Psychotic Disorder and Schizophrenia Drug Treatment PDF

Psychotic disorder and schizophrenia Drug WE MAKE DOCTORS Simon Quetzalcoatl Rodríguez Lara M.D., PhD. Objectives Define the classification of the antipsychotic drug Differentiate the pharmacokinetics and pharmacodynamics of the main Antipsychotics. Understand the pharmacoki...

Psychotic disorder and schizophrenia Drug WE MAKE DOCTORS Simon Quetzalcoatl Rodríguez Lara M.D., PhD. Objectives Define the classification of the antipsychotic drug Differentiate the pharmacokinetics and pharmacodynamics of the main Antipsychotics. Understand the pharmacokinetics, pharmacodynamics, adverse effects, and drug interactions of Antipsychotics.  Definition The psychotic spectrum is the category that groups together a series of disorders linked to a symptomatology in which we witness the fragmentation of the plane of reality until it is completely broken. Perrotta G. Psychotic spectrum disorders: definitions, classifications, neural correlates and clinical profiles. Annals of Psychiatry and Treatment. 2020 Dec 31;4(1):070-84. Definition According to the DSM-V nosography, the disorders under examination are schizophrenia, delusional disorder, paranoid disorder, schizoid disorder, schizotypic disorder, schizoaffective disorder, brief psychotic disorder, psychotic break and catatonia. Perrotta G. Psychotic spectrum disorders: definitions, classifications, neural correlates and clinical profiles. Annals of Psychiatry and Treatment. 2020 Dec 31;4(1):070-84. Clinical concept They are defined by abnormalities in one or more of the following five domains: Positive symptoms: Delusion, illusion & Hallucinations Disorganized thinking (speech) Grossly disorganized Abnormal motor behavior (including catatonia) Negative symptoms: Autistic symptoms, catatonia and isolation Perrotta G. Psychotic spectrum disorders: definitions, classifications, neural correlates and clinical profiles. Annals of Psychiatry and Treatment. 2020 Dec 31;4(1):070-84. Universidad de Guadalajara, A.C., 2019. 5 Universidad de Guadalajara, A.C., 2019. 6 Schizophrenia Physiopathology A, In healthy individuals, B, In individuals with schizophrenia, the excitatory output of several mechanisms appear to be cortical pyramidal cells is altered within these cortical circuits. tempered secondary to Loss of pyramidal cell dendritic gamma aminobutyric acid spines leads to a net reduction in (GABA)–ergic inhibition excitatory activity (1); reduced from interneurons. The excitatory input to GABAergic interplay between interneurons leads to reduced excitatory and inhibitory inhibition of pyramidal cells (2); and neurons generates gamma reduced interneuron inhibition of oscillations, which in turn pyramidal cells occurs (3). These are crucial to the alterations are proposed to lead to generation of slow aberrant gamma activity and fluctuations in neural dysfunction of functional networks activity that underlie and thereby contribute to the functional brain networks. cognitive and negative symptoms of the illness. Universidad de Guadalajara, A.C., 2019. 8 McCutcheon RA, Marques TR, Howes OD. Schizophrenia—an overview. JAMA psychiatry. 2020 Feb 1;77(2):201-10.  Stress, dopamine and psychosis Psychosocial stressors sensitize the subcortical dopamine system to increase the response to subsequent triggers, while cortical deficits mean that regulatory control is also impaired. Later triggers, such as stress, then lead to inappropriate striatal dopamine release. This leads to the aberrant assignment of salience to stimuli and the development of psychotic symptoms. Psychosis itself is stressful, and this in turn may provide feedback that further dysregulates the system. Universidad de Guadalajara, A.C., 2019. 9 McCutcheon RA, Marques TR, Howes OD. Schizophrenia—an overview. JAMA psychiatry. 2020 Feb 1;77(2):201-10.  Theory’s related to the pharmacological treatment. Dopamine Glutamate First generation (FGA), typical Amphetamine & NMDA antagonist as Bromocriptine induce phencyclidine, Second generation (SGA), or conventional Atypical antipsychotic schizophrenic episode ketamine and antipsychotic drug. didizocilpine can drug Chlorpromazine Reserpine produce psychotic Clozapine Haloperidol Is effective in control it symptoms Risperidone Fluphenazine Sertindole Flupentixol Clopentixol Serotonin Quetiapine Amisulpride 5-HT agonists (LSD Aripiprazole and mescaline) Zotepine induce hallucinations. 5-HT2AR blockade is a Ziprasidone key factor in the mechanism of action of thede Universidad main class A.C., Guadalajara, of 2019. 10 SGA.psychiatry. 2020 Feb 1;77(2):201-10. McCutcheon RA, Marques TR, Howes OD. Schizophrenia—an overview. JAMA Universidad de Guadalajara, A.C., 2019. 11 Universidad Autonoma de Guadalajara, A.C., 2019. 12 Universidad Autonoma de Guadalajara, A.C., 2019. 13 First generation drugs Universidad de Guadalajara, A.C., 2019. 14  The prototypical phenothiazine antipsychotic drug. Antipsychotic actions are thought to be Chlorpromazine due to long-term adaptation by the brain to blocking dopamine receptors. Uses, including as an antiemetic and in the treatment of intractable hiccup. Chlorpromazine Mechanism of action Antagonist (blocking agent) on different postsynaptic receptors - on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2), with anxiolytic, anti-depressive and anti-aggressive properties, histaminergic-receptors (H1-receptors), muscarinic (cholinergic) M1/M3-receptors, inhibitor of Dopamine reuptake. Universidad de Guadalajara, A.C., 2019. 16  Chlorpromazine Genitourinary Drowsiness, (Breast Contact dystonia, Cardiovascular engorgement, dermatitis, skin Corneal extrapyramidal (hypotension, ejaculatory photosensitivity, Weight gain deposits, visual reaction, syncope, QT disorders, skin impairment neuroleptic changes) priapism, pigmentation malignant urinary (slate gray) syndrome. retention) Adverse effects  A phenyl-piperidinyl- It is also used for the butyrophenone, traditional management of It is a potent antiemetic and Haloperidol antipsychotic drug that is used primarily to treat schizoaffective disorder, delusional disorders, is used in the treatment of intractable hiccups. schizophrenia and other ballism, and Tourette psychoses. syndrome (a drug of choice) Haloperidol Mechanism of action Inhibits the effects of dopamine and increases its turnover. Bind more tightly than dopamine itself to the dopamine D2 receptor. Competitively blocks post-synaptic dopamine (D2) receptors in the brain, eliminating dopamine neurotransmission and leading to the relief of delusions and hallucinations that are commonly associated with psychosis. Antagonistic activity regulated through dopamine D2 receptors in the chemoreceptive trigger zone (CTZ) of the brain renders its antiemetic activity. Universidad de Guadalajara, A.C., 2019. 19  Haloperidol adverse effects Central Gastrointes Neuromusc Diaphoresis Breast Cataract, Cardiovasc Others nervous tinal ular , engorgeme retinopathy, ular effects (Neurolepti system (constipatio (hyperkineti Hyperglyce nt, visual (sudden c Malignant (Extrapyram n, c muscle mia, impotence, disturbance death, QT- Syndrome, idal abdominal activity, hyponatrem lactation, s. prolongatio transient reactions, pain, tremor, ia. increase of n, and leukopenia parkinsonis sialorrhea) bradykinesi libido. Torsades de and m, a, akinesia) Pointes) leukocytosi dystonia, s) drowsiness, akathisia) Haloperidol Liver Effects Impaired liver function and/or jaundice may occur. Dermatologic Reactions Maculopapular and acne-like skin reactions and isolated cases of photosensitivity and loss of hair. Universidad de Guadalajara, A.C., 2019. 21 Second generation Universidad de Guadalajara, A.C., 2019. 22 Clozapine A tricyclic dibenzodiazepine, classified as an atypical antipsychotic agent. Psychotropic agent belonging to the chemical class of benzisoxazole derivatives and is indicated for the treatment of schizophrenia. For use in patients with treatment-resistant schizophrenia. Clozapine Mechanism of action Selective monoaminergic antagonist with high affinity for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), alpha 1 and 2 adrenergic, and H1 histaminergic receptors. Antagonism at receptors other than dopamine and 5HT2, antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Antagonism of adrenergic a1 receptors. Universidad de Guadalajara, A.C., 2019. 24 Clozapine adverse effects Tachycardia, hypertension or hypotension Drowsiness, sedation, dizziness, insomnia, vertigo. Sialorrhea, weight gain, constipation, nausea vomiting, dyspepsia Fever Clozapine Other Adverse reaction Increases in transaminases were observed as hepatic, fever, leukocytosis, ataxia, and dysarthria. Agranulocytosis, leucopenia. Toxic delirium and grand mal seizure. Neuroleptic malignant syndrome. Universidad de Guadalajara, A.C., 2019. 26  Hyperthermia High fever (> 38 °C, often > 40 °C) without an obvious infectious cause). Generalized muscle rigidity Elevated CPK, elevated serum and ("Lead-pipe" rigidity or severe urine myoglobin, leukocytosis, akinesia, Rhabdomyolysis may Hyper or hyponatremia, occur secondary to muscle Clinical criteria hyperkalemia, hypocalcemia, damage, leading to elevated hypomagnesemia, elevated BUN. 1.- Acute onset following the creatine kinase (CK) levels. ) exposure to antipsychotics medications (typically Neuroleptic Malignant dopamine antagonist Syndrome (NMS) 2.- Key symptoms: Hyperthermia Muscle rigidity Altered mental status Extrapyramidal symptoms Altered mental status (Tremors, bradykinesia, (Confusion, agitation, Autonomic-dysfunction dystonia) delirium, stupor, or coma.) Autonomic dysfunction (Hyper or hypotension, Tachycardia, Diaphoresis, tachypnea)  Is a second-generation antipsychotic (SGA) medication used in the treatment of a number of mood and mental health conditions including schizophrenia and bipolar disorder. Paliperidone, another Is a member of the class commonly used SGA, is of pyridopyrimidines. the primary active metabolite of risperidone Risperidone Risperidone Belongs to the class of medications known as second-generation atypical antipsychotics. Mechanism of action The primary action of risperidone is to decrease dopaminergic and serotonergic pathway activity in the brain, therefore decreasing symptoms of schizophrenia and mood disorders. Has high affinity binding to serotonergic 5-HT2A receptors versus dopaminergic D2 receptors in the brain. Target Serotonin receptors, dopamine receptors, adrenergic receptors, histamine receptors, antagonist. Universidad de Guadalajara, A.C., 2019. 29  Bradycardia, bundle branch Weight gain, Sedate state, Erectile Hyperprolactine block, first increase drowsiness, Nasopharyngitis, disfunction, mia, Fever, increase degree appetite, extrapyramidal cough, sexual disorder, galactorrhea, in thirst. atrioventricular constipation, symptoms, rhinorrhea. delayed gynecomastia block, prolonged abdominal pain, akathisia. ejaculation. QT interval, hypotension. Risperidone adverse effects Quetiapine Is indicated for the treatment of schizophrenia as well as for the treatment of acute manic episodes associated with bipolar I disorder. The antipsychotic effect of quetiapine is thought by some to be mediated through antagonist activity at dopamine and serotonin receptors. Universidad de Guadalajara, A.C., 2019. 31 Quetiapine Mechanism of action Specifically the D1 and D2 dopamine, the alpha 1 adrenoreceptor and alpha 2 adrenoreceptor, and 5-HT1A and 5-HT2 serotonin receptor subtypes are antagonized. Universidad de Guadalajara, A.C., 2019. 32  Quetiapine adverse effects Increase blood Drowsiness, Skin rash, acne Hyperprolactine Nausea, pressure, headache, vulgaris, mia, increased abdominal pain, peripherial agitation, diaphoresis, thirst, decrease diarrhea, GERD. edema, dizziness, hyperhidrosis, libido. hypertension, extrapyramidal pallor. orthostatic symptoms, hypotension, dysarthria, syncope. akathisia, ataxia, confusion. Lithium Lithium has been used to treat manic episodes since the 19th century. The guidelines of major international psychiatric associations recommend lithium as a first-line therapy for bipolar disease. Lithium serves as the most successful drug in preventing suicide among all antidepressants and mood-stabilizing drugs. Though it is widely used, its mechanism of action is still unknown. Lithium carbonate has a narrow therapeutic range and so careful monitoring is required to avoid adverse effects. Universidad de Guadalajara, A.C., 2019. 34 Lithium Mechanism of action The “inositol depletion theory” suggests 3 main potential targets. These targets are inositol monophosphatase, inositol polyphosphatase, and glycogen synthase kinase 3(GSK-3). Inositol depletion theory suggests lithium behaves as an uncompetitive inhibitor of inositol monophosphatase (Myoinositol pathway) in a manner inversely proportional to the degree of stimulus. Lithium acts on inositol polyphosphatase (IP3 pathway) as an uncompetitive inhibitor. This inhibition is thought to have multiple downstream effects that have yet to be clarified. Regulates phosphorylation of GSK-3 which regulates other enzymes through phosphorylation (gen expression modulation). GABA enhancing by acting directly in the GABA receptor and increasing the GABA concentration in the synapsis. Modulation in cAMP and Brain Derived Neurotrophic Factor (BDNF). Universidad de Guadalajara, A.C., 2019. 35 Universidad de Guadalajara, A.C., 2019. 36 Universidad de Guadalajara, A.C., 2019. 37 Universidad de Guadalajara, A.C., 2019. 38 Lithium is a typical mood stabilizer and has bot the antimanic and Inhibition of second extraordinary antidepressant activity messenger Replaces enzymes (e.g. sodium and alters Inositol intracellular monophosphat calcium e) Potential of lithium for the treatment of Regulates neurodegenerative diseases cAMP- and Inhibits the Ca2+- release of dependent noradrenaline, intracellular Lithium serotonin and Modulation of signaling dopamine. cascades Mechanism G proteins Lithium enhances of action in immunological response the brain and natural killer activity Interaction at various sites with But the doses require to Stabilizes the Regulates downstream system of signal induce beneficial effects secondary Na+/K+-ATPase transduction pump cascades (e.g. induce side effects such messengers Inhibition of thyroid, parathyroid and GSK3β, PKC. renal disfunction. Universidad de Guadalajara, A.C., 2019. 39 Lithium Elimination: Is primarily eliminated through the kidneys and elimination in the feces is insignificant. Toxicity: Increase in the level of lithium over 1.2 mM in the blood causes acute toxicity (nausea, diarrhea, trembling etc.), and the death may occur above 2-3.5 mM (narrow therapeutical range). Universidad de Guadalajara, A.C., 2019. 40 Lithium The disadvantages of lithium therapy are also delayed effects in repairing clinical symptoms (for example 6-8 weeks for bipolar depression). Common acute adverse effects of lithium include gastrointestinal side effects such as: nausea, vomiting, loss of appetite or diarrhea. Additionally, lithium treatment may be associated with cognitive, dermatological, endocrine, gastrointestinal, immunological, metabolic, nephrogenic, neurologic, sexual and teratogenic adverse effects. Universidad de Guadalajara, A.C., 2019. 41 Lithium Adverse effects Male reproductive organs, spermatogenesis, and testosterone levels. Shown adverse effects on the fetus and fertility overall The risk and benefit of lithium use in pregnancy must be weighed and should lithium treatment continue in pregnancy, serum lithium concentrations should be regularly monitored, dosages should be adjusted, and lithium should be decreased or stopped 2 or 3 days before delivery to avoid maternal and/or neonatal toxicity. Breastfeeding is not recommended with maternal lithium use but if it is continued, the infant should be monitored for thyroid function and symptoms of lithium toxicity such as hypertonia, hypothermia, cyanosis, and ECG changes Universidad de Guadalajara, A.C., 2019. 42 Lithium adverse effects Hydroelectrolytic imbalances Drugs interaction Hearth Unwanted Low Thyroid Hypercalcemia, Thiazides, ACEi, Teratogenesis: Movements: (Hypothyroidism) polyuria NSAIDs induces Ebstein anomaly Tremor (Nephrogenic toxicity diabetes Insipidus) LiTHIUM LITHIUM Adverse effects UNIVERSIDAD DE GUADALAJARA, A.C., 2019. 44 Common adverse effects in psychosis drugs Universidad de Guadalajara, A.C., 2019. 45  PHARMACOLOGICAL THEORY IN TREATMENT RESPONSE AND ADVERSE EFFECTS. A female patient was prescribed with amisulpride and her psychotic symptoms improved, but she No clinical subsequently developed extrapyramidal adverse respond effects, which improved after dosage reduction. The adverse effects can be understood in terms of the neurobiology of schizophrenia and the Therapeutical mechanism of antipsychotic drugs. window All current pharmacological treatments for schizophrenia are Dopamine D2-receptors blockers, and PET studies in affected patients Adverse show that substantial occupancy of D2-receptors, effect generally more than 60% of occupancy, is required presentation for a high likelihood of response. But studies have shown that movement-associated adverse effects become more likely with higher D2- receptors occupancy, generally greater than 80%. UNIVERSIDAD DE GUADALAJARA, A.C., 2019. 46  Sequence of treatment in schizophrenia First episode Treatment Maintenance Relapses & remission resistance All antipsychotics are Before making diagnosis of equally effective for the resistance is required: treatment of positive comorbid substance misuse symptoms. The period of duration of and treatment adherence. the treatment is 1-2 The most important years. Are the same drugs Clozapine is universally consideration to chose the recommended as treatment treatment are adverse effects. use in first episode. of choice. Olanzapine & A trial of olanzapine, Most of the guidelines risperidone are the first risperidone or amisulpride recommend SGA. line of therapy. most be considered before the trial of clozapine. Olanzapine is specifically The trial for clozapine excluded for the initial Quetiapine is specifically excluded for must have up to 1 year of treatment. duration. maintenance treatment. Haloperidol is the only With the dosage If there is partial response FGA used with not good posology used in despite dose optimization is results. Intermittent treatment is the first episode. recommended the used with succeed to combination with another Is recommended in some reduce adverse effects, antipsychotic drug. patients an antipsychotic free assessment period using but high risk of relapses. Lamotrigine is recommended Benzodiazepines to help as clozapine augmentation alleviate distress. strategy. Universidad de Guadalajara, A.C., 2019. 47 The recommendation for the duration of the initial trial of treatment is 4 weeks. references 1. Grohmann R, Rüther E, Sassim N, Schmidt L. Adverse effects of clozapine. Psychopharmacology. 1989;99(1):S101-S4. 2. Howes OD, McCutcheon R, Agid O, De Bartolomeis A, Van Beveren NJ, Birnbaum ML, et al. Treatment-resistant schizophrenia: treatment response and resistance in psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. American Journal of Psychiatry. 2016;174(3):216-29. 3. Brenner GM, Stevens C. Brenner and Stevens’ Pharmacology E-Book: Elsevier Health Sciences; 2024. 4. Katzung BG. Basic and Clinical Pharmacology 16th Edition: McGraw-Hill Education; 2024. 5. Ritter PCPGKSTMSJM, Flower RJ, Henderson G, Yoon Kong Loke MBBMMD, MacEwan D, Rang HP. Rang & Dale's Pharmacology E-Book: Elsevier Health Sciences; 2018. 6. McCutcheon, R. A., Marques, T. R., & Howes, O. D. (2020). Schizophrenia—an overview. JAMA psychiatry, 77(2), 201-210. 7. Kane, J. M., Agid, O., Baldwin, M. L., Howes, O., Lindenmayer, J. P., Marder, S.,... & Correll, C. U. (2019). Clinical guidance on the identification and management of treatment-resistant schizophrenia. The Journal of clinical psychiatry, 80(2), 0-0. 8. Keating, D., McWilliams, S., Schneider, I., Hynes, C., Cousins, G., Strawbridge, J., & Clarke, M. (2017). Pharmacological guidelines for schizophrenia: a systematic review and comparison of recommendations for the first episode. BMJ open, 7(1), e013881. 9. Medić, B., Stojanović, M., Stimec, B. V., Divac, N., Vujović, K. S., Stojanović, R.,... & Prostran, M. (2020). Lithium-pharmacological and toxicological aspects: The current state of the art. Current medicinal chemistry, 27(3), 337-351. 10. Perrotta G. Psychotic spectrum disorders: definitions, classifications, neural correlates and clinical profiles. Annals of Psychiatry and Treatment. 2020 Dec 31;4(1):070-84. 11. Correll CU, Martin A, Patel C, Benson C, Goulding R, Kern-Sliwa J, Joshi K, Schiller E, Kim E. Systematic literature review of schizophrenia clinical practice guidelines on acute and maintenance management with antipsychotics. Schizophrenia. 2022 Feb 24;8(1):5. Universidad de Guadalajara, A.C., 2019. 48