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NEUROPSYCHIATRY AND ANTIPSYCHOTICSBy Ekam Emefiele(Med. Student)
Dopamine pathways relevant to antipsychotic pharmacology in the treatment of schizophrenia are:Mesolimbic pathwayMesocortical pathwayNigrostriatal pathwayTuberoinfundibular pathway By blocking these pathways, antipsychotics can produce both therapeutic and adverse effects.
Mesolimbic PathwayThis is relevant to positive symptoms of schizophrenia (delusion and hallucination)Anatomy: it is made up of projections from the ventral tegmental area (VTA) to the nucleus accumbens.Physiology: it is the centre for motivation, emotions, pleasure, compulsion.Implication: D2 antagonism reduces positive symptoms of schizophreniaMesocortical PathwayAnatomy: This tract is made up of dopaminergic neurons that projects from the VTA to the pre-frontal cortex.
Physiology: it is relevant to the physiology of cognition, negative symptoms, emotions and affects.
Implications: Hypofunction of this pathway might be related to cognitive and negative symptoms of schizophreniaNigrostriatal PathwayThis tract contains about 80% of the brains dopamineAnatomy: It projects from the substantia nigra to basal ganglia.
Physiology: It plays a key role in regulating movements.
Implication: D2 antagonism of this tract induces extrapyramidal symptoms (pseudo-parkinsonism, akathisia, acute dystonia) and Tardive dyskinesia (abnormal writhing movement of the tongue, face and body).Tuberoinfundibular PathwayThis pathway influences prolactin release.
Anatomy: This tract projects from the hypothalamus to the anterior pituitary.
Physiology: Dopamine tonically inhibits prolactin
Implication: D2 antagonism increases prolactin levelAntipsychoticsPsychosisPsychosis is a thought disorder characterized by disturbances of reality and perception, impaired cognitive functioning, and inappropriate or diminished affect (mood).Psychosis denotes many mental disorders.Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance.Substances that can induce psychotic symptomThese includes;AlcoholCannabis (Marijuana)CocaineAmphetaminesL. dopaSchizophreniaIt is a thought disorder.The disorder is characterized by a divorcement from reality in the mind of the person (psychosis).Pathogenesis is unknown.Onset of schizophrenia is in the late teens early twenties.Genetic predisposition -- Familial incidence.Multiple genes are involved.Afflicts 1% of the population worldwide.May or may not be present with anatomical changesSymptomsPositive Symptoms :Hallucinations, delusions, paranoia, excited motor behaviour.
Negative Symptoms :Slow thought or speech, social withdrawal, emotional blunting, cognitive deficits, extreme inattentiveness or lack of motivation to interact with the environment.Antipsychotic Medications (APMs)Used to treat manifestations of psychosis and other psychiatry disordersPrecise mechanism of action is unknown, however APMs blocks several populations of dopamine (D2, D4) receptors in the brain.The newer APMs also block serotonin (5-HT2) receptors, a property that may be associated with increased efficacy.APMs also variably blocks central and peripheral cholinergic, histamine and alpha receptorsClassification of antipsychotic drugs PHARMACOLOGICAL CLASSIFICATION
FIRST-GENERATION ANTIPSYCHOTIC (low potency) Chlorpromazine Prochlorperazine Thioridazine
FIRST-GENERATION ANTIPSYCHOTIC (high potency) Fluphenazine (Modecate)Haloperidol (Haldol)PimozideThiothixene Zuclopenthixol (Clopixol) SECOND GENERATION ANTIPSYCHOTIC Aripiprazole Asenapine Clozapine Iloperidone Lurasidone Olanzapine Quetiapine Paliperidone Risperidone Ziprasidone
Division of APMs based on receptor blockadeThere are three (3) main groups;Pure D2 antagonist: Typical APMs (low and high potency).D2-5HT2 antagonist: RisperidoneMultireceptor antagonist:a. Clozapine - D2, D4, 5HT2b. Olanzapine - D2, D4, 5HT2c. Quetiapine - D2, D4, 5HT2d. Ziprasidone - D2, D4, 5HT2e. Aripiprazole - D2, D4, 5HT2
Typical versus Atypical APMsTypicalOlder agentsDopamine effectsMany side effectsTreatment of positive symptomsAtypicalNewer agentsDopamine and serotonin effectsFewer side effectsTreatment of positive and negative symptomsIndications for APMsPsychomotor agitationSchizophreniaOther psychotic disorders delusional, brief psychotic, schizophreniform, schizoaffective, substance-induced psychotic disordersMood disorders useful for the treatment of agitation and psychosis during mood episode.General Adverse effects of APMsWeight gain (olanzapine)Sedation due to antihistamine activityHypotension effect is due to alpha adrenergic blockade. It is most common with low potency APMsAnticholinergic symptoms dry mouth, blurred vision, urinary retention, constipation, etcEndocrine effects gynecomastia, galactorrhea, amenorrhea, due to blockade of tuberoinfundibular tractHematological problems such as agranulocytosis with atypical APMs (clozapine as the most problematic agent).Neurologic effectsPseudoparkinsonism: It is characterized by muscle rigidity, shuffling gait, masklike facial expression, resting tremor.
Acute dystonia: Prolonged muscle spasm. More common in men younger than 40yrs. It may mimic seizure
Akathisia: Subjective feeling of motor restlessness.
Tardive dyskinesia: A disorder that involves involuntary, repetitive movements of the muscles of the tongue, face and body. You treat with low potency or atypical APMs.
Neuroleptic malignant syndrome: A rare but potentially life-threatening reaction to APMs. It causes fever, muscular rigidity, altered mental status, excessive sweating, salivation, increased BP and pulse rate. It is treated by stopping the agent and providing medical support.