Integrated theory to unify status among schizophrenia and manic depressive illness.

Tryptophan hydroxylase 1 is primarily expressed in the gastrointestinal tract, and has been associated with both schizophrenia and depression. Although decreased serotonin activity has been reported in both depression and mania, it is important to investigate the interaction between serotonin and other neurotransmitter systems. There are competitive relationships between branched-chain amino acids, and tryptophan and tyrosine that relate to physical activity, and between L-3,4-dihydroxyphenylalanine (L-DOPA) and 5-hydroxytryptophan (5-HTP), both highly dependent on intracellular tetrahydrobiopterin concentrations. Here, I propose a chaos theory for schizophrenia, mania, and depression using the competitive interaction between tryptophan and tyrosine with regard to the blood-brain barrier and coenzyme tetrahydrobiopterin. Mania may be due to the initial conditions of physical hyperactivity and hypofunctional 5-HTP-producing cells inducing increased dopamine. Depression may be due to the initial conditions of physical hypoactivity and hypofunctional 5-HTP-producing cells inducing decreased serotonin. Psychomotor excitation may be due to the initial conditions of physical hyperactivity and hyperfunctional 5-HTP-producing cells inducing increased serotonin and substantially increased dopamine. The hallucinatory-paranoid state may be due to the initial conditions of physical hypoactivity and hyperfunctional 5-HTP-producing cells inducing increased serotonin and dopamine.

Neuroleptic malignant syndrome in a patient with Parkinson's disease: a case study.

Neuroleptic malignant syndrome (NMS) is a potentially lethal condition that has been described in patients with idiopathic Parkinson's disease (PD) after long-term dopaminergic medications are suddenly stopped or moderately decreased. If patients with PD develop severe rigidity, stupor, and hyperthermia, L-Dopa withdrawal should be suspected and the dopaminergic drug restarted as soon as possible to prevent rhabdomyolysis and renal failure. Nurses who are knowledgeable about NMS can provide prompt identification of the PD patient's condition and prevent a potentially lethal cascade of symptoms.

Coagulation-fibrinolysis abnormalities in patients receiving antiparkinsonian agents.

Neuroleptic malignant syndrome (NMS) is induced by alteration of medication in Parkinson's disease (PD); and blood coagulation disorder is regarded as one of the mechanisms implicated in NMS. We have studied markers of blood coagulation and fibrinolysis in 270 patients with PD and 159 healthy controls matched in age and gender. The average values of prothrombin time (international normalized ratio) and plasma levels of prothrombin fragment(1+2), D-dimer, plasmin-alpha 2 antiplasmin complex, thrombomodulin and E-selectin were higher in patients receiving antiparkinsonian agents as compared to the patients without any medication or healthy controls. The effect of antiparkinsonian drugs was analyzed by dividing the patients into three groups according to the medication: the patients under the combination therapy with levodopa and a dopamine agonist, the patients administered levodopa, and those that received a dopamine agonist. Of the three groups, the patients under the combination therapy had the highest values of these markers, and those treated with only levodopa had the lowest values. PD patients receiving antiparkinsonian drugs are often associated with blood coagulation abnormalities, and plasma hemostatic markers should be routinely assessed in the management of such patients. Further study is needed to determine whether these abnormalities predispose to the development of NMS.

Genetic predisposition to neuroleptic malignant syndrome : implications for antipsychotic therapy.

The pathogenetic mechanism of neuroleptic malignant syndrome (NMS), a potentially lethal adverse effect of antipsychotics, is not well understood. In addition to acquired risk factors, clinical observations suggest a number of genetic factors predisposing patients to NMS. Recent findings in pharmacogenetics indicate that the genetic polymorphisms for drug-metabolizing enzymes, drug transporters, and possibly drug-targeting molecules, are associated with the interindividual differences in drug responses concerning both efficacy and adverse reactions. Genetic association studies have sought to identify polymorphisms influencing susceptibility to NMS, especially with respect to the dopamine D(2) receptor, serotonin receptor, and cytochrome p450 2D6. While a few candidate polymorphisms were associated with NMS, a large controlled study is needed to attain statistical power. On the other hand, NMS might include heterogeneous conditions with common characteristic symptoms but different causative mechanisms. Further analysis of individuals with identified genetic mutations or polymorphisms should advance our understanding of mechanisms underlying NMS.

Biopterin metabolism in patients with malignant syndrome.

We examined the autopsied brains of two parkinsonian patients who had malignant syndrome (MS). Neopterin and biopterin contents, and GTP cyclohydrolase I activity were measured in various region of the brain. We found relatively higher GTP cyclohydrolase I activities in the hypothalamus compared with other regions of the brain from patients with MS. This finding suggested a possible involvement of biopterin metabolism in pathophysiology of MS. This is the first report on biopterin metabolism in the brains of patients with MS.

Is neuroleptic malignant syndrome a neurogenic form of malignant hyperthermia?

Neuroleptic malignant syndrome is a rare and potentially lethal disorder associated with the use of antipsychotic medications. Heightened vigilance on the part of clinical providers has reduced morbidity and mortality caused by this disorder over the past decade, but there is still no consensus regarding its diagnosis, pathophysiology, or treatment. Efforts to demonstrate a direct link between neuroleptic malignant syndrome and malignant hyperthermia have been unsuccessful, indicating mutually distinct etiologies despite striking clinical similarities. This paper concisely reviews essential aspects of electromechanical transduction in muscle and nerve cells and current knowledge concerning the pathophysiology of malignant hyperthermia and neuroleptic malignant syndrome. Utilizing this conceptual framework, the author proposes that neuroleptic malignant syndrome may be caused by a spectrum of inherited defects in genes that are responsible for a variety of calcium regulatory proteins within sympathetic neurons or the higher order assemblies that regulate them. In this proposed model, neuroleptic malignant syndrome may be understood as a neurogenic form of malignant hyperthermia.

Neuroleptic malignant syndrome in a patient with succinic semialdehyde dehydrogenase deficiency.

A patient suffering from a rare enzyme deficiency developed a malignant neuroleptic syndrome after having been treated with one single dose of haloperidol. We investigated the patient's serum for all frequent polymorphisms in cytochrome P450 2D6, assuming him to be a poor neuroleptic metabolizer. We will also discuss other potential mechanisms inducing this disturbance and its differential diagnoses.

Neuroleptic malignant syndrome without neuroleptics.

Neuroleptic malignant syndrome is an uncommon condition characterised by hyperthermia, rigidity, altered mentation and autonomic instability. Recognition of this condition is essential because its complications are potentially lethal, leading to death in 20% of patients. Not all cases of this syndrome are associated with the use of neuroleptics and there is an increasing number of reports of this condition occurring after withdrawal of therapy with dopaminergic drugs, typically in patients with Parkinsonism. In this setting, there is tremendous potential for misdiagnosis and delay in institution of treatment because of the traditional and common association of the syndrome with the use of neuroleptics only. We report a case of neuroleptic malignant syndrome in a patient with Parkinsonism subsequent to the withdrawal of levodopa and bromocriptine.

Selective destruction of nigrostriatal dopaminergic neurons does not alter [3H]-ryanodine binding in rat striatum.

Dopamine nigrostriatal neurons are important for motor control and may contain a particularly dense population of ryanodine receptors involved in the control of dopamine release. To test this hypothesis, we used a classical model of unilateral selective lesion of these neurons in rats based on 6-hydroxydopamine (6-OHDA) injection into the substantia nigra. Binding of [3H]-GBR 12935, used as a presynaptic marker since it labels specifically the dopamine uptake complex, was dramatically decreased by 83-100% in striatum homogenates after 6-OHDA lesion. On the contrary, no reduction of [3H]-ryanodine binding was observed. The present data indicate that [3H]-ryanodine binding sites present in rat striatum are not preferentially localized in dopaminergic terminals.

Selective destruction of nigrostriatal dopaminergic neurons does not alter [3H]-ryanodine binding in rat striatum

Dopamine nigrostriatal neurons are important for motor control and may contain a particularly dense population of ryanodine receptors involved in the control of dopamine release. To test this hypothesis, we used a classical model of unilateral selective lesion of these neurons in rats based on 6-hydroxydopamine (6-OHDA) injection into the substantia nigra. Binding of [3H]-GBR 12935, used as a presynaptic marker since it labels specifically the dopamine uptake complex, was dramatically decreased by 83-100 percent in striatum homogenates after 6-OHDA lesion. On the contrary, no reduction of [3H]-ryanodine binding was observed. The present data indicate that [3H]-ryanodine binding sites present in rat striatum are not preferentially localized in dopaminergic terminals

Structural change in dopamine D2 receptor gene in a patient with neuroleptic malignant syndrome.

Dysfunction of the dopaminergic system has been suggested as a pathogenic mechanism in neuroleptic malignant syndrome. Therefore, we examined the complete coding sequences of the dopamine D2 receptor (DRD2) gene for structural abnormalities in 12 patients with a history of NMS, including two cases of familial NMS. Mutational analysis was performed by denaturing gradient gel electrophoresis (DGGE), a highly sensitive technique for detecting sequences differences. We found in one patient with a history of NMS a nucleotide substitution at codon 310 (CCG-->TCG) of exon 7 of the DRD2 gene which predicts the replacement of proline to serine in the third cytoplasmic loop of the receptor, a part of the receptor that interacts with G-proteins. A larger series of patients with NMS needs to be investigated to establish whether this allele is associated with an increased susceptibility to NMS.

D1 and D2 dopamine receptor distribution in the neuroleptic nonresponsive and neuroleptic responsive lines of mice, a quantitative receptor autoradiographic study.

The present study uses quantitative receptor autoradiography to examine D1 and D2 receptor binding in the neuroleptic responsive and neuroleptic nonresponsive (NNR) lines of mice. The neuroleptic responsive and NNR mice have differed for at least eight generations by an order of magnitude in their sensitivity (ED50s) to catalepsy induced by neuroleptics with a high D2/D1 receptor activity profile. Across the entire rostral-caudal dimensions of the lateral caudate-putamen (CPu), of the dorsomedial CPu, the nucleus accumbens and substantia nigra zona reticulata, we found no difference in the density of [3H]SCH 23390 binding sites. [3H]Spiroperidol binding sites were not different in the dorsomedial CPu or nucleus accumbens but were significantly decreased (20-30%) in the NNR line in the caudal aspect of the lateral CPu. The NNR line also showed a significant elevation of D2 autoreceptors across all the midbrain dopamine cell groups (A8, A9 and A10); the increases ranged from 20 to 50%. Overall, the data show that selection of mice for response and nonresponse to neuroleptic-induced catalepsy is associated with significant changes in D2 but not D1 receptor density.

Clinical profile of clozapine: adverse reactions and agranulocytosis.

The arrival of clozapine has been one of the most significant developments in antipsychotic drug treatment since the advent of chlorpromazine ushered in the psychopharmacologic era. However, its utilization has been significantly limited and complicated by its potential to cause adverse effects and agranulocytosis in particular. It must be emphasized that clozapine has a side effect profile that is in many ways distinct from standard typical antipsychotic drugs. Side effects with clozapine are common and range from the benign to the potentially lethal. The most common side effects include sedation, dizziness, and sialorrhea during sleep; the most serious are agranulocytosis, seizures and respiratory depression. Although side effects from clozapine are not necessarily preventable, they are for the most part manageable. Even with the most serious adverse effects, proper knowledge of the medication's actions, clinical vigilance, and prompt intervention can prevent the occurrence of significant morbidity and mortality as a consequence of clozapine treatment.

Low melanin content of substantia nigra in a case of neuroleptic malignant syndrome.

A 19-year-old man suffering from a first episode of schizophrenia developed a neuroleptic malignant syndrome (NMS) after administration of haloperidol and levomepromazine. After five weeks of neuroleptic treatment he died of an unknown cause. Histological examination of the brain revealed a low melanin content in neurons in the substantia nigra (SN). Since neuromelanin in SN is the end-product of nonenzymatic dopamine degradation, the amount of melanin probably depends on the overall amount of dopamine produced during life. Thus, dopamine production must have been low in the reported case. In addition, ectopic neurons were found in subcortical white matter.

[A case of metoclopramide-induced neuroleptic malignant syndrome with cerebrospinal fluid lactic acidosis].

A case of metoclopramide-induced neuroleptic malignant syndrome with cerebrospinal fluid (CSF) lactic acidosis was reported. A 44-year-old Japanese woman noted tarry stool on July 2, 1988 and was treated with metoclopramide and cimetidine for nausea and vomiting. Hydroxyzine pamoate was also administered for insomnia at 3:10 am and she became comatose with muscle rigidity at 3:40-4:30 am on July 3. Tachycardia and high fever (39.5 degrees C) were evident at 8:00 am on July 4. She was transferred to the Kyushu University Hospital. On admission, serum creatine kinase was elevated to 1640 IU/1; MM fraction was 100%. She was diagnosed as malignant syndrome. Cerebrospinal fluid was normocellular with protein 38 mg/dl and glucose 122 mg/dl. Cerebrospinal fluid lactate increased markedly to 3.43 mmol/l, CSF pH was 7.264, HCO3- 14.4 mEq/l, indicating CSF metabolic acidosis. She became afebrile after the 10th hospital day, and gradually but completely recovered within a month. She was discharged on August 16, 1988. The anti-dopaminergic activity of metoclopramide was considered to be primarily responsible for the development of malignant syndrome in this case. Cerebrospinal fluid lactic acidosis seemed to reflect hyperpyrexia or malignant syndrome induced derangement of the brain metabolism.

Positron emission tomographic studies of changes in cerebral blood flow and oxygen metabolism in neuroleptic malignant syndrome.

Three patients with neuroleptic malignant syndrome were studied by positron emission tomography (PET), using the steady-state technique with C15O2 and 15O2. In 2 patients the PET examination was repeated after resolution of the syndrome. In 2 patients, under treatment with bromocriptine, high blood flow and oxygen metabolism were demonstrated in the striatum, cerebellum and occipital cerebral cortex during the neuroleptic malignant phase, showing that not only the dopaminergic system is disturbed but also other neurotransmitter systems are involved. In the 3rd case the PET scan findings were not as conclusive.