psychosis pharmacology

ANTI-PSYCHOTICS LECTURE APRIL 2014 DR T. IBRAHIM

ANTI-PSYCHOTICS(NEUROLEPTICS/MAJOR TRANQUILISERS)

PsychosisIt is a term used to describe a group of severe mental illness characterized by hallucination, delusions, extreme abnormalities of behavior including marked over-activity, retardation, catatonia and usually a lack of insight.

Functional psychoses: Schizophrenia and affective disorders, Schizo-affective disorders, mood disorders (bipolar).

Organic psychoses: secondary to pre-existing medical condition. May be due to illicit substance use…

Examples of drugs causing psychosisCocaine, Amphetamine, Levodopa, Methyl phenidate, Ketamine, Cannabinoids, Steroids..

Anti-psychotic drugsThese are group of drugs used to treat psychiatric disorders characterized by disturbed thought and behavior-primarily Schizophrenia.

Note: These drugs are notcurative and do not eliminate the chronic thought disorder but they often decrease the intensity of hallucinations, delusions and permit the person with Schizophrenia to function in a supportive environment.

HallucinationsA hallucination is a perception in the absence of apparent stimulus that has qualities of real perception. It may affect all the five senses. Auditory hallucination is very common while visual hallucination is abit rare.

IllusionIt is a wrong or mis-interpreted perception of a sensory experience.

DelusionA false belief that cannot be dislodged even by solid proof of contradictory evidence or by reasoning the subject.

Bizarre delusion: very strange and completely implausible.Non-bizarre delusion: A delusion though false but is at least possible.Delusion of grandiosity: eg the patient is King, Queen, God….Delusion of thought insertion: belief that another person thinks through the mind of the person.

SchizophreniaIt comes from the Greek word meaning “split” and “mind”.People with Schizophrenia are split off from the reality and cannot distinguish between real and not real. It is the most common and debilitating form mental illness.

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Three major symptoms of Schizophrenia:1. Positive symptoms: Hallucination (auditory), delusions (Gradiosity, persecution, Paranoid…)

Catatonia (purposeless motor activity and immobility).2. Negative symptoms: social isolation, Blunted affects, Anhedonia (Inability to derive pleasure) impoverished speech (alogia: absence of words), flattening of emotional responses.3. Cognitive symptoms: deficit in working the memory, cognitive control of behavior.

EpidemiologySchizophrenia occurs in 1% of the population world-wide. It usually affects during late adolescence or early adulthood. It has a strong genetic predisposition.

Risk factorsEnvironmental factors: prenatal exposure to viral infections, pre-natal poor nutrition, per-natal hypoxia, advanced paternal age, birth rank, season of birth.

Pathogenesis1. Dopamine Hypothesis of Schizophrenia(no longer considered adequate to explain all aspects of Schizophrenia but enough to understand positive and negative symptoms).

Excessive limbic dopaminergic activity plays a role in psychosis. Post-mortem studies of Schizophrenia subjects have reported increased dopamine levels and D2-

receptor density in nucleus accumbens, caudate and putamen. Diminished cortical and hippocampal dopaminergic activity underlie cognitive impairment and

negative symptoms of Schizophrenia.

2. Glutamate hypothesisAbnormal concentration of glutamate in hippocampus and pre-frontal cortex (PFC) occurs in Schizophrenia subjects.

Note: The main neurotransmitters involved in the pathogenesis of Schizophrenia are dopamine and glutamate.

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Anti-psychotics

First generation anti-psychotics Acts predominantly by blocking the dopamine D2-receptors in the brain.

A. Phenothiazines: 3 groupsGroup IThey are characterized by profound sedation and moderate anti-muscarinic and Extra pyramidal side-effects, EPS.Drugs Chlorpromazine levomepromazine PromazineDose/route Oral/IM/PR

Initial oral dose: 25 mg TDS (75-300 mg/day)IM: 25-500 mg q 6-8 hoursPR: 100 mg q 6-8 hours.

25-100 mg/day 100-200mg QID

Remarks Limited use nowadays -------------------- -------------------

Group IIFewer EPS compared to Group I and group III; moderate sedative effects.Drugs Pericyazine Pipotiazine MesoridazineDose 15-75 mg/day IM at 4 weeks interval 50-400nmg/day

Group IIIFewer sedative and anti-muscarinic effecs; more EPS compared to GP I and II.Drugs Fluphenazine

decanoatePerphenazine Prochlorperazine Tri fluoperazine

Dose 25 mg IM q 2 weeks Oral: 75-100 mg/dayIM: 12.5-25 mg TDS

5-10 mg/day

B. Butyrophenones Benperidol Haloperidol (3-5 mg, 2-3 times/day, max: 30 mg/day); depot preparation also available.

C. Diphenyl butyl piperidines Pimozide: 2-20 mg/day ( removed due to high risk of QT elongation).

D. Piperazine Fluphenazine

E. Thioxanthene Thiothixene

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Low potency anti-psychoticsChlorpromazineProchlorperazineThioridazine

Moderate potencyMolindone: 15-20 mg/day

High potency Anti-psychoticsFluphenazineHaloperidolPimozideFlupenthixol (can cause excitation and gynaecomastia)ZuclopentixolSulpiride: 200-400 mg BD (maximum: 800 mg/day)

Atypical Anti-psychotics/second generation anti-psychotics1. AripiprazoleDose: 15 mg OD (max: 30 mg/day); 5, 10, 15 g tabs

No weight gain D 2-partial agonist with weak 5 HT1A partial agonism. Unlike other anti-psychotics, it lowers prolactin level and also cause nausea. Least risk of EPS, negligible effect on QT interval and least likely to cause hyperglycemia.

2. ClozapineIt is a di benzo-diazepine derivative.Dose: initially 12.5-25 mg /day; maintenance of 300-600 mg by gradual titration; 25, 100mg tabs.It has high affinity for D4 receptor; it also blocks D1, D2, 5 HT2A, -adrenoceptor and muscarinic receptors.

Main adverse effects: Agranulocytosis (WBC initially to be monitored every week for 2 months then greater spacing).Postural hypotension, collapseSeizure 3-5%Myocarditis and cardiomyopathy.Risk of weight gain and hyperglycemia:+++

Note: it is the only agent indicated to reduce risk of suicide.

3. Olanzapine It is a thiene-benzodiazepine derivative. It causes D1, D2, D4, 5HT2 antagonism. Dose: 5-10 mg/day. T1/2: 33 hours. Weight gain/ hyperglycemia: +++ It is associated with the greatest risk of stroke in elderly patient.

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4. RisperidoneBest effects seen at doses less than 6 mg/day; dose range: 0.5-10 mg/day.Depot preparation available.

5. PaliperidoneIt is the active metabolite of Risperidone.Dose: 6 mg OD.

6. AmisulprideSelective dopamine antagonist with high affinity for mesolimbic D2 and D3 receptors.Dose: 400-800 mg daily.

7. AsenapineIt is a dibenzo-oxepriopyrroleAvailable for oral and sublingual use.Dose: 10-20 mg/day; 5, 10 mg tabs.Approved for treatment of Bipolar disorder.

8. QuetiapineIt is D1, D2, 5HT2, - receptor, H1 receptor antagonist; 5HT1A partial agonist.Short T1/2: 6 hoursDose: 300-450 mg/day (max:750 mg/day); start with 50 mg/day and titrate up.Practically no EPS

Other drugsZiprasidone, Remoxipride, Zotepine, Sertindole (cause nasal congestion and risk of ventricular arrhythmia), Iloperidone, Lurasidone.

Examples of anti-psychotic drugs available as Depot preparationsProtiazinepalmitate: Im every 4 weeks-50 ng/mlFluphenazinedecanoate: 25 mg deep IM q 2 weeksHaloperidol decanoate: 100 mg deep IM q 4 weeksFlupentixol: 40 mg IM q 2 weeksZuclopentixol: 200 mg IM q 2 weeksPaliperidonepalmiatte, Risperidone, Ziprasidone, Aripiprazole…

Advantages of Atypical over typical anti-psychotics.1. Able to decrease the negative symptoms of Schizophrenia; typical anti-psychotics decrease only the positive symptoms.2. Absence or marked reduction in occurrence of EPS.3. Less incidence of hyperprolactinemia (Aripiprazole actually decreases the serum prolactin level).4. Sexual dysfunction and skin problem are less.5. Little effect or not effect on QT interval.6. Atypical anti-psychotics have been found to have neuro-protective action also.

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7. Better tolerance and compliance to the drug.

Disadvantages of second generation anti-psychotics1. High risk of weight gain and hyperglycemia.2. Risk of agranulocytosis with Clozapine.3. Increase incidence of cardiovascular disorders.

Mechanism of action1. All the older (first generation) and most of the newer neuroleptics block dopamine receptors in the brain and its periphery.Dopamine receptors: 5 types (D1, D2, D3, D4, D5)D1andD5 receptors activate adenylyl cyclase, often exciting neurone.D2, D3, D4 receptors: inhibit adenylyl cyclase and mediate membrane K+ channel opening leading to neuronal hyperpolarization.

Clinical efficacy of typical neuroleptics is related to their ability to block D2receptors on mesolimbic system of the brain.Atypical anti-psychotics have more affinity for other dopamine receptors.

Note: Clozapine and Risperidone cause substantial blockade of -receptors which may account for their beneficial effect on negative symptoms of Schizophrenia.

2. Serotonin-Blocking activity in brainMost of the newer atypicalagents exert part of their action by inhibition of 5HT receptors, particularly 5HT2A receptors.Examples:Clozapine: D1,D4, D2, 5HT2, muscarinic, -receptorsOlanzapine and Risperidone: 5HT2A….

Pharmacological actions Anti-psychotics actions are due to blockade of dopamine receptors and serotonin receptors. However, these drugs also block muscarinic, adrenergic and histaminergic receptors, H1.

1. Anti-psychotic actions Decreases the positive symptoms of Schizophrenia by causing D2-receptor blockade in

mesolimbic system of brain. Atypical anti-psychotics such as Clozapine improve the negative symptoms also. Calming effects and reduction in spontaneous physical movements.

Note: Anti-psychotics take about 2-4 weeks to show optimum action.

2. Blockade of Dopamine receptors in the Nigrostriatal pathway leads to EPS, which is characterized by Akathisia, Parkinsonism, Tardive dyskinesia, Dystonia (sustained contraction of muscles leading to twisting and distorted posture).Note: Atypical anti-psychotics have less risk of causing EPS.

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3. Blockade of dopamine receptors in Tubero-infundibular pathway leads to hyperprolactinemia which in turn leads to galactorrhoea, infertility, menstrual disturbances in females. In males, the consequence is gynaecomastia, impotence and infertility.Dopamine released by these neurons physiologically inhibit prolactin secretion from the anterior pituitary.

4. Blockade of dopamine receptors in Medullary peri-ventricular pathway is involved in eating behavior and that of Incerto-hypothalamic pathway is involved in copulatory behavior in animal.

5. Anti-emetic effectsMost anti-psychotics (except Aripiprazole and Thioridazine) have anti emetic action which is mediated by D2-receptor blockade in the CTZ.

6. Anti-muscarinic effectsCommon with Thioridazine, Chlorpromazine, Clozapine, Olanzapine. They lead to adverse effects such as blurring of vision, urinary retention, constipation, dry mouth (except clozapine which despite having anti-muscarinic action causes hypersalivation).

7. Blockade of α-1 adrenergic receptorsLeads to orthostatic hypotention.

Pharmacokinetics

1. All anti-psychotic medications are highly lipophilic, highly membrane bound or protein bound and accumulates in the brain and other tissues with rich blood supply such as the lungs..

2. After oral administration, neuroleptics shows variable absorption which is unaffected by food in most cases (except Ziprasidone and Paliperidone whose absorption increase with food)Phenothiazine are erratically absorbed after oral administration but its absorption is good following intramuscular administration.

3. Volume of distribution varies from 7-20 L/Kg

4. Plasma t1/2 of most anti-psychotics varies from 15-30 hours.Examples:Long-acting: t1/2 Haloperidol: 18 hourst1/2 olanzapine: 33 hourst1/2 Aripiprazole: 3 days

Short-actingt1/2 Quetiapine: 6 hourst1/2 Ziprasidone: 8 hours

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Some depot preparation are also available for slow release and their duration of action varies from 2-4 weeks.Example Fluphenazine decanoate: 2-3 weeks.

5. They are metabolized to many different substances by CYP 450 system (particularly CYP2D6, CYP1A2, CYP3A4).

Indications

Psychiatric1. Schizophrenia

Note: catatonic Schizophrenia is best treated managed by IV anti-psychotics.Depot preparation can also be used for maintenance when compliance with oral treatment is a problem.Examples: Flupentixol decanoate.

2. Manic phase of bipolar disorder and in hypomania.IV haloperidol for rapid control of symptoms followed by Quetiapine or Chlorpromazine or Riseridone along with mood stabilizers.

3. Schizo-affective disorders.

4. Psychotic depression

5. For short term adjunctive management of severe anxiety associated with psychomotor agitation, excitement, violence or impulsive behavior.

6. Senile psychosis, Alzheimer

7. Deviant social and sexual behavior: benperidol 0.25-1.5 mg/day.

Other uses1. Anti-emetic

To treat nausea and vomiting or to prevent nausea and vomiting which is drug induced. Vertigo in Meniere’s disease. Labyrinthitis Migraine

Drugs used:Prochlorperazine: 5-20 mg/day (stemetil)Haloperidol: 1-2 mg IM/IVLevopromazine: 6 mg oral/scBenzquinamide

2. Intractable hiccups

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Chlorpromazine: 10-25 mg oral q 4-6 hourly (25-50 mg IM)Haloperidol: 1.5 mg tds

3. Pain control (in painful terminal illness)Levopromazine 12.5mg-50 mg, Sc infusion every 24 hours.Haloperidol + diamorphine Sc infusion.They reduce emotional response to pain and potentiate some central effects of narcotic analgesics.

4. Acute “behavioural emergencies” such as violent patients with range of psycho-pathologies including mania and toxic delirium. Clozapine is the only Atypical agent indicated to reduce risk of suicide.

5. As component of Neuroleptanalgesia (droperidol and Fentanyl)andNeuroleptanaesthesia (droperidol+ Fentanyl+nitrous oxide)

6. Huntington’s choreaHaloperidol/Risperidone (2-8 mg/day), OlanzapineClozapine: 50-600 mg/dayQuetiapine: 50-600 mg/day

Tetrabenazine and baclofen are also used in its management.

7. Gille de la Tourette SyndromeHaloperidol: 0.5-1.5 mgOlanzapine/Risperidone

8. AutismThey decrease the disruptive behaviour and irritability.Risperidone: 0.25 mg (<25 kg); 0.5-3 mg/day (>25 kg)Aripiprazole: 30 mg/day.

9. PruritusTrimeprazine is useful because of its high anti-histaminic and sedative action.

10. Anxiety disordersObsessive Compulsive disorder, OCD and Post Traumatic Stress Disorder, PTSDDrug used: olanzapine/Risperidone/Quetiapine along with SSRI

11. Shock (off-label use)12. Hypertension reaction complicating MAO inhibitors and TCA therapy (off label use)

Prophylactic uses1. Droperidol: prevention and treatment of post-operative nausea and vomiting2. Promethazine (avomine): motion sickness.

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Adverse effectsAll anti-psychotics produce adverse effects that are extension of their pharmacological action.

1. “pseudo depression” with older anti-psychotics due to drug induced akinesia (respond to anti-parkinson treatment).

2. Extrapyramidal symptoms, EPSDue to blockade of Nigrostriatal pathwayCommon with first generation anti-psychotics, clozapine, olanzapine.Least with Quetiapine.

EPS is characterized by:i. Parkinsonism: bradykinesia, rigidity, tremors, mask facies.

Management: respond to centrally acting anti-cholinergics (Biperiden 2-12 mg, benztropine 1-6 mg) and H1-antagonist with significant anticholinergic action such as diphenhydramine.

ii Akathisia (uncontrollable restlessness) along with dystonic reaction (torticollis/retrocollis). It occurs after large initial dose.

Treatment: centrally acting anticholinergic + clonazepam.

iii Tardive dyskinesia

It is the most serous manifestation of EPS and is usually irreversible even on withdrawal of the causative agent. It is most common with the first generation of anti-psychotics and occurs after several months to years of treatment.

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The treatment incorporates:1. Withdrawal of the offending drug. Replace typical anti-psychotics by atypical

anti-psychotics such as clozapine (50 mg/day), Olanzapine (5-10 mg/day), risperidone (4-10 mg/day), Quetiapine (300-750 mg/day), Ziprasidone, Aripiprazole (10-15 mg/day to max 30mg/day), Amisulpride (800-1200 mg/day). Diazepam 10-20 mg/day (Gradual titration if needed) can be used to enhance GABA- ergic activity. After discontinuation, reassess the treatment periodically.

2. Elimination of stimulants or TCA and Anti-cholinergics drugs.3. Refractory cases of choreo-athetoid or choreatic tardive dyskinesia can be

treated by catecholamine (dopamine) depletors such as Reserpine, a small dose of 0.125 mg/day and escalated slowly up to 6 mg/day or use Tetrabenazine initially with 12.5 mg/day up to 200 mg/day. There is difficulty due to dose dependent sedation and orthostatic hypotension with these drugs.

4. Use of Lecithin is indicated as it helps in providing choline with increasing acetylcholine in striatum.

5. Other drugs used to increase GABA ergic Transmission are: Muscimol (5-9 mg/day), Baclofen (40-80 mg/day), Clonazepam (1-8 mg/day) and Valproic acid (750-3000 mg/day). They increase GABA concentration in extrapyramidal system.

6. Vit E, if given early- it reduces voluntary movements.


3. Sedation and drowsiness4. Toxic confusional stae5. Neuroleptic Malignant Syndrome

Characterized by extreme form of rigidity, fever, unstable BP, myoglobinemia.. it can occur as fast as the first week of therapy or after months to years of treatment.

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The treatment incorporates:1. Withdrawal of the offending drug. Replace typical anti-psychotics by atypical

anti-psychotics such as clozapine (50 mg/day), Olanzapine (5-10 mg/day), risperidone (4-10 mg/day), Quetiapine (300-750 mg/day), Ziprasidone, Aripiprazole (10-15 mg/day to max 30mg/day), Amisulpride (800-1200 mg/day). Diazepam 10-20 mg/day (Gradual titration if needed) can be used to enhance GABA- ergic activity. After discontinuation, reassess the treatment periodically.

2. Elimination of stimulants or TCA and Anti-cholinergics drugs.3. Refractory cases of choreo-athetoid or choreatic tardive dyskinesia can be

treated by catecholamine (dopamine) depletors such as Reserpine, a small dose of 0.125 mg/day and escalated slowly up to 6 mg/day or use Tetrabenazine initially with 12.5 mg/day up to 200 mg/day. There is difficulty due to dose dependent sedation and orthostatic hypotension with these drugs.

4. Use of Lecithin is indicated as it helps in providing choline with increasing acetylcholine in striatum.

5. Other drugs used to increase GABA ergic Transmission are: Muscimol (5-9 mg/day), Baclofen (40-80 mg/day), Clonazepam (1-8 mg/day) and Valproic acid (750-3000 mg/day). They increase GABA concentration in extrapyramidal system.

6. Vit E, if given early- it reduces voluntary movements.

Treatment:

1. The most important intervention is to discontinue all antipsychotics. In most cases, symptoms will resolve in 1-2 weeks. Neuroleptic malignant syndrome precipitated by long-acting depot injections of antipsychotics can last as long as a month.

2. During the course of neuroleptic malignant syndrome, use supportive care aggressively.

3. Supportive measures are aimed at preventing further complications and maintaining organ function.

I. Patients should receive circulatory and ventilatory support as needed. II. Cooling blankets and antipyretics can be used to control temperature. III. Aggressive fluid resuscitation and alkalization of urine can help prevent acute renal failure and enhance excretion of muscle breakdown products.

4. Benzodiazepines: Diazepam 5-10mg/day. They reduce recovery time in neuroleptic malignant syndrome and are beneficial in managing agitated and hyperactive patients.

5. Dopaminergic agonists Bromocriptine: Dosage very much from 2.5-5 mg TDS, the suitable dose is 5-15mg/day to maximum 35mg/day. Every patient therapy is to be individualized. Other drug used is Amantadine 100-300mg/day (D1/D2 agonist).

6. Direct acting skeletal muscle relaxant Dantrolene: 1mg/kg, IV initially, to be increased up to 10mg/kg,Iv. After short term therapy oral medication with Dantrolene is started using 25mg/day to 100mg QID depending upon the nature and duration of the disease. It can be given concurrently with the dopaminergic agonists. The drug Dantrolene is hepatotoxic although rarely does it cause liver damage but liver function isto be monitored during therapy.

7. Treatment of complications Hemodialysis: For preventing renal failure to occur from rhabdomyolysis a major complication responsible for increased mortality.


6. ANS: Orthostatic hypotention, Impotence (common with typical antipsychotics, Risperidone, Quetiapine)Failure to ejaculate.

7. Anti-muscarinic effects Blurring of vision, dryness of mouth (except clozapine which causes hypersalivation- can

be controlled by giving Hyoscine butyl bromide). Urinary retention Constipation Increase in intra-ocular pressure. Tachycardia with risk of arrhythmia (least with aripiprazole).

8. Effects on tubero-infundibular pathways.First generation anti-psychotics, Amisulpride, Risperidone.Hyper-prolactinemia (absent with aripiprazole and less with olanzapine, clozapine, Quetiapine).Galactorrhoea, menstrual disturbance, gynaecomastia, infertility.

9. Photoxicity, urticarial reaction.10. Weight gain (less with Haloperidol, Aripiprazole, Loxapine).

Common with first generation anti-psychotics, Clozapine, Olazapine, Risperidone.11. Hyperglycemia: highest risk with Clozapine, olanzapine, Quetiapine, Risperidone.12. Seizure-decrease in seizure threshold.13. Cholestatic jaundice14. Blood dyscrasia (clozapine-agranulocytosis)15. Cardiotoxicity (thioridazine, Pimozide, Clozapine)16. Corneal and lens toxicity: Thioridazine-retinal deposit resembling retinitis pigmentosa.17. Pregnancy: dysmorphogenesis.

Drug interactions

Important drug interaction occurs when they are combined with sedatives, α-adrenergic blocking agents, anti-cholinergics and quinidine.

Contra-indications

1. DM (especially second generation drugs such as Clozapine, olanzapine, Quetiapine, Risperidone.

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2. Patient with history of QT prolongation or severe cardiac disorders such as myocarditis, cardiac failure.

3. Neutropenia, agranulocytosis: clozapine is contra-indicated.4. Uncontrolled epilepsy5. Comatoes state6. Severe CNS depression7. Prolactin dependent tumours8. Severe renal and hepatic disorders.9. Parkinson’s disease10. Angle closure glaucoma11. BPH12. Phaeochromocytoma13. Myasthenia gravis with CYP 450 inhibitors.

References

1. BERTRAM,G.K., SUSAN,B. & ANTHONY, J.T.,2010. Basic and clinical pharmacology. 12th ed. US: Mc Graw Hill.

2. GOODMAN & GILMAN’S.,2011. The pharmacological basis of therapeutics. 12th ed. US: Mc Graw Hill.3. ROYAL PHARMACEUTICAL SOCIETY., 2013. BNF. London: BNF publication.4. HARRISON., 2012. Principle of internal medicine. 18th ed. US:Mc Graw Hill.5. Kaplan text book of psychiatry6. SHUKLA, J.S, 2014. Essential of therapeutics. 3rd ed

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psychosis pharmacology

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