OVERVIEW• Psychosis & Schizophrenia• Symptom dimensions• Neurotransmitters & Circuits

•Antipsychotics• Conventional & Atypical• Other pharmacological actions• Individual drugs

• Future treatments for Schizophrenia.

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

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

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.

• 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

POSITIVE SYMPTOMS• Delusions

• Hallucinations

• Distortions/ exaggerations in language and communication

• Disorganized speech

• Disorganized behavior

• Catatonic behavior

• Agitation

NEGATIVE SYMPTOMS

• 5 types• Alogia

• Affective blunting/ flattening

• Asociality

• Anhedonia

• Avolition

COGNITIVE SYMPTOMS

• Problems focusing & sustaining attention

• Problems evaluating functions & monitoring performance

• Impaired verbal fluency

•Difficulty with problem solving

NEUROTRANSMITTERS AND

CIRCUITS IN SCHIZOPHRENIA

DOPAMINE

DOPAMINE HYPOTHESIS OF

SCHIZOPHRENIA: POSITIVE SYMPTOMS

DOPAMINE HYPOTHESIS OF

SCHIZOPHRENIA: NEGATIVE, COGNITIVE

& AFFECTIVE SYMPTOMS

GLUTAMATE

NMDA RECEPTOR HYPOFUNCTION

HYPOTHESIS OF SCHIZOPHRENIA

Linking the NMDA hypo function hypothesis of

schizophrenia with the dopamine hypothesis of

schizophrenia: Positive symptoms.

SEROTONIN

SEROTONERGIC CONTROL OF DOPAMINE RELEASE

• Serotonin important influence on dopamine.

•Varies among different dopamine pathways

ACTION ON PROLACTIN

ANTIPSYCHOTICS

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

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.

THANK YOU

ANTIPSYCHOTICS

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

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.

What makes an antipsychotic typical/atypical??

Typical antipsychotics

• Conventional/ First generation antipsychotics.

• Primary pharmacological property D2 antagonism.

•Neurolepsis Neuroleptics

Mesolimbic pathway..

Mesocortical pathway..

Nigrostriatal pathway..

Tuberoinfundibular pathway

Other pharmacological properties of Conventional antipsychotics

•Muscarinic anticholinergic (M1)

•Antihistaminic (H1)

• α-1 adrenergic antagonist.

Reciprocal relationship of dopamine and acetylcholine

Side effects of conventional antipsychotics

EXTRAPYRAMIDAL SYMPTOMS

• Parkinsonism

•Acute muscular dystonia

•Akathisia

•Malignant Neuroleptic Syndrome

• Tardive dyskinesia.

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

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

5HT1B/D receptors

• Terminal autoreceptor

• Located on axon terminal

• Promotes 5HT release antidepressant actions

• Iloperidone, Ziprasidone, Asenapine.

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.

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

Other Pharmacological actions..

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.

Antimaniac actions

• D2 antagonism/partial agonism combined with 5HT2A antagonism.

• Aripiprazole & Cariprazine additional efficacy due to 5HT1A partial agonism.

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.

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.

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.

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.

Cardio metabolic actions

•High metabolic risk Clozapine, Olanzapine

•Moderate metabolic risk Risperidone, Paliperidone, Quetiapine, Iloperidone

• Low risk Ziprasidone, Aripiprazole, Lurasidone, Asenapine, Brexpiprazole, Cariprazine.

Individual antipsychotics- typical

CHLORPROMAZINE (CPZ)

• Prototype drug; D2 antagonist

• Similar to procaine as local anesthetic.

•High doses Q-T prolongation; Suppression of T-wave

•Overdose Arrhythmia

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

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.

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

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.

Individual antipsychotics- atypical

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.

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.

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

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.

QUETIAPINE•Active metabolite- Norquetiapine.• Properties:

• Norepinephrine reuptake inhibition

• 5HT7, 5HT2C, α2 antagonism

• 5HT1A partial agonism

• Formulations:

• Immediate release (IR)

• Extended release (XR)

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.

ASENAPINE

•Newer drug

•D2, 5HT2A, 5HT2C, H1 and α2 antagonism : antidepressant action

•Given sublingually

• Causes sedation; Not EPS/ metabolic risks.

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.

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)

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.

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

ILOPERIDONE

•Newer drug

• Low level EPS; dyslipidemia

•Moderate level weight gain.

•Dose dependent QTc prolongation

• Reduce nightmares in PTSD patients

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

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

• 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

FUTURE TREATMENTS FOR SCHIZOPHRENIA

•Glutamate-linked mechanisms:

• AMPAkines (CX546, CX619/Org 24448, LY293558)

• mGluR presynaptic antagonists/postsynaptic agonists (LY2140023)

• Glycine agonists

• GlyT1 inhibitors

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.

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