PHTH1011 010 Antipsychotic Antidepressant Anxiolytic drugs - Sandiford (2).pdf

Antidepressant and Antipsychotic Drugs Dr. Simone Sandiford [email protected] Depression Most common of the affective disorders Ranges from a very mild condition, to severe depression accompanied by hallucinations and delusions Major cause of disability and premature death worldwide Of...

Antidepressant and Antipsychotic Drugs Dr. Simone Sandiford [email protected] Depression Most common of the affective disorders Ranges from a very mild condition, to severe depression accompanied by hallucinations and delusions Major cause of disability and premature death worldwide Often associated with other psychiatric conditions anxiety, eating disorders and drug addiction Involves the circuitry linking different parts of the brain Major Depressive Disorder Characterized by depressed mood most of the time for at least 2 weeks Loss of interest or pleasure in most activities Disturbances in sleep and appetite Deficits in cognition and energy Thoughts of guilt, worthlessness and suicide are common Neurotransmitter signalling in the brain www.NIDA.org Theories of depression: monoamine hypothesis Depression associated with changes in serotonin /5-HT (5 hydroxytryptamine) or norepinephrine signaling in the brain Antidepressants cause changes in amine signaling Major weakness Amine levels increase immediately with antidepressant use Beneficial effects not seen for several weeks Theories of depression: neurotrophic hypothesis § Nerve growth factors such as brain derived neurotrophic factor (BDNF) critical in regulating neural plasticity, resilience and neurogenesis § Changes in trophic factors especially BDNF and hormones play a role in development of major depression § Successful treatment results in changes in these factors Pharmacological treatment of depression Goals: Alleviate the symptoms of depression Increase the concentration of monoamines in the brain Serotonin/ 5-HT Norepinephrine The use of antidepressant drugs is advisable in the treatment of moderate to severe depression Antidepressants take several weeks before taking effect Classification of antidepressants Classic tricyclic antidepressants Selective serotonin (5-HT) reuptake inhibitors Monoamine oxidase inhibitors 5-HT and norepinephrine reuptake inhibitors 5-HT receptor modulators Tetracyclic and unicyclic antidepressants Tricyclic antidepressants (TCAs) Block norepinephrine and serotonin reuptake into the neurons Cause increased concentrations of monoamines in the synaptic cleft Also block other receptors leading to many adverse effects Dangerous in overdose May cause ventricular dysrhythmias Imipramine (Tofranil) Amitriptyline (Elavil) Mechanism of action of TCAs www.institute.progress.im TCAs ADVERSE EFFECTS Dry mouth, blurred vision, constipation and urinary retention (block of muscarinic receptors) Postural hypotension (block of adrenergic receptors) Sedation (block of histamine receptors) Sexual dysfunction METABOLISM AND EXCRETION Metabolism: Hepatic Excretion: Renal Selective serotonin reuptake inhibitors (SSRIs) Chemically diverse antidepressant drugs that specifically inhibit serotonin reuptake Leads to increased concentrations of serotonin in the synaptic cleft Relatively safe in overdose compared with TCAs Can still give rise to ventricular arrhythmias Fluoxetine (Prozac) Paroxetine (Paxil) Sertraline (Zoloft) Mechanism of action of SSRIs www.wikipedia.com Role of 5HT receptors in depression 7 types of 5HT receptors: 5HT1 – 5HT7 Agonist action of serotonin on 5HT1A receptors cause therapeutic effects Agonist action of serotonin on 5HT2A and 5HT2C responsible for adverse effects (sexual dysfunction, anxiety, insomnia) SSRIs ADVERSE EFFECTS Nausea Anorexia Insomnia Loss of libido Anorgasmia Weight gain METABOLISM AND EXCRETION Metabolism: hepatic Excretion: renal Antidepressant drug selection Choice of antidepressant depends first on the indication Not all conditions are equally responsive to all antidepressants Treatment choice also rests on practical considerations such as cost, availability, adverse effects, patient history and potential drug interactions At present SSRIs are the most commonly prescribed first line treatment agents Antipsychotic drugs Antipsychotic drugs are able to reduce psychotic symptoms in a wide variety of conditions: Schizophrenia Bipolar disorder Psychotic depression Psychoses associated with dementia Drug induced psychoses Improve mood, reduce anxiety and sleep disturbances NOT treatment of choice when symptoms occur in nonpsychotic patient Psychosis and schizophrenia Psychoses – mental disorders that are characterised by the inability to distinguish between what is real and what is not Delusions Hallucinations Grossly disorganised thinking Schizophrenia is a type of psychosis that affects how a person thinks, feels and behaves Persons may appear like they have lost touch with reality Schizophrenia Affects about 1% of the population Responsible for approximately half of long-term psychiatric hospitalizations Considered to be a neurodevelopmental disorder whose cause is likely multifactorial Most commonly has its onset in late adolescence or early adulthood Chronic and usually highly disabling Twin, adoption and family studies have established that it is a genetic disorder with high heritability Clinical features of schizophrenia Positive symptoms – psychotic behaviours not generally seen in healthy persons Delusions Hallucinations Thought disorder Negative symptoms – Disruption to normal emotions and behaviours Withdrawal from social contacts Flattening of emotional responses Reluctance to perform everyday tasks Reduced speaking Cognitive symptoms Impaired attention Impaired working memory Impaired executive function Neurochemical basis of Schizophrenia Main neurotransmitters thought to be involved are dopamine and glutamate Positive symptoms – overactivity of mesolimbic dopamine receptors Negative symptoms – decreased activity in mesocortical dopamine receptors Rang and Dale’s Pharmacology 8th edition Figure 39.3 Pharmacological treatment of psychoses Goals: Treatments focus on eliminating the symptoms of the disease Permit the person to function in a supportive environment Prevent relapse Classification of antipsychotic drugs Typical / first generation / conventional / classical Chlorpromazine, haloperidol Atypical / second generation Clozapine, risperidone Typical antipsychotic drugs Chlorpromazine (Thorazine) and Haloperidol (Haldol) Antipsychotic effects due to blocking of D2 dopamine receptors Also block a variety of other receptors (muscarinic, histamine adrenergic ) Reduce the positive symptoms associated with schizophrenia Negative symptoms are not as responsive to therapy Atypical antipsychotic drugs Risperidone (Risperdal) and clozapine (Clozaril) Antipsychotic effects due to blocking of D2 dopamine receptors Also work on other receptors (block 5HT2A, activate 5HT1A) Ameliorate the positive and negative symptoms associated with schizophrenia to some extent especially clozapine Unwanted effects of antipsychotic drugs ¢ Extrapyramidal side effects Blocking of D2 dopamine receptors in the nigrostriatal pathway Acute dystonias Involuntary movements, tremors and rigidity Occur commonly in the first few weeks, often declining with time Reversible on stopping treatment Tardive dyskinesias Involuntary movements often of the face and tongue, but also trunk and limbs Develops after months or years in 20-40% of patients treated with first generation antipsychotic drugs Disabling and often irreversible Unwanted effects of antipsychotic drugs ¢ Endocrine Due to increased prolactin release caused by blocking of D2 receptor Breast swelling, pain and lactation ¢ Metabolic Mostly the atypical drugs ¢ Other side effects Weight gain, metabolic syndrome that may increase the risk of coronary artery disease, stroke, hypertension, diabetes disturbances side effects due to blocking a variety of receptors Sexual dysfunction Drowsiness and sedation Blurring of vision, dry mouth, constipation, urinary retention Orthostatic hypotension Jaundice (chlorpromazine) Leukopenia (clozapine) Metabolism and excretion of antipsychotic drugs TYPICAL Chlorpromazine Metabolism: Hepatic and renal Excretion: Urine Haloperidol ATYPICAL Metabolism: Hepatic Excretion: Urine and faeces Clozapine Metabolism: Hepatic Excretion: Urine and faeces Risperidone Metabolism: Hepatic Excretion: Urine Antipsychotic drug selection Choice among antipsychotic drugs is based mainly on differences in adverse effects and efficacy, cost and availability Most drugs are given orally or in urgent situations by intramuscular injection Slow-release preparations are available and drug acts for 2-4 weeks Approximately 20% patients have an insufficient response Clozapine has shown to be effective but can produce serious side effects such as bone marrow suppression, seizures and cardiovascular events Learning objectives Understand the importance of antipsychotic and antidepressant drugs and how they work Give examples of antipsychotic and antidepressant drugs and their adverse effects