ontogeny of NADPH-diaphorase neurons in serum-free striatal cultures parallels in vivo development.

Nitric oxide synthase is co-localized with somatostatin and neuropeptide Y in a subpopulation of striatal interneurons that stain selectively for NADPH-diaphorase. We studied the ontogeny of diaphorase-positive neurons in striatal serum-free cultures derived from 15-16-day-old CD1 mice. NADPH-diaphorase staining was detected as early as embryological day 18 in vivo and day 5 in vitro. Over the next seven days the number of neurons staining for NADPH-diaphorase increased rapidly and then levelled off at about 0.5-1% of the total neuronal population both in vivo and in vitro. The cultured diaphorase neurons were also similar to their in vivo counterparts in terms of morphology and dendritic branching. Striatal neurons expressing NADPH-diaphorase exhibit similar ontogeny, morphology and neurochemical characteristics in vivo and in serum-free primary neuronal cultures. The culture system may represent a useful model for studying this important subgroup of striatal neurons.

Cortical peptide changes in Huntington's disease may be independent of striatal degeneration.

Patients with Huntington's disease (HD) develop pathological changes in cerebral cortex as well as in striatum. We studied levels of neuropeptide immunoreactivity in 13 areas of postmortem cerebral cortex dissected from 24 cases of HD and 12 controls. Concentrations of immunoreactive cholecystokinin (CCK-LI) were consistently elevated 57 to 153% in HD cortex. Levels of vasoactive intestinal polypeptide (VIP-LI) and neuropeptide Y (NPY-LI) were significantly increased in 10 and 8 of the 13 cortical regions, respectively. Concentrations of somatostatin (SRIF-LI) were increased in only 3 areas, while substance P (SP-LI) was, for the most part, unchanged. Detailed analyses of the CCK-LI and VIP-LI data showed there to be no relationship between the increased cortical peptide levels and the degree of striatal atrophy. We studied the same cortical peptides in rats with long-standing striatal lesions and found no significant changes of CCK-LI, NPY-LI, VIP-LI, or SRIF-LI in any of the 8 cortical regions that were examined. These results indicate that there are widespread and differential changes in cortical neuropeptide systems in HD and that these changes occur independently of the striatal pathology that characterizes the illness.

The ontogeny of NADPH-diaphorase neurons in serum-free striatal cultures parallels in vivo development.

Nitric oxide synthase is co-localized with somatostatin and neuropeptide Y in a subpopulation of striatal interneurons that stain selectively for NADPH-diaphorase. We studied the ontogeny of diaphorase-positive neurons in striatal serum-free cultures derived from 15-16-day-old CD1 mice. NADPH-diaphorase staining was detected as early as embryological day 18 in vivo and day 5 in vitro. Over the next seven days the number of neurons staining for NADPH-diaphorase increased rapidly and then levelled off at about 0.5-1% of the total neuronal population both in vivo and in vitro. The cultured diaphorase neurons were also similar to their in vivo counterparts in terms of morphology and dendritic branching. Striatal neurons expressing NADPH-diaphorase exhibit similar ontogeny, morphology and neurochemical characteristics in vivo and in serum-free primary neuronal cultures. The culture system may represent a useful model for studying this important subgroup of striatal neurons.