Current Psychiatry Reviews - Volume 1, Issue 2, 2005

Background. There is a body of literature on metamphetamine psychosis dating back to the 1950's with a recent resurgence of interest following increase in use worldwide. Distinct similarities appear to exist between metamphetamine psychosis and schizophrenia. Aims. The aim of this paper is to critically review the literature on metamphetamine psychosis. Method. Searches on Medline, Psycinfo and Cochrane were undertaken, references were followed and recent editions of major journals reviewed. There is a vast array of literature on stimulants and psychosis. I have deliberately limited my data to that on metamphetamines, only citing other data if particularly well known and relevant to distinguish. Data in Japanese has been quoted with reference to where cited. Results. Metamphetamine psychosis has been observed as a paranoid hallucinatory state developing gradually with repeated metamphetamine abuse and possibly continueing after metamphetamine withdrawal. Also noted is a lasting susceptibility to recurrence of the paranoid hallucinatory state with neuroleptics preventing this recurrence. Patients with persistent metamphetamine psychosis can develop long lasting residual symptoms resembling negative symptoms of schizophrenia. In animals intermittent administration of smaller doses of metamphetamine appears to lead to augmentation of behaviour, and increases in dopamine and seretonin levels. Also it appears that a challenge injection or stress can cause the same responses, which are inhibited by dopamine antagonists. Larger repeated doses of metamphetamine appear to lead to long lasting depletion of dopamine and seretonin. Conclusions and clinical importance. There are clear clinical similarities between metamphetamine psychosis and schizophrenia altered in both conditions with the use of antipsychotics. A major as yet unanswered question is whether metamphetamine can cause schizophrenia. The literature describes a number of changes in dopamine and seretonin systems. More research in this field could increase our understanding of transmitters and receptors, thereby helping our quest in improved drug development for both illnesses. Declaration of interest. Nil.

A growing body of evidence suggests that cytokines have a role in schizophrenia. Cytokines are involved in neurodevelopment, schizophrenic psychopathology, and neurodegeneration, and these processes are all part of the pathophysiology of schizophrenia. Cytokines modulate neuronal action, differentiation, and survival during neurodevelopment and are important factors in the processes of neurotoxicity and neurodegeneration. Cytokines also play a role in the activity and survival of neurons that utilize certain neurotransmitters, particularly dopamine, serotonin, and glutamate. This paper addresses the potential role of the cytokine network in the pathophysiology of schizophrenia.

Idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome, GS) is a relatively common congenital hyperbilirubinemia occurring in 3-7% of the world population. It has been recognized as a benign familial condition in which hyperbilirubinemia occurs in the absence of structural liver disease or hemolysis, and the plasma concentration of conjugated bilirubin is normal. Recently, it was reported that unconjugated bilirubin had neurotoxicity in the developing nervous system. The ‘neurodevelopmental hypothesis’ of schizophrenia was proposes that a yet-unidentified event occurring in utero or early postnatal life. We have observed that patients suffering from schizophrenia frequently present an increased bilirubin plasma concentration when admitted to the hospital. Therefore, we had notice the relation between unconjugated bilirubin and the etiology and vulnerability of schizophrenia.

Recent studies on animals and humans point to the possibility that environmental events might impact on genetic predisposition to abnormal reactions after CNS lesion, causing deviations in the natural course of brain maturation that may result in neuropsychiatric disorders. The literature on the genetic basis of obstetric complications risk is here summarized and linked to the large body of studies indicating perinatal and prenatal adverse events as significant antecedents of schizophrenia. The hypothesis of an important link between obstetric complications on a genetic basis and the risk of schizophrenia is put forward, with an illustration of the studies that will allow accepting or rejecting the proposed hypothesis.

Multiple lines of evidence suggest that genetic factors and environmental factors as well as a dysfunction in the glutamatergic neurotransmission contribute to the pathophysiology of schizophrenia. Communication between neurons and glia is essential for axonal conduction, synaptic neurotransmission, and information processing, and thus is required for normal functioning of the nervous system during development and throughout adult life. A number of studies have demonstrated that the substances which communicate between neurons and glia are altered in the blood, cerebrospinal fluid (CSF), and postmortem brain samples of schizophrenic patients. These findings suggest that neuron-glia communication might be impaired in the brains of schizophrenic patients. In this article, we review the imbalance of neuron-glia communication presented in the neurodevelopmental hypothesis as well as the glutamate hypothesis of schizophrenia. First, we discuss the role of growth factors (e.g., basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), midkine), brain-derived neurotrophic factor (BDNF) and cytokines in the pathophysiology of schizophrenia. Second, we focus on the role of endogenous substances (glutamate, glutamine, D-serine, kynurenic acid, and glutathione), which modulate the NMDA receptor function, in the pathophysiology of schizophrenia.

The clinical outcome of patients suffering from schizophrenic psychoses has been considerably improved with typical antipsychotic drugs, however, up to 40 % of the cases show treatment resistant symptoms. Even therapy with atypical substances such as risperidone, olanzapine, quetiapine, sulpiride, amisulpride, and ziprasidone often fails in reaching complete remission due to resistant schizophrenic symptoms or dose-limiting side effects. As this also holds true for monotherapy with clozapine, a substance with proved efficacy in formerly resistant cases, increasing numbers of patients receive atypical antipsychotic drugs in addition to clozapine. This review systematically evaluates case reports and clinical investigations on the combined application of clozapine with other atypical antipsychotic drugs. Details about indication, methodology and effects of the investigations are summarized. Only one double blind, placebo-controlled trial on the combination with sulpiride was found in a total number of 34 publications, encompassing a total of 1250 patients. Favorable effects on psychotic symptoms or improvements of clozapine-induced side effects were described for every combination approach. In some cases, pharmacokinetic interactions or serious unfavorable effects were reported. In conclusion, most of the combination therapies follow a neurobiological rationale. There are major differences in the level of evidence regarding their safety, tolerability and effectiveness. We discuss criteria for the indication of a clozapine augmentation and differential indication for existing alternatives. Additional randomized prospective trials are needed in order to systematically evaluate these strategies.

Recent in vitro and in vivo studies reveal that mood stabilizers lithium and valproate activate the extracellular signal-regulated kinase (ERK) pathway and the phosphoinositide 3-kinase (PI3K) pathways. The activations of the ERK and PI3K pathways are major signaling mechanisms by which neurotrophic factors modulate neurogenesis, neuronal growth and regeneration, neuronal survival, and synaptic plasticity. Like neurotrophic factors, lithium and valproate promote neurite outgrowth and axonal regeneration in cultured neuronal cells and in injury models utilizing retinal cells, sciatic nerve, and spinal cord. These mood stabilizers also enhance neurogenesis in cultured cortical and hippocampal cells and in the hippocampal dentate gyrus of adult animals. Treatments with these mood stabilizers protect cultured cells against a variety of insults and reduce neuronal loss and associated functional deficits in animal models of Alzheimer's disease, HIV-associated encephalitis and dementia, Huntington's disease, ischemia, and Parkinson's disease. Crosssectional and longitudinal brain imaging studies show that lithium treatment increases brain N-acetyl aspartate levels and cerebral gray matter volumes in patients with mood disorders. These data suggest that mood stabilizers and neurotrophins share common mechanisms of action that may contribute to their therapeutic effects.

Suicidal ideation is not uncommon in the general population and is even more prevalent in psychiatric samples; however, most individuals who experience ideation will not attempt suicide and even fewer will complete suicide. Despite these discrepancies, the number of studies investigating risk factors for serious suicidal behavior (i.e., attempts and completions) is relatively small. We first review studies in the literature which focus on the distinction between attempted and completed suicide and/or which predict completion status. We then highlight a program of research in our own laboratory which is grounded in Joiner's interpersonal-psychological theory of attempted and completed suicide. The theory posits that serious suicidal behavior will not occur unless an individual has both the desire to commit suicide and the ability to do so. Two factors contribute to an individual's desire for suicide, a thwarted sense of belongingness and a sense of perceived burdensomeness on others, while the ability to commit suicide can be acquired over time through habituation to the physical and mental pain involved in self-injury. Finally, we discuss implications of the theory for assessment and treatment of suicidal behavior.

Over the past half century, most studies investigating the neural substrates of drug addiction have focused on the mesolimbic dopamine reward circuitry. Yet recent evidence suggests a critical role for glutamate neurotransmission in addiction-related behaviors. Glutamate receptors, both ionotropic and metabotropic, are widely expressed throughout the central nervous system. Dissection of the role of individual glutamate receptor subtypes in addictive processes has been aided by the development of pharmacological ligands selective for glutamate receptor subtypes, and by the generation of genetically altered rodents in which the gene encoding an individual glutamate receptor protein or receptor subunit has been deleted or altered. A pivotal study identifying a specific role for the type 5 metabotropic glutamate receptor (mGlu5) in drug addiction was published in 2001 by Chiamulera and colleagues. These investigators demonstrated that mice lacking functional mGlu5 receptors failed to self-administer cocaine and did not exhibit cocaine-induced hyperlocomotion, while food seeking behavior remained unaltered. These findings, and a subsequent flurry of other animal studies utilizing selective mGlu5 antagonists, have confirmed that inhibition of mGlu5 receptor function reduces drug self-administration and/or other behaviors induced by abused drugs including cocaine, amphetamine, nicotine, and alcohol. In this paper these preclinical studies demonstrating a clear role for mGlu5 receptors in drug addiction are reviewed. Summaries of the neuroanatomical distribution, pharmacology and neurotransmitter release-altering properties of mGlu5 receptors are also given. From this review, it is clear that additional studies are needed to determine (1) the efficacy of mGlu5 antagonists in reducing selfadministration of all drugs of abuse, (2) neuroanatomical loci and neurochemical mechanisms by which mGlu5 regulate addictive behaviors, (3) the efficacy of mGlu5 antagonists in various models of craving and relapse, and (4) the ability of mGlu5 antagonists to alter various forms of neuronal plasticity associated with acute or chronic drug exposure. Such studies will hopefully prove a basis for developing novel mGlu5-based pharmacotherapies to aid in the treatment of drug addiction in humans.

Background. The majority of those suffering from anxiety or related disorders are outpatients, and presumably involved in daily activities such as driving a car. However, anxiolytic drugs may possess sedative properties that reduce alertness and produce sleepiness. Therefore, it must be questioned whether it is safe to drive a car when treated with these drugs. Methods. A MEDLINE literature search (keywords driving and anxiety) and cross-references identified 14 placebo-controlled, double-blind studies that examined the effects of anxiolytic drugs on driving ability by conducting the on-the-road driving test during normal traffic. Primary parameter of the driving test is the Standard Deviation of Lateral Position (SDLP), the weaving of the car. Data from epidemiological studies was summarized as supportive evidence. Results. After single dose administration of benzodiazepines and related GABAergic compounds (diazepam, lorazepam, alprazolam, oxazepam, alpidem, suriclone, zolpidem) driving performance was significantly impaired. Further, although tolerance develops, driving studies show that the impairing effects of benzodiazepines and related GABAergic compounds may still be present after on week of daily treatment (demonstrated for diazepam, lorazepam, alpidem, suriclone). Driving performance was also significantly impaired after single dose administration of TCAs (imipramine, amitriptyline), but after repeated use of TCAs tolerance developed to the impairing effects on driving ability. In contrast, SSRIs (paroxetine, fluoxetine), venlafaxine, 5HT-antagonists (ritanserin, ondansetron) and buspirone produced no significant impairment on the driving test after both acute and repeated administration. These findings were in line with epidemiological evidence. Conclusions. Patients treated with benzodiazepines, GABAergic compounds, or TCAs should be cautioned when driving a car. Driving a car when treated with buspirone, venlafaxine, 5HT-antagonists, and SSRIs seems relatively safe.