Efficacy of high doses of classical neuroleptics in the treatmentresistant patient

There is no published evidence for the efficacy of high dose medication as an effective strategy either to accelerate therapeutic response or to increase the number of patients who respond to medication. Neither is there any objective evidence to show that escalating the dose of a ''classical'' neuroleptic is likely to produce a beneficial response in chronically resistant patients. Furthermore, there are anecdotal reports that high dose neuroleptics can cause sudden death (due to...

Neuroanatomy of the basal ganglia relevance to Parkinsons disease

There are two main efferent pathways from the striatum to the globus pallidus, the direct pathway, which is a monosynaptic pathway making contact with the internal globus pallidus and to a lesser extent the substantia nigra, and the indirect pathway that indirectly connects to these brain regions via the lateral globus pallidus and the subthalamic nuclei. The internal globus pallidus and, to a lesser extent, the substantia nigra modulate the activity of the circuits via the thalamocortical...

Structure and function of nerve cells

Nerve cells have two distinct properties that distinguish them from all other types of cells in the body. First, they conduct bioelectrical signals for relatively long distances without any loss of signal strength. Second, they possess specific, intracellular connections with other cells and with tissues that they innervate such as muscles and glands. These connections determine the type of information a neuron can receive and also the nature of the responses it can yield. It is not within the...

Serotonin and the antipsychotic activity of neuroleptics

Given the complexity of the serotonergic system and its interaction with multiple neurotransmitter systems in the mammalian brain, it is not surprising to find that 5-HT plays a role in the aetiology of schizophrenia. Meltzer has suggested that in schizophrenia a malfunction of the mechanism whereby 5-HT modulates the release of dopamine (for example, due to the decreased inhibition by 5-HT of the release of dopamine in the mesencephalon and frontal cortex) might contribute to the enhanced...

Neurotransmitter receptor mechanisms

Role of ion channels in nerve conduction Ion channels are large proteins which form pores through the neuronal membrane. The precise structure and function of the ion channels depend on their physiological function and distribution along the dendrites and cell body. These include specialized neurotransmitter-sensitive receptor channels. In addition, some ion channels are activated by specific metal ions such as sodium or calcium. The structure of the voltage-dependent sodium channel has been...

Some types of cell that are important to brain function

The neurons are surrounded by neuroglia (or glia) cells. These differ from the neurons in that they do not have electrically excitable membranes. They comprise nearly half the brain volume and function to separate and support the neurons. There are two main types of neuroglial cells, termed the macroglia and microglia. The macroglia are divided into the astrocytes, oligodendrocytes and ependymal cells. The astrocytes are characterized by long narrow cellular processes which give them a...

The striatal dopaminergic system and Parkinsonism

The classical studies of Hornykiewicz and colleagues in the early 1960s clearly established that the symptoms of Parkinsonism were correlated with a defect in the dopamine content of the striatum. The pigmented neurons of the substantia nigra contain dopamine as the major neurotransmitter, accounting for 80 of the total dopamine content of the brain, and the principal motor abnormalities of the disease occur when the transmitter has been depleted by about 80 . While it is now established that...

Serotonin and hallucinogenic activity

There is abundant experimental evidence to show that serotonin plays a major role in the mechanism of action of hallucinogens, but it is presently unclear whether the actions of hallucinogens can be explained by their agonistic or antagonistic actions. LSD, for example, may behave either as an agonist or antagonist depending on the particular tissue, concentration and experimental condition, whereas the tryptamine type of hallucinogens usually act as agonists. Experimental evidence nevertheless...

Sedative drugs of abuse

Alcohol, the barbiturates and the benzodiazepines are included in this group, all of which facilitate GABAergic activity. The use of alcohol (ethanol) prepared from the fermentation of sugars, starches and other carbohydrates dates back to the beginning of recorded history. Alcohol is the most important drug of dependence in all industrialized countries, and the clinical and social problems that arise from its widespread abuse are legion. In the US, the total annual economic cost of alcoholism...

Phencyclidine and related compounds

Phencyclidine (PCP) was first developed as a dissociative anaesthetic in the 1950s, but its use was mainly confined to veterinary anaesthesia after it had been established that it caused delirium and hallucinations in patients undergoing anaesthesia. A closely related congener, ketamine, is however still used clinically, especially in children, as a dissociative anaesthetic, as such psychotomimetic effects are minimal. Both drugs produce intense analgesia, amnesia and finally anaesthesia after...

Psychopharmacology of Drugs of Abuse

Mankind has always shown a surprising ingenuity for finding drugs which have a pleasurable effect. Alcohol in its various forms is perhaps the oldest drug to be used for its effects on the brain, closely followed by various naturally occurring hallucinogens for example fungi have long been known to be an important component of religious ritual in many societies. Other drugs, some of which have had therapeutic uses, include the opioid analgesics such as morphine and codeine, cannabis, cocaine...

Drug dependence

Three factors are generally involved in drug dependence tolerance, physical dependence and psychological dependence. Tolerance often occurs, whereby an increasing amount of the drug must be administered to obtain the required pharmacological effect tolerance may occur as a result of the drug being more rapidly metabolized, so-called metabolic tolerance, or through a drug-induced insensitivity of the receptors or target sites upon which it acts within the brain, termed tissue tolerance. Thus...

Use of psychotropic drugs in specific childhood disorders

Attention deficit hyperactivity disorder (ADHD) This is a heterogeneous disorder of inattention, hyperactivity and impulsivity that starts in childhood and may persist into adulthood. Children with the disorder can be identified by their inattention which leads to daydreaming, distractability and difficulty in sustaining an effort to complete a task. Their impulsivity makes them accident prone and disruptive while their hyperactivity, combined with excessive talking, is poorly tolerated...

Anxiety disorders

The DSM-IV classifies anxiety disorders in children into four categories, namely social anxiety, over-anxious disorder, phobias and separation anxiety. Only separation anxiety, a fear of losing a loved one or a close attachment, has been reasonably well studied from the point of view of drug treatment. School phobia is perhaps the most severe form of separation anxiety and there are several trials to show that imipramine, in daily doses of up to 5mg kg, is effective. Many patients require drug...

The abuse potential of designer drugs

The term ''designer drug'' was first used in the US to describe a synthetic opioid analogue that was sold to heroin addicts in California in 1980 as a very potent form of heroin (called ''China white'', and reputed to be 200 times more potent than morphine). Subsequently the compound was identified as alpha-methyl fentanyl, an analogue of the dissociative analgesic fentanyl. It has been estimated that this compound has caused several hundred deaths through overdose in California alone, the main...

Serotonin and drugs of abuse

The role of 5-HT in the control of alcohol intake has received considerable attention following the discovery that 5-HT reuptake inhibitors reduce alcohol intake in alcohol dependent rats. Similar effects have been found for intracerebroventricularly administered 5-HT or its precursor 5-HTP. Regarding the type of 5-HT receptor involved, there is experimental evidence that the 5-HT1A partial agonists buspirone and gepirone are effective. Differences were found between the effects of the 5-HT3...

Huntingtons disease also known as Huntingtons chorea

Huntington's disease is named after a 19th century New York neurologist who studied several families who suffered from a severe, and lethal, motor disorder which appeared to be inherited as an autosomal dominant gene. It was calculated that 50 of the offspring of an affected person have a probability of contracting the disease. The frequency in the general population is 0.01 . Symptomatically, Huntington's disease is characterized by dyskinesias (choreoform movements) which start with the...

Affective disorders of childhood and adolescence

There is much controversy regarding the occurrence of major depressive disorder in prepubertal children. However, several studies in both the United States and Britain have suggested that depressive disorder does exist, although the frequency appears to be lower than in adolescents. There is endocrinological evidence, based on the hypersecretion of cortisol and an abnormal growth hormone response to insulin-induced hypoglycaemia, to suggest that children with major depressive disorder show...

Key References for Further Reading

No attempt will be made to give details of the experimental and clinical studies which have been surveyed in this text. I trust that the authors of these studies will forgive me for this deliberate omission, but my intention has been to create a readable text, not a detailed monograph, in which the flavour and excitement of the advances in psychopharmacology will encourage those interested to read further. With this in mind, a list of key monographs, review articles and textbooks is included...

Use of human brain tissue in drug discovery

Despite the success in using animal models to develop drugs which have similar pharmacological properties to those drugs in clinical use, they are much less successful in detecting novel compounds that have pharmacological properties, and possible therapeutic indications, that differ from the drugs that are currently available. In an attempt to improve the chance of discovering novel drugs and, at the same time, reduce the cost and increase the number of compounds which may be screened for...

Imaging methods their application to psychopharmacology

Ten years ago, neuroimaging was largely restricted to determining the localization of pathological lesions in the human brain. Due to the rapid advances in magnetic resonance imaging (MRI) and related technologies, methods have now been developed to determine the precise functional importance of brain lesions, how cognitive operations are carried out within the brain and why they fail. MRI is an example of the technological development that is no longer restricted to the crude location of a...

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Summary of the inter-relationship between the noradrenergic, serotonergic and GABAergic systems that play a role g in generalized anxiety disorder. O Figure 9.5. Diagram of the main noradrenergic tracts that are thought to be hyperactive in generalized anxiety disorder. Figure 9.5. Diagram of the main noradrenergic tracts that are thought to be hyperactive in generalized anxiety disorder. HT1A), leading to a decrease in serotonergic release. Despite the connection between the...

Serotonin and anxiolytic activity

Although the benzodiazepine anxiolytics primarily interact with the GABA receptor complex, there is ample experimental evidence to show that secondary changes occur in the turnover, release and firing of 5-HT neurons as a consequence of the activation of the GABA-benzodiazepine receptor. Similar changes are observed in the raphe nuclei where a high density of 5-HT1A receptors occurs. Such findings suggest that 5-HT may play a key role in anxiety disorders. Undoubtedly one of the most important...

Clinical pharmacology of the typical classical neuroleptics

Despite the wide differences in the potency of the neuroleptics in current use, and the differences in specificity regarding their effects on various neurotransmitter systems in the mammalian brain, there is little evidence to suggest that their overall efficacy in treating the symptoms of schizophrenia, mania and other psychoses markedly differs. Thus the ''classical'' neuroleptics appear to be effective in attenuating the positive symptoms of schizophrenia (e.g. hallucinations and delusions)...

Neurotransmitters and the pathogenesis of schizophrenia

In its original form, the dopamine hypothesis of schizophrenia postulated that the positive symptoms of the illness arose as a consequence of the Table 11.2. Risk factors for schizophrenia 1. Genetic factors - polygenic inheritance 2. Pre- and perinatal events, e.g. maternal viral infection during second trimester toxaemia and or hypoxia at birth 3. Environmental factors, e.g. the use of cannabis, brain trauma hyperactivity of the dopaminergic system, particularly in the mesocortico-limbic...

Pharmacogenetics and psychopharmacology

For more than 40 years, epidemiological studies have clearly demonstrated a tendency for diseases such as schizophrenia, bipolar disorder and autism to run in families. Thus it has been shown that such disorders are much more frequent in close relatives of patients than in the general population. For example, estimates of the increased risk of suffering from the disorder if the patient has a sibling with the disorder range from nine- to eleven-fold for schizophrenia and about sevenfold for...

Classification of the typical neuroleptics

In addition to their well-established antipsychotic properties, the neuro-leptics have a number of clinically important properties that include their antiemetic and antinauseant actions, their antihistaminic effects and their ability to potentiate the actions of analgesics and general anaesthetics. Reserpine is unique among the neuroleptics in that it is a naturally occurring alkaloid obtained from the snake plant Rauwolfia serpentina. The use of aqueous extracts of the root of this plant for...

Pseudodementia

This is defined as any condition which mimics dementia. The commonest psychiatric disorder which mimics dementia is depression in which the retardation can be confused with the apathy of dementia. The guiding principle is careful clinical assessment and, if in doubt, a trial of an appropriate antidepressant. GERIATRIC PSYCHOPHARMACOLOGY Depression A disturbance in the sleep pattern is a common symptom of depression but changes in the sleep pattern also occur as a consequence of ageing. Once...

Relationship between plasma antidepressant concentrations and the therapeutic response

Over the past 20 years there has been widespread interest in monitoring plasma antidepressant, particularly tricyclic, levels to optimize the response to treatment. One aspect of this research that is universally agreed upon concerns the extensive interindividual variability among patients, but it is still uncertain whether a knowledge of the plasma drug concentration is of clinical value. For the tricyclic antidepressants (TCAs) the two major oxidative pathways that occur in the liver are...

Functional Neuroanatomy of the Brain

Understanding the relationship between brain structure and function, and particularly how this relationship becomes disturbed in the mentally ill, is one of the major challenges to clinical and experimental neuroscientists. The brain may be described in terms of its general structure and key anatomical areas. It may also be described in terms of the cellular or subcellular structure of the different types of cells that constitute the brain. Finally it may be considered in terms of its...

Drugs used in Parkinsons disease

The discovery that dopamine was depleted in the basal ganglia of patients who suffered from Parkinsonism at the time of death led to the rational development of the therapeutic treatment, namely the use of L-dopa. Since dopamine does not cross the blood-brain barrier, and is rapidly catabolized in the wall of the intestinal tract by monoamine oxidase (MAO) the amine itself cannot be administered. However, L-dopa is rapidly decarboxylated in the brain to dopamine and it was found that high doses...

The biochemical basis of important drug interactions

The biotransformation of a drug may either lead to the termination of its pharmacological activity or, occasionally, to its activation to a pharmacologically effective entity. It is also possible that a drug may be metabolized to form pharmacologically or toxicologically active metabolites. Whatever the outcome, the biotransformation of a drug ultimately involves its conversion to a more hydrophilic form thereby facilitating its excretion into the urine. However, some lipophilic drugs and their...

Cannabis and the cannabinoids

The hemp plant, Cannabis sativa, has been known for its commercial use as a source of hemp for the manufacture of rope, sacking and so on for well over 2000 years. The hemp seeds have also been used as a source of oil, as an animal feed and as a form of soap, while the leaves were first used in China because of the psychoactive ingredients they contained. From China, the use of hemp spread first to India and then to Europe via the Middle East in the 16th century. All parts of the hemp plant...

Biochemical pathways leading to the synthesis and metabolism of the major neurotransmitters in the mammalian brain

No attempt will be made to give an overview of the main pathways of the several dozen neurotransmitters, neuromodulators and co-transmitters which are possibly involved in the aetiology of mental illness. Instead a summary is given of the relevant pathways involved in the synthesis and metabolism of those transmitters which have conventionally been considered to be involved in the major psychiatric and neurological diseases and through which the psychotropic drugs used in the treatment of such...

Some Important Psychotropic Drug Interactions

Tricyclic antidepressants + fluoxetine, paroxetine or sertraline increased pharmacological and toxicological effects of the tricyclic due to decreased hepatic metabolism. This is a potentially hazardous combination. Tricyclic antidepressants + MAOIs stroke, hyperpyrexia and convulsions can occur. Potentially a hazardous combination. Tricyclic antidepressants + directly acting sympathomimetic amines (e.g. noradrenaline, adrenaline) hypertension and arrhythmias due to enhancement of the...

Gaba

Increased density of D2 receptors Increased cortical DA innervation Increased D4-like receptor binding Alterations in D3 receptor binding Decreased presynaptic markers Decreased HC AMPA and kainate receptor expression Minor changes in FC NMDA R sub-units Altered glutamate fibres in cingulate cortex Decreased FC 5-HT2a receptor expression Increased FC 5-HT1A receptors Increased 5-HT transporter affinity Developmental and trophic roles of 5-HT Increased density of FC GABAergic terminals Increased...

Summary of the pharmacological properties of antidepressants in general use in Europe

Sertraline Muscarinic

This group of drugs was introduced during the early 1960s following the chance discovery of the antidepressant effects of imipramine. The therapeutic efficacy of the TCAs has been ascribed to their ability to inhibit the reuptake of noradrenaline and serotonin into the neuron following the release of these transmitters into the synaptic cleft. In addition, these drugs inhibit the muscarinic receptors (causing dry mouth, impaired vision, tachycardia, difficulty in micturition), histamine type-1...

Psychotropic Drug Structure

Amantadine Parkinson

Relationship between the efficacy of L-dopa treatment and time. It should be noted that patients who fail to show any improvement (< 50 ) after short-term (< 1 year) treatment with L-dopa are probably not suffering from idiopathic Non-specific MAO inhibitors such as phenelzine, isocarboxazid or tranylcypromine are contraindicated in patients on L-dopa therapy as they are likely to precipitate hyperpyrexia and hypertension. However, recently the selective MAO-B inhibitor...

The psychostimulants cocaine and the amphetamines

Psychotropics Chemical Diagram

Cocaine is a major alkaloidal component from the Andean bush Erythroxylon coca. Leaves of this plant are chewed by Andean Indians to decrease the feeling of hunger and fatigue there is little evidence that dependence is caused by this means of administration. A major health problem arises, however, when cocaine is used in industrialized countries. Thus in the US over 20 million people are estimated to use the drug, by nasal administration (snorting), injection of the salts, or smoking the free...

Neurochemical changes associated with Alzheimers disease

Scan Extrapyramidal Tracts

The pathological lesions seen in the brain of those with AD are inevitably associated with dysfunctions of the neurotransmitter systems. Of these, deficits in the neocortical cholinergic system have been well established for over a decade but more recently changes in the concentrations of the neuropeptides somatostatin and corticotrophin releasing factor (CRF) have been added to the list. Deficits in the biogenic amines noradrenaline and serotonin have also been reported to occur but a...

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Summary of the site of action of mirtazepine (NaSSA). The inhibitory a2 adrenoceptors facilitate the release of both noradrenaline and serotonin (via the heteroceptor on the 5-HT neuron). This is further enhanced by the aj receptor on the serotonin cell body. Thus mirtazepine (and to a lesser extent mianserin) enhance both noradrenergic and serotonergic Herbal antidepressants - St John's Wort (Hypericum officinalis) St John's Wort in recent years has become widely used in Europe and...

Generic and Proprietary Names of Some Common Psychotropic Drugs

This list of drugs is not intended to be entirely comprehensive and in most cases only the most frequently used proprietary names are given. For detailed coverage of the area the reader is referred to a local pharmacopoeia. Our best efforts to ensure accuracy have been made. The publisher bears no responsibility for inaccuracy. European (mainly Irish UK) trade name Concilium Madopar (with L-dopa) Artane Cogentin Akineton Lexotan Parlodel Elaril Endep Asendin Benzedrine Auralgan European (mainly...

Serotonin and its role in depression

Serotonin is believed to play a multifunctional role in depression which is to be anticipated from its involvement in the physiological processes of sleep, mood, vigilance, feeding and possibly sexual behaviour and learning, all of which are deranged to varying extents in severe depression. However, the involvement of precise serotonin receptor subtypes in depression, and in the action of antidepressants, is still far from clear. One approach to unravelling the changes in serotonin receptors in...

Relationship between plasma anxiolytic concentrations and the therapeutic response

While the individual drugs in the benzodiazepine group differ in potency, all benzodiazepines in common use have anxiolytic, sedative-hypnotic, anticonvulsant and muscle-relaxant activity in ascending order of dose. The main clinical difference between the individual drugs lies in the time of onset of their therapeutic effect, and the intensity and duration of their clinical activity. All benzodiazepines are derived from weak organic acids and some, such as midazolam, form water-soluble salts...

Novel antipsychotics in development

Serotonin receptor antagonists as antipsychotics The improvement of the secondary negative symptoms, and the symptoms of depression often associated with schizophrenia, has been an important feature of the atypical antipsychotics. Such pharmacological features may reside in the actions of the atypical antipsychotics on 5-HT2 receptors in addition to their actions on dopamine receptors. For example, all these drugs have a high affinity for 5-HT2A and 2C receptors, and to a lesser extent 5-HT6...

Aspects of the biochemical basis of depression

Research into the chemical pathology of depression has mainly concentrated on four major areas 1. Changes in biogenic amine neurotransmitters in post-mortem brains from suicide victims. 2. Changes in cerebrospinal fluid (CSF) concentrations of amine metabolites from patients with depression. 3. Endocrine disturbances which appear to be coincidentally related to the onset of the illness. 4. Changes in neurotransmitter receptor function and density on platelets and lymphocytes from patients...

Enantiomers their importance in psychopharmacology Introduction

The majority of naturally occurring drugs and biologically active compounds are asymmetrical in their chemical structure. This means that the molecule is structured around one or more carbon atoms in such a way that the molecule is distributed mostly on the right (R rectus) or left (S sinister) of the symmetrical carbon atom, the so-called chiral centre of the molecule. Thus a large proportion of psychotropic drugs in current use possess one or more chiral centres and therefore exist in pairs...

Classification of neurotransmitter receptors

Muscarinic Receptor Camp

The British physiologist Langley, in 1905, was first to postulate that most drugs, hormones and transmitters produce their effects by interacting with specific sites on the cell membrane which we now call receptors. Langley's postulate was based on his observation that drugs can mimic both the specificity and potency of endogenous hormones and neurotransmitters, while others appear to be able to selectively antagonize the actions of such substances. Thus, substances which stimulate the...

The Interrelationship Between Psychopharmacology and Psychoneuroimmunology

The adverse effects of stress and depression, the effects of bereavement, unemployment and social isolation on mental and physical health have been known since antiquity. Aristotle advised physicians, ''Just as you ought not to attempt to cure eyes without head or head without body, so you should not treat body without soul.'' One of the fathers of modern medicine put it more scientifically in the 19th century when he recommended that when attempting to predict health outcomes from tuberculosis...

Glossary of some Common Terms Used in Psychopharmacology

This glossary should be used in conjunction with the index. Action potential Addiction Adenylate cyclase Use of a legal or illicit substance or medication for non-medical or pleasurable purposes unconnected with medically approved indications. Capacity of a drug to produce physiological or psychological dependence and alter the behaviour in a manner detrimental to the individual. Refers to ability to acetylate organic compounds in the liver. A rapid acetylator refers to an individual whose...

Historical development of antidepressants

The use of cocaine, extracted in a crude form from the leaves of the Andean coca plant, has been used for centuries in South America to alleviate fatigue and elevate the mood. It was only relatively recently, however, that the same pharmacological effect was discovered when the amphetamines were introduced into Western medicine as anorexiants with stimulant properties. Opiates, generally as a galenical mixture, were also widely used for centuries for their mood-elevating effects throughout the...

Potential cardiotoxicity of antipsychotic drugs

Most antipsychotic drugs have effects on the heart as a consequence of their pharmacological actions. Recently, thioridazine has been subjected to a restricted indication notice and the atypical antipsychotic sertindole had its licence withdrawn because of concerns about its potential cardiotoxicity. It has been known since the 1960s that ECG abnormalities are relatively common in those patients on antipsychotics, occurring in approximately 25 of all cases. The most commonly reported changes...

Nipecotic Acid

Folic Acid Psychotropic Drugs Decrease

Clozapine Amoxapine Clomipramine Amitriptyline of nipecotic acid, guvacine which also have anticonvulsant activity at least in experimental animals. However, the major development in the pharmacology of the GABAergic system has been in drugs which facilitate the functioning of the GABA-A receptors. These will be discussed later. There are three types of GABA receptor, A, B and C. Unlike the ionotropic GABA-A receptors, the GABA-B receptors are metabotropic and coupled via inhibitory G-proteins...

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Main function of brain areas shown Amygdala - An anatomically coherent subsystem within the basal forebrain. Verbal and non-verbal expressions of fear and anger are interpreted by the amygdala. Cerebellum - One of the seven parts of the brain that is responsible for muscle co-ordination and modulation of the force and range of movement. It is involved in the learning of motor skills. Cortex - The most highly developed area in humans and divided into four main regions, namely...