Felix-Martin Werner

Classical Neurotransmitters and Neuropeptides Involved in Major Depression: a Review

ABSTRACT We propose several pathways that could be involved in major depression. According to our proposal, noradrenaline hypoactivity could occur through a strong presynaptic GABAergic inhibition, via GABAB receptors, and serotonin hypoactivity through a strong glutaminergic inhibition via subreceptor 5 of the metabotropic glutaminergic receptor. In this sense, it is important to know whether the antagonists of such receptors might be able to improve the symptoms observed in major depression. Some neuropeptides are also altered in such states (corticotropin-releasing hormone, neuropeptide Y, galanin). It is also important to know whether in addition to current antidepressants the administration of neuropeptides and their agonists/antagonists could ameliorate depressive symptoms.

Safety of antipsychotic drugs: focus on therapeutic and adverse effects

Introduction: Schizophrenia is a chronic psychiatric disease, which is treated by antipsychotic drugs. These drugs are mostly D2 and 5-HT2A antagonists and have extrapyramidal side effects depending on the D2 antagonistic effect. Recently admitted antipsychotic drugs also have systemic side effects. Clozapine, which has the strongest antipsychotic effect, can cause neutropenia. A problem in the treatment of schizophrenia is poor patient compliance leading to the recurrence of psychotic symptoms. Areas covered: A search was carried out in Medline using the following terms: antipsychotic drugs, antipsychotic effect, risperidone, olanzapine, clozapine, ziprasidone, aripiprazol, asenapine, questiapine, cariprazine, lurasidone, arrythmia, diabetes mellitus, weight gain, epileptic activity, extrapyramidal symptoms, sexual activity, clinical trials and tolerability. Expert opinion: Most clinical trials describe a good antipsychotic effect of the currently used antipsychotic drugs. The efficacy and safety of the antipsychotic drugs also depend on the form of schizophrenia, for example, the chronic recurrent form of schizophrenia. Clozapine and olanzapine have the safest therapeutic effect, while the side effect of neutropenia must be controlled by 3 weekly blood controls. If schizophrenia has remitted and if patients show a good compliance, the adverse effects can be controlled. The pharmacological treatment should be combined with social therapies and psychoeducation in order to reach a good therapeutic outcome.

Serotonergic Drugs: Agonists/Antagonists at Specific Serotonergic Subreceptors for the Treatment of Cognitive, Depressant and Psychotic Symptoms in Alzheimer's Disease.

BACKGROUND Alzheimers disease is a neurodegenerative disease showing alterations in classical neurotransmitters, above all in the hippocampus and prefrontal/temporal cortices. In this disease, acetylcholine shows hypoactivity, noradrenaline first shows hyperactivity, and during the course of the disease an increasing hypoactivity, glutamate shows hyperactivity and excitotoxicity and GABA shows hypoactivity. In post-mortem studies, serotonin levels and the number of specific serotonergic subreceptors, for example 5-HT1B receptors, decreased. METHODS We summarized the alterations of classical neurotransmitters in the brain regions involved in cognitive, depressive and psychotic symptoms in Alzheimers disease. Starting from these neurotransmitter alterations, we describe neural networks including specific serotonergic subreceptors in the involved brain regions. RESULTS In the hippocampus and prefrontal cortex, serotonin levels are associated with cognitive functions, whereas in the brainstem serotonin levels are related with affective symptoms. Psychotic symptoms which can occur in patients with Alzheimers disease are associated with dopamine and serotonin hyperactivity in the mesolimbic system and hippocampus. The interaction between classical neurotransmitters and their specific subreceptors is shown in different brain areas. CONCLUSION In clinical trials, the therapeutic effects of 5-HT4, 5-HT7 agonists and 5-HT3, 5-HT6 antagonists have been examined to improve cognitive symptoms in Alzheimers disease. In these trials, 5-HT4 agonists and 5-HT4 antagonists showed a significant better effect in improving cognitive functions than placebo. The effect of such drugs on the formation of amyloid plaques is also examined. The appropriate use of antidepressant and antipsychotic drugs with an agonism or antagonism at specific serotonergic subreceptors is pointed out. Serotonin-selective antidepressant drugs significantly improve depressant symptoms and daily activities in Alzheimer patients and they are used to treat aggressive behaviour. Among the second-generations antipsychotic drugs (D2 and 5-HT2A antagonists), drugs with a favorable metabolic profile should be used.

Classical Neurotransmitters and Neuropeptides Involved in Schizophrenia: How to Choose the Appropriate Antipsychotic Drug?

We summarize the alterations of classical neurotransmitters and neuropeptides, including their specific subreceptors, involved in schizophrenia. The essential susceptibility genes in schizophrenia and their coherence to neurotransmitter alterations are highlighted. In this sense, dopamine and serotonin hyperactivity in the mesolimbic system and the hippocampus is due to a reduced presynaptic inhibition carried out by GABA and glutamate, which is due to the susceptibility genes. A neuronal network in the brain regions involved in schizophrenia is developed in order to derive novel therapeutic approaches. A survey of the mechanisms of action of conventional and newer antipsychotic drug is given. We suggest the appropriate antipsychotic drugs considering the symptoms of schizophrenic and their possible side effects. It is important to examine the susceptibility genes in a cohort of patients in order to find out which patients profit more from antipsychotic drugs: those that exert a stronger D2 antagonistic effect or those that exert a stronger 5HT2A antagonistic effect. One question to be answered is whether refractory symptoms such as persistent acoustic hallucinations could be improved with novel antipsychotic drugs.

New developments in the management of schizophrenia and bipolar disorder: potential use of cariprazine.

Cariprazine is a recently developed antipsychotic drug with a partial agonism for the D2 and D3 receptors. It shows a tenfold greater affinity for the D3 receptor. In clinical trials, its therapeutic effect has been tested in patients with an acute exacerbation of schizophrenia and in patients with acute mania in bipolar disorder. Like risperidone, cariprazine improves positive and negative schizophrenic symptoms, and ameliorates cognitive functions. Cariprazine induces extrapyramidal symptoms less often than risperidone and can cause acute akathisia. It is a prolactin-sparing antipsychotic drug and has a favorable metabolic profile. In acute mania in bipolar disorder, it treats manic symptoms significantly better than placebo. As a consequence of its improved adverse effects, cariprazine improves patients’ quality of life to a greater extent than other second-generation antipsychotic drugs. Cariprazine is a promising antipsychotic drug in the treatment of schizophrenia, acute mania in bipolar disorder, and in schizophrenia with mania. In these patients, its long-term therapeutic effect and its action in comparison with other second-generation antipsychotic drugs, above all aripiprazole, remain to be tested in clinical trials.

Might Combined GABAA Agonists and NMDA Antagonists have a Therapeutic and maybe a Prophylactic Effect in Alzheimer's and Parkinson's Disease?

Alzheimer’s and Parkinson’s diseases are neurodegenerative diseases which cannot be cured so far. In both diseases, a GABAergic-glutaminergic neurotransmitter imbalance might occur. Neural networks are suggested for Parkinson’s disease in the extrapyramidal system and for Alzheimer’s disease in the hippocampus and the temporal cortex. Combined GABAA agonists and NMDA antagonists might have therapeutic and maybe prophylactic properties in Alzheimer’s and Parkinson’s disease. It is important to examine the neural networks in the brain areas involved in both diseases. This would offer the possibility to try an early beginning pharmacotherapy of these, up to now, incurable diseases.

Additional Antidepressant Pharmacotherapies According to a Neural Network

Major depression, a frequent psychiatric disease, is associated with neurotransmitter alterations in the midbrain, hypothalamus and hippocampus. Deficiency of postsynaptic excitatory neurotransmitters such as dopamine, noradrenaline and serotonin and a surplus of presynaptic inhibitory neurotransmitters such as GABA and glutamate (mainly a postsynaptic excitatory and partly a presynaptic inhibitory neurotransmitter), can be found in the involved brain regions. However, neuropeptide alterations (galanin, neuropeptide Y, substance P) also play an important role in its pathogenesis. A neural network is described, including the alterations of neuroactive substances at specific subreceptors. Currently, major depression is treated with monoamine reuptake inhibitors. An additional therapeutic option could be the administration of antagonists of presynaptic inhibitory neurotransmitters or the administration of agonists/antagonists of neuropeptides.

Pharmacological options in the treatment of antipsychotic-inducedextrapyramidal symptoms

Schizophrenia is treated by second-generation antipsychotic drugs, which are mostly D2 and 5-HT2A antagonists, and partly by first-generation antipsychotic drugs. Extrapyramidal symptoms, for example dyskinesia, dystonia or parkinsonism can occur as a consequence of the D2 receptor blockade. The functions of classical neurotransmitters in the mesolimbic and extrapyramidal systems are described, and neural networks are added. A D2 receptor blockade leads to a dopaminergic-cholinergic neurotransmitter imbalance in the extrapyramidal system. Pharmacologial options to treat transiently extrapyramidal symptoms are M4 antagonists, GABAA agonists and NMDA antagonists. The development of newer second-generation antipsychotic drug such as aripiprazole and cariprazine reduces the frequency and severeness of extrapyramidal symptoms, because these antipsychotic drugs have a partial agonism at the D2 receptor.

Treatment of Bipolar Disorder according to a Neural Network

Here, we describe the alterations of excitatory neurotransmitters (dopamine, serotonin, noradrenaline, acetylcholine), glutamate and GABA (a presynaptic inhibitory neurotransmitter) in the brain areas (brainstem, hypothalamus, hippocampus) involved in bipolar disorder. The coherence between the pituitary hypothalamicadrenocortical axis and the existing neurotransmitter alterations is pointed out. Neural networks are described in the concerned brain areas, including the neurotransmitters and the depending subreceptors, on which the prophylactic drugs exert their effects. A survey of the commonly used prophylactic drugs is also given.

Classical Neurotransmitters and Neuropeptides involved in Parkinson's Disease: A Multi-Neurotransmitter System

Parkinson’s disease is a neurodegenerative disease with motor and non-motor symptoms. In Parkinson’s disease, a neurotransmitter imbalance occurs in the extrapyramidal system with a dopamine and GABA deficiency and an acetylcholine and glutamate surplus. Other classical neurotransmitters such as serotonin, the neuroactive substance adenosine and neuropeptides such as dynorphin and substance P are also involved in the pathophysiology of the disease. Here, we describe the alterations of the involved neuroactive substances and the relationships between them in the extrapyramidal system. From the findings previously reported in the literature, here a neural network is developed in the extrapyramidal system. Additional anti-Parkinsonian drugs and their actions in the neural network are also pointed out, since a multimodal pharmacotherapy of the disease might improve its outcome.