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Antipsychotics
- 2. OVERVIEW • Psychosis & Schizophrenia • Symptom dimensions • Neurotransmitters & Circuits • Antipsychotics • Conventional & Atypical • Other pharmacological actions • Individual drugs • Future treatments for Schizophrenia.
- 4. PSYCHOSIS • Set of symptoms impairing a person’s- • Mental capacity • Affective response • Capacity to recognize reality, communicate & relate to others. • Perceptual distortions; Motor disturbances • Paranoid, Disorganized/excited, Depressive
- 5. PSYCHOSIS • Psychosis, a defining feature: • Schizophrenia • Substance induced • Schizophreniform disorder • Schizoaffective disorder • Delusional disorder • Brief psychotic disorder • Psychosis, an associated feature: • Mania • Depression • Cognitive disorders • Alzheimer’s dementia
- 7. SCHIZOPHRENIA • A disturbance that must last for 6 months/ longer, including one month of delusions, hallucinations, disorganized speech, grossly disorganized/ catatonic behavior. • Acute episodes (positive symptoms) recur frequently • May progress to chronic schizophrenia with predominant negative symptoms.
- 8. • Incidence 1% with significant hereditary component. • Genetic linkage suggests involvement of multiple genes but no single ‘schizophrenia gene’. • 5 symptom dimensions of schizophrenia: • Positive symptoms • Negative symptoms • Cognitive symptoms • Aggressive symptoms • Affective symptoms
- 9. POSITIVE SYMPTOMS • Delusions • Hallucinations • Distortions/ exaggerations in language and communication • Disorganized speech • Disorganized behavior • Catatonic behavior • Agitation
- 10. NEGATIVE SYMPTOMS • 5 types • Alogia • Affective blunting/ flattening • Asociality • Anhedonia • Avolition
- 11. COGNITIVE SYMPTOMS • Problems focusing & sustaining attention • Problems evaluating functions & monitoring performance • Impaired verbal fluency • Difficulty with problem solving
- 12. NEUROTRANSMITTERS AND CIRCUITS IN SCHIZOPHRENIA
- 14. DOPAMINE
- 20. DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA: POSITIVE SYMPTOMS
- 22. DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA: NEGATIVE, COGNITIVE & AFFECTIVE SYMPTOMS
- 25. GLUTAMATE
- 29. NMDA RECEPTOR HYPOFUNCTION HYPOTHESIS OF SCHIZOPHRENIA
- 30. Linking the NMDA hypo function hypothesis of schizophrenia with the dopamine hypothesis of schizophrenia: Positive symptoms.
- 32. SEROTONIN
- 35. SEROTONERGIC CONTROL OF DOPAMINE RELEASE • Serotonin important influence on dopamine. • Varies among different dopamine pathways
- 41. ANTIPSYCHOTICS
- 42. First generation/typical/classical/conventional antipsychotics • PHENOTHIAZINES • Aliphatic side chain: Chlorpromazine; Triflupromazine • Piperidine side chain: Thioridazine; • Piperazine side chain: Trifluperazine; Fluphenazine. • BUTYROPHENONES: Haloperidol; Trifluperidol; Penfluperidol. • THIOXANTHENES: Flupenthixol • OTHER HETEROCYCLICS: Pimozide, Loxapine
- 43. Second generation/ Atypical antipsychotics. • Clozapine, Olanzapine, Zotepine, Quetiapine, Asenapine • Risperidone, Paliperidone, Ziprasidone, Iloperidone, Lurasidone. • Aripiprazole, Brexpiprazole, Cariprazine. (‘pines’; ‘dones’; two ‘pip’s and a ‘rip’) • Amisulpride, Sertindole, Perospirone.
- 44. THANK YOU
- 46. ANTIPSYCHOTICS
- 47. First generation/typical/classical/conventional antipsychotics • PHENOTHIAZINES • Aliphatic side chain: Chlorpromazine; Triflupromazine • Piperidine side chain: Thioridazine; • Piperazine side chain: Trifluperazine; Fluphenazine. • BUTYROPHENONES: Haloperidol; Trifluperidol; Penfluperidol. • THIOXANTHENES: Flupenthixol • OTHER HETEROCYCLICS: Pimozide, Loxapine
- 48. Second generation/ Atypical antipsychotics. • Clozapine, Olanzapine, Zotepine, Quetiapine, Asenapine • Risperidone, Paliperidone, Ziprasidone, Iloperidone, Lurasidone. • Aripiprazole, Brexpiprazole, Cariprazine. (‘pines’; ‘dones’; two ‘pip’s and a ‘rip’) • Amisulpride, Sertindole, Perospirone.
- 49. What makes an antipsychotic typical/atypical??
- 51. Typical antipsychotics • Conventional/ First generation antipsychotics. • Primary pharmacological property D2 antagonism. • Neurolepsis Neuroleptics
- 58. Other pharmacological properties of Conventional antipsychotics • Muscarinic anticholinergic (M1) • Antihistaminic (H1) • α-1 adrenergic antagonist.
- 59. Reciprocal relationship of dopamine and acetylcholine
- 63. Side effects of conventional antipsychotics
- 66. EXTRAPYRAMIDAL SYMPTOMS • Parkinsonism • Acute muscular dystonia • Akathisia • Malignant Neuroleptic Syndrome • Tardive dyskinesia.
- 67. Atypical antipsychotics. • Distinguished by their clinical profile • Positive symptoms antipsychotic action • Low EPS • Less Hyperprolactinemia • Serotonin- dopamine antagonists (SDA) • 5HT2A antagonism • D2 partial agonistic action • Partial agonist at 5HT1A receptor
- 75. 5HT1A receptors • Autoreceptors • Located on the somatodendritic end of the synapse • Cause shutdown of the downstream serotonin secretion • Action similar to 5HT2A receptor antagonism • Partial agonist action seen in • Aripiprazole, brexpiprazole, cariprazine • Clozapine, quetiapine • Lurasidone, iloperidone, ziprasidone
- 76. 5HT1B/D receptors • Terminal autoreceptor • Located on axon terminal • Promotes 5HT release antidepressant actions • Iloperidone, Ziprasidone, Asenapine.
- 77. 5HT2C receptors • Postsynaptic; regulate dopamine & nor epinephrine release • Stimulation suppresses dopamine release more from mesolimbic pathway antipsychotic without EPS. • 5HT2C selective agonist Vabacaserin (under trial for schizophrenia) • Lorcaserin Treatment of obesity.
- 78. D2 partial agonism (DPA) • Intrinsic ability to bind receptors in such a manner that causes signal transduction from the receptor intermediate between no output to full output • More than silent antagonist and less than full agonist • Antagonist at D2 receptors in the mesolimbic pathway and agonist at nigrostriatal pathway to mitigate EPS
- 80. Antidepressant actions • Mechanisms: • 5HT1A partial agonism; • Antagonism of 5HT1B/D, 5HT2C, 5HT3, 5HT7. • Serotonin and/or norepinephrine reuptake inhibition quetiapine, ziprasidone, zotepine. • α-2 antagonism quetiapine, clozapine, risperidone, aripiprazole.
- 81. Antimaniac actions • D2 antagonism/partial agonism combined with 5HT2A antagonism. • Aripiprazole & Cariprazine additional efficacy due to 5HT1A partial agonism.
- 82. Anxiolytic actions • Controversial use of atypical antipsychotics in Rx of various anxiety disorders especially Posttraumatic stress disorder (PTSD) • ?? Antihistamine & anticholinergic sedative properties of these are causing calming effects. • Clinical evidence greatest for quetiapine.
- 83. Sedative-hypnotic actions • Sedation short term Rx desired therapeutic effect • Sedation long term Rx side effect cognitive impairment • Mechanism Blockade of H1-histamine receptors; M1- muscarinic cholinergic receptors; α-1 adrenergic receptors.
- 84. Sedative-hypnotic actions • Potent antihistamine actions Clozapine, Quetiapine, Olanzapine, Iloperidone. • Potent anticholinergic actions Clozapine, Quetiapine, Olanzapine • Potent α-1 adrenergic antagonism Clozapine, Quetiapine, Risperidone, Iloperidone.
- 85. Cardio metabolic actions • Weight gain, Obesity risks, dyslipidemia, diabetes, accelerated cardiovascular disease, premature death Metabolic highway. • Receptors associated with increased weight gain H1 histamine receptor; 5HT2C serotonin receptor.
- 87. Cardio metabolic actions • High metabolic risk Clozapine, Olanzapine • Moderate metabolic risk Risperidone, Paliperidone, Quetiapine, Iloperidone • Low risk Ziprasidone, Aripiprazole, Lurasidone, Asenapine, Brexpiprazole, Cariprazine.
- 89. CHLORPROMAZINE (CPZ) • Prototype drug; D2 antagonist • Similar to procaine as local anesthetic. • High doses Q-T prolongation; Suppression of T-wave • Overdose Arrhythmia
- 90. TRIFLUPROMAZINE: • More potent than CPZ • Used mainly as antiemetic • Produces acute muscle dystonia THIORIDAZINE • Low potency phenothiazine; Marked central anticholinergic action • Low EPS • ADR Cardiac arrhythmias; interference with male sexual function • Long term use eye damage
- 91. TRIFLUOPERAZINE; FLUPHENAZINE: • High potency piperazine side chain phenothiazines • Minimum autonomic actions • Hypotension; Sedation; Lowering of seizure threshold insignificant • Low chance impair glucose tolerance, jaundice, hypersensitivity reactions. • Marked EPS • Fluphenazine decanoate Depot IM injection every 2-4 weeks in uncooperative patients.
- 92. HALOPERIDOL • Resembles piperazine substituted phenothiazines. • Low chance autonomic effects; seizures, weight gain; jaundice. • Preferred drug in Acute Schizophrenia, Huntington’s disease. PENFLURIDOL • Long acting neuroleptic • Uses chronic schizophrenia; affective withdrawal; social maladjustment
- 93. PIMOZIDE • Selective D2 antagonist with little α adrenergic/ cholinergic blocking activity • Good for maintenance therapy but not when agitation is prominent • Low chance dystonia • Risk of arrhythmia.
- 95. CLOZAPINE • Prototype. 5HT2A-dopamine D2 antagonist • Gold standard for Rx of schizophrenia esp. for aggression and violence in patients • Only antipsychotic to reduce risk of suicide; severity of tardive dyskinesia • Due to side effects, not a first line of Rx; Used only when other antipsychotics fail.
- 96. CLOZAPINE-ADVERSE EFFECTS • Life threatening Agranulocytosis. • Increased risk of seizures; myocarditis. • Sedation; Excessive salivation. • High dose severe constipation, paralytic ileus • Greatest degree of weight gain & cardio metabolic risk.
- 97. OLANZAPINE • Lacks EPS • Lacks extreme sedating properties of clozapine • Has antagonist properties at M1, H1, α1, α2, 5HT2C, 5HT7 receptors. • Improves mood in schizophrenia, bipolar disorder, treatment resistant depression
- 98. OLANZAPINE- ADVERSE EFFECTS • Weight gain • Greatest cardio metabolic risk increases fasting triglyceride level; insulin resistance. • Available as: • Oral disintegrating tablet • Acute intramuscular injection • Long-acting 4-week intramuscular depot.
- 99. QUETIAPINE • Active metabolite- Norquetiapine. • Properties: • Norepinephrine reuptake inhibition • 5HT7, 5HT2C, α2 antagonism • 5HT1A partial agonism • Formulations: • Immediate release (IR) • Extended release (XR)
- 101. QUETIAPINE- USES • Bipolar depression • As an augmenting agent to SSRIs/SNRIs in unipolar treatment-resistant depression. • Patients with Parkinson’s disease who require treatment for psychosis.
- 102. ASENAPINE • Newer drug • D2, 5HT2A, 5HT2C, H1 and α2 antagonism : antidepressant action • Given sublingually • Causes sedation; Not EPS/ metabolic risks.
- 103. RISPERIDONE • High doses EPS • Low doses Raise prolactin levels; Weight gain; Dyslipidemia. • Available as: • Long term depot injectable formulations lasting for 2 weeks. • Orally disintegrating tablet • Liquid formulation.
- 104. RISPERIDONE-USES • Moderate doses Schizophrenia; Bipolar mania • In children and adolescents • Irritability associated with autistic disorder (age 5-16) • Aggresion, deliberate self-injury, mood swings (age 10-17) • Schizophrenia (age 13-17)
- 105. PALIPERIDONE • Active metabolite of risperidone • 5HT2A and D2 antagonism • Oral sustained dose preparation can be given once a day • Less EPS and sedation compared to risperidone • Depot palmitate formulation for long-term administration every 4 weeks.
- 106. ZIPRASIDONE • D2, 5HT2A, 5HT1B/1D , 5HT2C, H1, α2 antagonist • 5HT1A partial agonist • No propensity for weight gain, sedation • Less risk of metabolic side effects • May produce weight loss and reduce dyslipidemia in patients who are switched to ziprasidone due to metabolic abnormalities from other agents
- 107. ILOPERIDONE • Newer drug • Low level EPS; dyslipidemia • Moderate level weight gain. • Dose dependent QTc prolongation • Reduce nightmares in PTSD patients
- 108. ARIPIPRAZOLE • D2 partial agonist • Reduced EPS and hyperprolactinemia inspite of no action on 5HT2A • 5HT1A partial agonist • Non sedating: no H1/M1 blockade • No propensity for weight gain/metabolic effects, may reverse effects of other agents
- 109. ARIPIPRAZOLE • Uses : • Schizophrenia and mania • Schizophrenia in Children (13 and older) • Acute mania (10 and older) • Autism related irritability (6-17) • Antidepressant: augmenting SSRI/SNRI in treatment resistant major depressive disorder and bipolar depression • Can cause vomiting, akathesia in some patients
- 110. • Brexpiprazole : • Still under late stage clinical trial • Antipsychotic, anti manic and antidepressant property • Similar to aripiprazole but less EPS and akathesia • Cariprazine: • Under trial for schizophrenia, acute bipolar mania, bipolar depression and treatment resistant depression
- 111. FUTURE TREATMENTS FOR SCHIZOPHRENIA • Glutamate-linked mechanisms: • AMPAkines (CX546, CX619/Org 24448, LY293558) • mGluR presynaptic antagonists/postsynaptic agonists (LY2140023) • Glycine agonists • GlyT1 inhibitors
- 112. References • Stahl’s Essential Psychopharmacology 4th edition • Stahl’s Essential Psychopharmacology 2nd edition • Rang & Dale’s Pharmacology 8th Edition • Essentials of Medical Pharmacology, K. D. Tripathi 7th edition.
- 113. THANK YOU
Editor's Notes
- Perceptual distortions distressed by hallucinatory voices, hearing voices that accuse, blame/ threaten, seeing visions. Motor disturbances rigid posture, overt signs of tension, inappropriate grins/giggles, talking to oneself. Paranoid psychosis preoccupied with delusional beliefs, believing that people are talking about oneself, verbal expression of feeling of hostility, complaining & finding fault, expression of suspicion. Disorganized/ Excited psychosis Giving irrelevant answers, repeating certain words/phrases, unaware about the time, place and person, expressing feelings without restraint. Depressive psychosis Psychomotor retardation, apathy, anxious self punishment and blame.
- Key brain regions and their hypothetical functions. Psychiatric disorders hypothetically result from alterations in neurotransmission within different brain regions. A different set of symptoms is unveiled depending on which brain area is functionally impaired.
- Alogia Dysfunction of communication; restrictions in fluency & productivity of thought and speech Affective blunting/flattening Restrictions in the range & intensity of emotional expression Asociality reduced social drive and interaction Anhedonia reduced ability to experience pleasure Avolition Reduced desire, motivation or persistence, restrictions in the initiation of goal-directed behavior.
- Aggressive symptoms Assaultiveness, verbal abuse, frank violence Affective symptoms depressed mood, anxious mood, guilt, tension, irritability.
- The hypothesis of pathophysiology of Schizophrenia is based upon 2 neurotransmitters dopamine and glutamate
- Positive symptoms are hypothetically modulated by malfunctioning of mesolimbic pathway Negative symptoms are linked to malfunctioning of mesocortical pathways; also involves mesolimbic regions namely nucleus accumbens. Cognitive symptoms associated with problematic information processed in the dorsolateral prefrontal cortex. Affective symptoms associated with ventromedial prefrontal cortex Aggressive symptoms orbitofrontal cortex and amygdala.
- Presynaptic D2 autoreceptors are gatekeepers for dopamine. So when these receptors are not bound by dopamine, they open a molecular gate causing dopamine release.
- When dopamine binds to the gatekeeping receptors (now the gatekeeper has the dopamine in his hands), they close the molecular gate preventing dopamine release.
- a. The nigrostriatal DA pathway is part of the extrapyramidal nervous system, projects from substantia nigra to basal ganglia/striatum which controls motor function and movement. b. The mesolimbic DA pathway is part of the brain’s limbic system, projects from midbrain ventral tegmental area to the nucleus accumbens which regulates behaviors including pleasurable sensations, the powerful euphoria of drugs of abuse, and the delusions and hallucinations seen in psychosis. c. The mesocortical DA pathway projects from midbrain ventral tegmental area, sends its axons to areas of prefrontal cortex where they have a role in mediating the cognitive symptoms (dorsolateral prefrontal cortex, DLPFC) and affective symptoms (ventromedial prefrontal cortex, VMPFC) of schizophrenia. d. The tuberoinfundibular DA pathway projects from the hypothalamus to the anterior pituitary gland and controls prolactin secretion. e. The fifth DA pathway arises from multiple sites, including the periaqueductal gray, ventral mesencephalon, hypothalamic nuclei, and lateral parabrachial nucleus and projects to the thalamus. Its function is not well known.
- The mesolimbic DA pathway sends DA projections from cell bodies in the ventral tegmental area to the nucleus accumbens in the ventral striatum. This pathway hypothetically regulates emotional behaviors, pleasure, and reward and is the main candidate thought to regulate the positive symptoms of psychosis. Specifically, it has been hypothesized that hyperactivity of this pathway accounts for the delusions and hallucinations observed in schizophrenia. This hypothesis is known both as the “DA hypothesis of schizophrenia” and perhaps more precisely as the ”mesolimbic DA hyperactivity hypothesis of positive symptoms of schizophrenia.”
- The mesocortical DA pathway is hypothetically also affected in schizophrenia. Here, DA cell bodies in the ventral tegmental area send projections to the DLPFC to regulate cognition and executive functions, to the VMPFC to regulate emotions and affect. Hypoactivation of this pathway theoretically results in the negative, cognitive, and affective symptoms seen in schizophrenia. This hypothesis is sometimes called the “mesocortical DA hypothesis of negative, cognitive, and affective symptoms” of schizophrenia.
- Nigrostriatal Dopamine Pathway: The nigrostriatal pathway sends DA projections from the substantia nigra to the striatum. This innervation of the basal ganglia regulates motor activity and is part of the extrapyramidal nervous system. A lack of DA here results in symptoms resembling Parkinson’s disease, whereas an excess of DA will lead to hyperkinetic movement disorders such as dyskinesia's. In untreated Schizophrenia, activation of this pathway is believed to be normal. Tuberoinfundibular Dopamine pathway: DA inhibits prolactin secretion via the tuberoinfundibular pathway as DA projections are sent from the hypothalamus to the anterior pituitary. In untreated Schizophrenia, activation of this pathway is believed to be normal.
- Glu Glutamate; Gln Glutamine; VGluT Vesicular glutamate transporter; EAAT Excitatory Amino Acid Transporter; GlnT Glutamine Transporter.
- The cortical brainstem glutamate projection descends from pyramidal neurons in the prefrontal cortex (PFC) to brainstem neurotransmitter centers, including the raphe (5HT), the locus coeruleus (norepinephrine), and the ventral tegmental area and substantia nigra (DA). This projection mainly regulates neurotransmitter release in the brainstem. The cortico-striatal glutamate pathway descends from the PFC to the striatum and the cortico-accumbens glutamate pathway sends projections to the nucleus accumbens. These pathways make up the “cortico-striatal” portion of cortico-striatalthalamic loops. Thalamo-cortical glutamate pathways encompass pathways ascending from the thalamus and innervating pyramidal neurons in the cortex. Cortico-thalamic glutamate pathways descend from the PFC to the thalamus. The cortico-cortical glutamatergic pathways allow intracortical pyramidal neurons to communicate with each other.
- Various theories have been put forth trying to explain the overactivity of the DA pathway in the mesolimbic system in schizophrenia. The descending cortico-brainstem glutamate pathway normally acts as a brake for the mesolimbic DA pathway, via gamma-aminobutyric acid (GABA) interneurons in the ventral tegmental area, leading to a tonic inhibition of the mesolimbic DA pathway (A). If glutamate projections become hypoactive, this tonic inhibition of the mesolimbic DA pathway will not occur, leading to hyperactivity in the mesolimbic DA pathway (B).
- Helps to understand the actions of various antipsychotics.
- Mechanism by which Serotonin release in the cortex can lead to decreased dopamine release in the striatum.
- Serotonin is released in the cortex, binds to 5HT2A receptors on glutamatergic pyramidal neurons causing activation of those neurons. Activation of glutamatergic pyramidal neurons leads to glutamate release in the brainstem, which inturn stimulates GABA release. GABA binds to dopaminergic neurons projecting from substantia nigra to striatum, inhibiting dopamine release. Dotted outline dopaminergic neuron.
- Nigral and striatal 5HT2A receptor stimulation decreases dopamine release.
- In the striatum, serotonergic projections synapse directly with dopaminergic neurons and indirectly with GABAergic neurons. At GABAergic neurons, serotonin binding to 5HT2A receptors disinhibits GABA release decreases dopamine release. When serotonin directly binds to dopamine neurons decreased dopamine release. 2. Serotonin released in the raphe nucleus binds to 5HT2A receptors o GABAergic neurons GABA released onto dopaminergic neurons in substantia nigra inhibiting dopamine release into striatum.
- Dopamine inhibits prolactin: Dopamine inhibits prolactin release from pituitary lactotroph cells in pituitary gland when it binds to D2 receptors. Serotonin stimulates prolactin: Serotonin stimulates prolactin release from pituitary lactotroph cells in the pituitary gland when it binds to 5HT2A receptors. Thus, serotonin and dopamine have a reciprocal regulatory action on prolactin release.
- Neurolepsis an extreme form of slowness/absence of motor movements as well as behavioural indifference in experimental animals. Hence named neuroleptics.
- In untreated Schizophrenia, the mesolimbic dopamine pathway is hypothesized to be hyperactive leading to excess dopamine positive symptoms delusions, hallucinations. Administration of D2 antagonist, blocks dopamine from binding to D2 receptor reduces hyperactivity of this pathway reduces positive symptoms.
- In untreated schizophrenia, the mesocortical dopamine pathways to dorsolateral prefrontal cortex and to ventromedial prefrontal cortex are hypothesized to be hypoactive. This is related to cognitive symptoms, negative symptoms and affective symptoms of schizophrenia. Administration of a D2 antagonist could further reduce activity in this pathway and thus not only not improve such symptoms but actually potentially worsen them.
- The nigrostriatal dopamine pathway is theoretically unaffected in untreated schizophrenia. However, blockade of D2 receptors prevents dopamine from binding there and can cause motor side effects termed as Extrapyramidal symptoms. When a substantial number of D2 receptors are blocked in the nigrostriatal dopamine pathway, it will produce various disorders of movement that can appear very much like those in Parkinson’s disease hence sometimes called drug-induced parkinsonism. Worse yet, chronic blockade of D2 receptors in the nigrostriatal dpamine pathway produce a hyperkinetic movement disorder known as tardive dyskinesia. 5% patients maintained on typical antipsychotics develop tardive dyskinesia every year.
- The tuberoinfundibular dopamine pathway which projects from the hypothalamus to the pituitary glands is normal in untreated schizophrenia. D2 antagonists reduce activity in this pathway by preventing dopamine from binding to D2 receptors causing rise in prolactin levels associated with side effects such as galactorrhea, amenorrhea.
- Conventional antipsychotics are D2 antagonists and thus oppose dopamine’s inhibitory role on prolactin secretion from pituitary lactotrophs. Thus, these drugs increase prolactin levels.
- Dopamine and acetylcholine have a reciprocal relationship in the nigrostriatal pathway. Dopamine neurons here make postsynaptic connections with cholinergic neurons. Normally, dopamine inhibits acetylcholine release from postsynaptic nigrostriatal cholinergic neurons suppressing acetylcholine activity.
- Blockade of dopamine receptors by conventional antipsychotic dopamine cannot suppress acetylcholine release overactivity of acetylcholine.
- Compensation of overactivity of acetylcholine block it with an anticholinergic agent. Thus, drugs with anticholinergic actions will diminish the excess acetylcholine activity caused by removal of dopamine inhibition when dopamine receptors are blocked. If anticholinergic properties are present in the same drug with D2 blocking properties, they will tend to mitigate the effects of D2 blockade in the nigrostriatal dopamine pathway. Thus, conventional antipsychotics with potent anticholinergic properties have lower EPS than those with weak anticholinergic properties.
- Blockade of muscarinic M1 receptors dry mouth, blurred vision, constipation, cognitive blunting.
- Undesired blockade of histamine H1 receptors weight gain, drowsiness.
- Blockade of α-1 adrenergic receptors CVS side effects orthostatic hypotension
- Parkinsonism rigidity, tremor, hypokinesia, mask like facies, shuffling gait; appears 1-4 weeks of therapy. Persists till dose is reduced. Acute muscular dystonias. muscle spasms involving linguo-facial muscles- grimacing, tongue thrusting, locked jaw. Occurs within few hours of single dose. Resoles spontaneously/ central anticholinergics promethazine injection, Akathisia restlessness, discomfort, agitation propranolol; changeover to atypical antipsychotic Malignant neuroleptic syndrome maked rigidity, immobility, tremor, hyperthermia, semiconsciousness, fluctuating B and heart rate, myoglobin present in blood. IV dantrolene, Bromocriptine. Tardive dyskinesia
- Blocking cortical 5HT2A receptors increases dopamine release.
- If 5HT2A receptors on glutamatergic pyramidal neurons are blocked, then these neurons cannot be activated by serotonin release in the cortex. If glutamate is not released from glutamatergic pyramidal neurons into the brainstem, then GABA release is not stimulated cannot inhibit dopamine release from substantia nigra into striatum.
- Blocking nigral and striatal 5HT2A receptors increases Dopamine release.
- If 5HT2A receptors on GABAergic interneurons in the striatum are blocked, then serotonin is unable to stimulate these receptors to cause release of GABA. Thus GABA is unable to inhibit dopamine release. Blockade of 5HT2A receptors directly striatal dopaminergic neurons prevents inhibition of dopamine release, increasing striatal dopamine. In the brainstem, blockade of 5HT2A receptors on GABAergic interneurons prevents GABA release onto dopaminergic neurons in the nigra dopamine can be released into striatum.
- Postsynaptic dopamine 2 receptors are being blocked by a serotonin-dopamine antagonist in nigrostriatal dopamine pathway. Shows dual action of the SDAs, in which both D2 and 5HT2A receptors are blocked. Interesting fact, second action of 5HT2A antagonism reverses the first action of D2 antagonism. This happens because dopamine is released when serotonin can no longer inhibit its release. This is called DISINHIBITION. Thus blocking a 5HT2A receptor disinhibits dopamine neuron causing dopamine to pour out of it. Consequence of this is that dopamine can compete with the SDA for the D2 receptor and reverse the inhibition. As D2 blockade is thereby reversed, SDAs cause little or no EPS or tardive dyskinesia.
- 5HT2A antagonism reverses the ability of D2 antagonism to increase prolactin secretion. As dopamine and serotonin have reciprocal regulatory roles in the control of prolactin secretion, one cancels the other. Thus, stimulating 5HT2A receptors reverses the effects of stimulating D2 receptors. The same thing works in reverse, namely, blockade of 5HT2A receptors reverses the effects of blocking D2 receptors.
- 5HT1A receptor stimulation in the cortex hypothetically stimulates downstream dopamine release in the striatum, by reducing glutamate release in the brainstem, which in turn fails to trigger the release of inhibitory GABA at dopamine neurons there.
- Drugs that block the 5HT1B/D autoreceptor can promote 5HT release and this could hypothetically result in antidepressant actions. Iloperidone, Ziprasidone, asenapine have 5HT1B/D binding properties.
- 5HT2C antagonists tricyclic antidepressants mirtazapine; Agomelatine.
- Serotonin/NE reuptake inhibition only quetiapine has potency greater than its D2 binding but other two have weak binding at these sites.
- All atypical antipsychotics share a class warning for weight gain, obesity…….. May complicate to diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome.
- Not used as local anaesthetic because of irritant actions
- Produces acute muscle dystonias in children especially when injected
- Maintainence therapy because of long duration of action after a single oral dose
- Agranulocytosis, a fatal complication in 0.5-2%. Requires monitoring blood counts. Cardiometabolic risks include increase in fasting plasma triglyceride levels and insulin resistance. Higher doses severe bowel obstruction due to paralytic ileus.
- Chemical structure related to clozapine; Also an antagonist of D2 and 5HT2A receptor; More potent than clozapine. Treatment resistant depression when combined with antidepressant fluoxetine.
- Chemical structure related to clozapine; Antagonist at D2 and 5HT2A receptor. Present in different doses and with different oral formulations. Immediate release formulation rapid onset and short duration of action; Taken once a day esp at night because it is most sedating. Hence it makes an ideal hypnotic rather than an ideal antipsychotic. Antipsychotic effect wears off in few hours. Extended release hits its peak very slowly; Less sedative; Duration of action lasts all day. Ideal antipsychotic.
- Low dose: 50 mg Baby Bear IR formulation. Can be used as a sedative hypnotic due to H1 blocking property. Not used as first line due to risk of metabolic abnormalities 300mg dose XR formulation, Mama Bear: antidepressant activity (partly due to norquetiapine) Antidepressant actions in unipolar and bipolar depressed patients. Activity of norquetiapine plays a role due to norepinephrine reuptake inhibition properties, 5HT2C, 5HT7, 5HT1B/D antagonist, 5HT1A partial agonist properties. 800mg dose XR formulation Papa Bear: antipsychotic
- At any dose, lacks EPS and doesn’t elevate prolactin hence used in Parkinson’s disease Side effects weight gain; increase in fasting triglyceride and insulin resistance.
- Given sublingually active drug is poorly bioavailable; extensive first pass metabolism Surface area of the oral cavity for oral absorption may limit size of the dose and extent of absorption at high doses hence given twice a day despite longer half life.
- Atypical in lower doses; Can become conventional at higher doses because EPS can occur if dose is too high
- May cause weight gain, insulin resistance and diabetes as well as prolactin elevation.
- Akathisia reduced by dose reduction/ administering an anticholinergic agent or benzodiazepine.
- AMPAkines alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid AMPA receptors regulate ion flow and neuronal depolarization NMDA receptor activation-> more efficacy for cognitive symptoms without showing activation of positive symptoms/neurotoxicity mGluR presynaptic antagonists/postsynaptic agonists An agent acting as a presynaptic mGlu agonist could potentially prevent excessive glutamate release consequence NMDA hypoactivity improving symptoms of schizophrenia Glycine agonists tested and known to reduce negative and/or cognitive symptoms (cycloserine) GlyT1 inhibitors Glycine transporters natural agent N-methylglycine, sarcosine, Also called as selective glycine reuptake inhibitors inhibit reuptake of other neurotransmitters such as SSRI’s.