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The psychoses are among the most severe psychiatric disorders. People with this disorder sufferfrom a marked impairment of behaviour. They have a serious inability to think coherently, tocomprehend reality, or to gain insight into these abnormalities. They may suffer from delusions andhallucinations.
- Organic psychoses: are associated with causes that are understood and definable e.g. toxic,metabolic or neuropathological changes. They are characterized by confusion, disorientation, memorydisturbances and behavioural disorganization.
- Functional (of unknown cause) psychoses: are characterized by retention of orientation and memoryin the presence of severely disordered thought or reasoning, emotion and behaviour. The functionalpsychoses include schizophrenia. Schizophrenia is characterized by chronically disordered thinking andemotional withdrawal and is often associated with paranoid delusions and auditory hallucinations
Affective (Mood) Disorders
Affective disorder are characterized primarily by a change in emotion or mood. Thus, an individual may exhibit depression, a feeling of unpleasantness or discomfort (dysphoria), irritability, lability of emotion, elation or mania. Affective disorders consist mainly of a single disorder of mood -either mania or severe depression. Mania is characterized by elation, hyperactivity, and uncontrollable thought and speech. An individual suffering from depression has feelings of intense sadness andself-disapproval, and physical and mental slowing.
In contrast to the psychoses, individuals suffering from neuroses retain the ability to comprehendreality. However, suffering and disability may be severe. The symptoms may involve mood changessuch as anxiety, panic or restlessness, and a feeling of being ill at ease. Individuals may exhibit limitedabnormalities of thought such as obsessions or irrational fears or of behaviour such as rituals orcompulsions.
Approximately one in 100 people develop schizophrenia in their lifetime. Symptoms ofschizophrenia are classified as positive and negative. The positive symptoms include delusions andhallucinations, bizarre behaviour, lack of logic and incoherence while apathy, social withdrawal and lossof motivation are among the symptoms referred to as negative symptoms.
The theory of schizophrenia
- the dopamine hypothesis is the most fully developed theory ofschizophrenia, but recent evidence indicates that other neurotransmitters such as serotonin, gammaaminobutyric acid, and glutamic acid may be involved in schizophrenia. The following lines ofcircumstantial evidence suggests that excessive dopaminergic activity explains, at least in part, thisdisorder.
- Two other transmitters have also been postulated to play a role in schizophrenia, serotonin and glutamate.The newer atypical antipschotics such as clopzapine and quetiapine are 5-HT antagonists and someglutamate agonists exacerbate the symptoms of schizophrenia.
characteristics of schizophrenia
- 1. Most antipsychotic drugs are potent blockers of postsynaptic dopamine receptors in the CNS. The binding affinity of antipsychotic drugs is highly correlated with their clinical antipsychoticpotency.
- 2. Drugs that increase dopaminergic activity such as levodopa (a precursor of dopamine),amphetamines (releasers of dopamine), or apomorphine (a direct dopamine receptor agonist) eitheraggravate schizophrenia or induce it in some individuals.
- 3. Dopamine receptor density has been found, in postmortem studies, to be increased in the brains ofschizophrenics who had not been treated with antipsychotic drugs. It is of interest that key studiesof this type were carried out by pharmacologists at the University of Toronto.
- 4. Using a technique known as positron emission tomography (PET), dopamine receptor density hasbeen shown to be higher in schizophrenic than in non-schizophrenic persons.
In the late 1950’s, the antipsychotic phenothiazines were introduced into therapy. In 1959,dopamine was recognized as a neurotransmitter in the CNS. In the 1960’s, it was shown that theeffects of dopamine on electrical activity in synapses of the CNS and on production of the secondmessenger, cyclic AMP, could be blocked by the phenothiazine antipsychotic drugs. It was thereforeconcluded that the phenothiazine antipsychotics are antagonists at dopamine receptors
Mechanism of Action of Antipsychotic Drugs
- Antipsychotic action can be explained by antagonism of dopamine receptors in the mesolimbic andmesofrontal systems of the brain (meso = middle). The limbic system controls emotion and behaviour
- Extrapyramidal movement disorders: Antagonism of dopamine receptors in the nigrostriatalsystem. Parkinsonism-like symptoms are observed – tremor, rigidity of limbs, slowing of movement, anda reduction in spontaneous activity. Also observed are dystonia (involuntary muscle spasms) andakathesia (anxiety, restlessness and repetitive purposeless action). Tardive dyskinesia is a seriousmovement disorder that can occur; it is characterized by involuntary movements of the face, tongue,trunk and limbs and can be severely disabling.
- Endocrine effects: Dopamine in the hypothalamus exerts a tonic inhibitory effect on prolactinrelease from the pituitary gland. By antagonizing dopamine receptors, excess prolactin will be released(hyperprolactinemia). This will result in women in the flow of milk from the breast, menstrual changes,and in men will cause sexual dysfunction.
Other Receptors Blocked by Phenothiazine Antipsychotics
- Cholinergic (muscarinic) receptors:Therapeutic effects: Reduction of extrapyramidal adverse effects. Adverse effects: Blurred vision, dry mouth, constipation, difficulty urinating
- Blockade of serotonin receptors:Therapeutic effects: Reduction of extrapyramidal adverse effects.Reduction in the negative symptoms of psychosis. Adverse effects: Unknown.
- Blockade of histamine receptors:Adverse effects: Sedation, drowsiness, and weight gain.
- Blockade of "-adrenoceptors:Adverse effects: Postural hypotension (hypotension when assuming an erect position),dizziness, reflex tachycardia
Haloperidol has a chemical structure which is very different to that of chlorpromazine (a prototypephenothiazine) and other phenothiazines. Like chlorpromazine, it competitively blocks dopaminereceptors and has very similar pharmacological effects. Its sedative and hypotensive action is less thanthat observed with chlorpromazine (and other phenothiazines), but it has a high propensity for producingextrapyramidal movement disorders. It is considered a useful alternative for patients who do not respondto or cannot tolerate phenothiazines.
Second-Generation Antipsychotics (Also called atypical antipsychotics)
Since 1990, a series of new antipsychotic agents have been introduced into therapy. While thephenothiazines and haloperidol provided relief primarily for the positive symptoms of schizophrenia, thesecond-generation of antipsychotic agents are claimed to relieve both positive and negative symptoms,while at the same time having a lower propensity to produce extrapyramidal side effects. It is thoughtthat these second-generation antipsychotics have a dual action by producing receptor blockade ofdopamine and serotonin receptors. Some of these second-generation agents are clozapine, risperidoneand olanzapine
Clozapine is a very useful addition to our therapeutic armamentarium of antipsychotic drugsbecause it relieves both the positive and negative symptoms of schizophrenia. Since patients have fewerextrapyramidal side effects when taking clozapine, compliance is better with clozapine than with olderantipsychotics. Clozapine can cause granulocytopenia (a decrease in the number of white blood cells) in1-2% of patients and this adverse effect can result in very serious problems. For this reason, patientsreceiving this drug are required to have blood counts at frequent intervals. Other atypical antipsychoticsare resperidone and olanzapine.
- Lithium carbonate is a mood-stabilizing agent which is used to prevent mood swings in patientswith manic-depressive disorder. It is also used to treat mania.
- The mechanism of action of lithium has not been resolved. Three possibilities are underinvestigation:
- 1. Effect on electrolytes and ion transport.
- 2. Effects on neurotransmitters and the release of neurotransmitters.
- 3. Effect on second messengers that mediate transmitter action.
Effect on second messengers that mediate transmitter action.
Phosphatidylinositol-4,5-biphosphate (P1P2) is the cell membrane precursor of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). This enzymic reaction is catalyzed by the enzymephospholipase C (PLC). IP3 and DAG are important second messengers for alpha-adrenergic (andmuscarinic) transmission as shown in the diagram below. After P1P2 is converted to the secondmessengers, IP3 + DAG, it must be reconstituted from IP3 via IP2, IP, and inositol (I). Lithium blocks twosteps in the reconstitution process, namely IP2 ÷ IP, and IP1 ÷ I, thus leading to depletion of P1P2. Theeffects of the transmitter on the receptor (R) and consequently on the cell will diminish. G denotes theG-protein involved in coupling the effects of drug combination with the receptor to the enzyme PLC.
lithium carbonate pic
Clinical Pharmacology of Lithium
Lithium is the drug of choice for long-term maintenance to prevent both manic and depressiveepisodes in patients with manic-depressive disorder. A period of 2-4 weeks of lithium administrationmay be required for lithium to have a full therapeutic effect; acutely manic patients often requiretemporary treatment with an antipsychotic drug such as haloperidol or a benzodiazepine such aslorazepam. During depressive episodes, an antidepressant is often needed temporarily in addition tolithium, but it may precipitate mania
Monitoring of Serum Concentration of Lithium
The safety and efficacy of lithium is enhanced by monitoring serum lithium concentration. Measurements should be made approximately 12 hours after the last dose. For many individuals, serumconcentrations of 0.6 to 0.7 mEqu/L are effective and well tolerated.
Adverse Effects of Lithium
Nausea and fatigue may occur in the first weeks of treatment. Tremor, thirst, excessive urination,edema and weight gain may persist for the duration of treatment. Confusion and loss of musclecoordination may occur. Toxic kidney effects are observed in individuals treated chronically withlithium but are uncommon. Mild hypothyroidism is fairly common. Can cause acne and skin reactions. When taken during pregnancy, can rarely cause cardiac malformations in the fetus.
Alternatives to Lithium
- For patients who cannot tolerate lithium, the anticonvulsants valproic acid, carbamazepine andclonazepam have been found to be useful agents. These agents have a more rapid onset of action thanlithium and are often preferred.
- Patients suffering from bipolar disorder are often given an antidepressant as well as the antipsychotics.
- Depression affects five to six percent of the population at any given time. There are several types ofdepression and depressions are classified as follows:
- 1. Reactive (secondary) depression. This is the most common type and accounts for over 60% of alldepressions. It occurs in response to real stimuli such as grief and illness. Reactive depression mayresolve spontaneously or may respond to a variety of treatments.
- 2. Major depression (endogenous). In major depression there are characteristic disturbances ofmajor body rhythms of sleep, hunger and appetite. A loss of pleasure and interest in most usualactivities is experienced. There is a decrease in sexual drive and mental slowing and loss ofconcentration is experienced. According to current evidence it is a genetically determinedbiochemical disorder which causes an inability to cope with ordinary stress. Major depressionaccounts for approximately 25% of all depressions and tends to recur throughout life. It usuallyresponds to antidepressant therapy.
- 3. Depression associated with manic-depressive disorder. This type of depression accounts forapproximately 10-15% of all depressions. Lithium is used to stabilize mood in this disorder anddepression is managed with antidepressants.
Theory of the Causes of Major Depression
- The major theory which has been proposed to explain major depression is known as the aminehypothesis. This hypothesis arose in the following manner. It will be recalled from an earlier section onthe History of Drug Use and Development that reserpine was introduced in the 1950’s for the treatmentof psychosis and hypertension. A serious adverse effect of reserpine was the induction of depression. Animal studies showed that reserpine inhibited reuptake and storage of serotonin and norepinephrine inthe vesicles of presynaptic nerve endings. As a result, there was a depletion of amine stores in thesevesicles and amine-dependent neurotransmission would be diminished. Since reserpine induceddepression and depleted stores of amine neurotransmitters, it was reasoned that depression might beassociated with decreased functional amine dependent neurotransmission.
- Consistent with the amino hypothesis is the fact that all antidepressant drugs have their primaryactions on the storage, metabolism, or re-uptake of serotonin or norepinephrine (and in some cases ofdopamine)
- The amine hypothesis does not explain all the effects of antidepressants in depression. The neurotrophichypothesis suggests that depression is associated with reduced neurotrophic (growth and interconnectivity of neurons) support and that antidepressants stimulate neurogenesis and synapticconnectivity in cortical areas.
Types of Antidepressants
- Tricyclic antidepressants: Imipramine is a member of this class of antidepressants which share athree-ring nucleus. Imipramine was introduced into therapeutics forty years ago.
- Second-generation (atypical)) antidepressants: Bupropion and amoxapine, introduced after1980, are structurally unrelated to the tricyclic antidepressants and were introduced in an attempt to haveavailable antidepressants with less adverse effects.
- Selective serotonin reuptake inhibitors (SSRI’s): This class of antidepressants was introducedfrom the late 1980’s to the mid-1990’s. The first of these agents, fluoxetine (Prozac), has received agreat deal of publicity. The tricyclic antidepressants have anticholinergic (muscarinic), antiadrenergic(alpha), and antihistaminic actions which do not contribute to their efficacy but do contribute to theirtoxicity. The SSRI’s, in contrast, have much less effect on the autonomic nervous system and thereforehave less toxicity.
- Drugs that block Serotonin and norepinephrine uptake: Drugs such as venlafaxine blocktransporters for both serotonin and norepinephrine and have an advantage over the tricyclicantidepressants due to their better safety profiles. (Less adverse effects).
- Monoamine oxide (MAO) inhibitors: There are two monoamine oxidase (MAO) enzymes,designated MAO-A and MAO-B. MAO-A is the enzyme primarily responsible for metabolism ofnorepinephrine, serotonin and tyramine. MAO-B is more selective for dopamine metabolism. Selectiveblockade of MAO-A is therefore considered more selective for therapy of depression.
- Phenelzine and tranylcypromine are non-selective inhibitors of MAO-A and MAO-B. Theycombine irreversibly with the enzymes and therefore have a prolonged duration of action. When theseinhibitors are used, the inhibition of the MAO enzymes persist even after the inhibitors are no longerdetectable in the serum. The inhibitory effect of tranylcypromine persists for seven days after the drug isadministered, while the inhibitory effect of phenelzine persists for two to three weeks after the drug isadministered. This persistence of inhibition has important therapeutic consequences and must be bornein mind to avoid drug and/or food interactions.
- In recent years, a selective MAO-A inhibitor has been introduced into therapy. Moclobemide is anew short-acting reversible inhibitor of MAO-A and 90% of the drug appears in urine within 12 hours ofadministration.
Action of Antidepressants on Biogenic Amine Neurotransmitters
The amine hypothesis of depression has been strengthened by studies on the mechanism of action ofthe different types of antidepressant drugs. Thus, tricyclic antidepressants block the amine(norepinephrine and serotonin) presynaptic transporter proteins which are the “off switches” of amineneurotransmission. Such an action permits a longer sojourn of the neurotransmitters at the receptor sites.
The MAO inhibitors block a major degradative pathway for the amine neurotransmitters, thuspermitting more amines to accumulate in presynaptic stores and more to be released when the nerveimpulse reaches the presynaptic neuron.
The SSRI’s are relatively selective for blockade of the serotonin transporter protein in thepresynaptic terminal. Their effect on the norepinephrine transporter protein is less than that on theserotonin transporter protein
Choice of Antidepressants
In the past, a tricyclic antidepressant such as imipramine has been considered as the drug of firstchoice for treatment of depression. In recent years, an SSRI such as fluoxetine (Prozac) is often usedinstead, especially for patients with mild to moderate depression. MAO inhibitors such as phenelzine areeffective antidepressants that can be helpful (used with appropriate precautions) for some patients whocannot tolerate or fail to respond to a tricyclic antidepressant or a SSRI.
Adverse Effects Tricyclic antidepressants:
Tricyclic antidepressants: The most common adverse effects that limit therapeutic usefulness areanticholinergic effects (dry mouth, urinary retention, constipation, and blurred vision), sedation, weightgain, sexual dysfunction, and hypotension with assuming an erect position (orthostatic hypotension). Aparticularly serious adverse effect is the propensity of this class of drugs to disturb the electrical rhythmof the heart. For a patient with a heart problem, it is preferable to use a different class of antidepressant. Over-dosage can be lethal and severe reactions are characterized by serious disturbances of the electricalrhythm of the heart, hypotension, convulsions and coma.
Adverse Effects SSRI’s:
SSRI’s: The SSRI’s cause nausea, headache, nervousness, and insomnia more commonly than thetricyclic antidepressants. There is a high incidence of sexual dysfunction with these drugs. Generally,the SSRI’s do not cause weight gain, are less likely to cause anticholinergic effects or orthostatichypotension. An important advantage of the SSRI’s is that they are much safer than the tricyclicantidepressants in over-dosage.
Adverse Effects MAO inhibitors:
MAO inhibitors: If MAO inhibitors are prescribed, patients must be warned that they interact withdangerous consequences with many other drugs, both prescription and over-the-counter, and withtyramine-containing foods. The use of a tricyclic antidepressant, SSRI or meperidine, ordextromethorphan in a patient taking a MAO inhibitor could cause delirium, high fever, convulsions,coma and death. One must wait for a considerable time for the effects of an MAO inhibitor to wear off,usually several weeks, before relaxing caution.