ATYPICAL ANTIPSYCHOtics and side effects .pptx

Atypical antipsychotic

1. ATYPICAL ANTIPSYCHOTICS-an overview Presenter: Dr. KUSHAGRA KHANDELWAL Moderator: Dr FAIZAN boss Chairperson: Dr DHARAMDEEP SIR

2. contents History Classification What makes 2 nd generation antipsychotics atypical MECHANISM of Action Dopamine pathways Other actions of SGAs Adverse effects of SGAs Doses & Prescribing Principles LAIs

3. History First atypical antipsychotic medication clozapine was discovered in 1950 & introduced in the clinical practice in the 1970. clozapine withdraw from market because of drug induced agranulocytosis. Unites states in 1990 opened the era of atypical antipsychotic drugs, which show a reduce potential to induce EPS, an increase affinity for negative symptoms.

4. Classification of atypical antipsychotics: ∙ The Pines (peens ): clozapine, olanzapine, quetiapine, Asenapine , Zotepine. The dones : Risperidone, paliperidone, ziprasidone, iloperidone, Lurasidone Pips & a rip : Aripiprazol , brexipiprazol , cariprazine . Others :Amisulpride , sertenidol , Perospirone On basis of receptor affinity: Serotonin & dopamine antagonists(SDA) :Risperidone, perospirone , Lurasidone Multi acting receptor targeted antipsychotics(MARTAs): clozapine, olanzapine, quetiapine D2 partial agonist : Aripiprazol

5. Dopamine pathways Mesolimbic :- Projections from the ventral tegmental area (VTA) to the nucleus accumbens . Responsible for Motivation, emotions, reward , positive symptoms of schizophrenia. D2 antagonists reduce positive symptoms of schizophrenia. Mesocortical :- Projections from the ventral tegmental area (VTA) to the cortex (PFC). Responsible for Cognition and executive functions (DLPFC), emotions and affect (VMPFC). Hypofunction of the mesocortical pathway might be related to cognitive and negative symptoms in schizophrenia Nigrostriatal:- Projections from substantia nigra (pars compacta) to striatum (caudate and putamen). responsible for Stimulation of purposeful movement. D2 antagonism in basal ganglia induces extrapyramidal symptoms tuberoinfundibular dopamine pathways :- Hypothalamus (arcuate and periventricular nuclei) to infundibular region (median eminence). Dopamine is released into the portal circulation connecting the median eminence with the anterior pituitary gland.Dopamine tonically inhibits prolactin release. D2 antagonism increases prolactin levels.

6. Serotonin & it’s receptors Serotonin is also known as 5-hydroxytryptamine. Synthesis of 5HT begins with the amino acid tryptophan presynaptic (5HT1A and 5HT1B/D) & postsynaptic (5HT1A, 5HT1B/D as well as 5HT2A, 5HT2C, 5HT3,5HT4, 5HT5, 5HT6, and 5HT7). Presynaptic 5HT receptors are autoreceptors 5HT1A receptors act as an accelerator for dopamine release, whereas 5HT2A receptors act as a brake on dopamine release

7. What does atypicality means? clinical perspective, it is “low EPS” and “good for negative symptoms. Cognitive enhancement Reduced risk of hyperprolectenemia Improve adherence From a pharmacological perspective, the atypical antipsychotics as “serotonin dopamine antagonists” What makes antipsychotic atypical? 1) 5HT2A antagonist At striatum &substantia nigra- reduction in EPS At prefrontal cortex- red. in neg. symp . At limbic system- red.+ ve symp At pitutary -prevent hyperprolactinemia (2) Rapid dissociation from D2 receptors (3) D2 partial agonism (4) 5HT1a partial agonism

8. Serotonin inhibits dopamine release, both at the level of the dopamine cell bodies in the brainstem substantia nigra and at the level of the axon terminals in the basal ganglia-neostriatum. In both cases, the release of serotonin acts as a brake on dopamine release.

9. 5HT2A antagonism makes an antipsychotic atypical 5HT2A antagonism reduces EPS 5HT2A antagonism stimulate dopamine release in striatum Increased dopamine competes with drug at D2 receptors and reduces binding of drug there enough to eliminate EPS.

10. 5HT2A antagonism reduces negative symptoms 5HT2A antagonism increase DA release in prefrontal cortex. The increased availability of dopamine to these areas may lead to improvement in the negative, cognitive, and affective symptoms.

11. 5HT2A antagonism may improve positive symptoms Activation of 5HT2A receptors in the prefrontal cortex may contribute to positive symptoms of hallucinations by enhancing the excitation of glutamate neuron. 5HT2A antagonists block glutamate release thus reducing hallucinations and other positive symptoms.

12. 5HT2A antagonist actions reduce hyperprolactinemia Dopamine inhibits prolactin whereas serotonin promotes prolactin release by stimulating 5HT2A receptors. Thus 5HT2A antagonism reduce prolactin release and chance of hyperprolactinemia

13. Rapid dissociation from D2 receptors makes an antipsychotic atypical • atypical antipsychotics also have the ability to rapidly dissociate from D2 receptors. Theoretically, such an agent is able to stay at D2 receptors long enough to exert an antipsychotic action but then leaves prior to producing an extrapyramidal side effect, elevation of prolactin, or worsening of negative symptoms

14. clozapine and quetiapine have faster dissociation from the D2 receptor than risperidone with olanzapine in the middle. This roughly correlates with the abilities of these drugs to cause motor side effects.. Sulpiride and amisulpride also dissociate rapidly from D2 receptor…this explain the atypical clinical properties of these drugs even in absence of serotonin antagonism

15. D2 partial agonism (DPA) makes an antipsychotic atypical DPAs theoretically bind to the D2 receptor in a manner that is neither too antagonizing, like a conventional antipsychotic nor too stimulating, like a stimulant or dopamine itself. DPAs reduce D2 hyperactivity in mesolimbic dopamine neurons to a degree that is sufficient to exert an antipsychotic action on positive symptoms, even though they do not completely shut down the D2 receptor. At the same time, DPAs reduce dopamine activity in the nigrostriatal system to a degree that is insufficient to cause EPS

16. 5HT1A partial agonist (SPA) actions make an antipsychotic atypical 5HT1A increase dopamine release and reduce glutamate release. Enhanced dopamine release in the striatum improve extrapyramidal actions; in the pituitary would reduce the risk of hyperprolactinemia;in the prefrontal cortex would improve negative, cognitive, and affective symptoms of schizophrenia Reduced glutamate release in prefrontal cortex could reduce positive symptoms.

17. Other actions of Atypical antipsychotics: Antidepressant actions in bipolar and unipolar depression Antimaniac action anxiolytic actions Sedative hypnotic and sedating actions

18. Antidepressant actions in bipolar and unipolar depression Serotonin and norepinephrine reuptake inhibition: quetiapine , ziprasidone and zotepine . Alpha-2 antagonism: quetiapine & clozapine, risperidone and aripiprazole .

19. Antimaniac action D2 antagonism /partial agonism combined with 5HT2A antagonism is responsible for antimaniac property. 5HT1A agonist/partial agonist action may contribute to antimaniac efficacy

20. Anxiolytic Actions use for GAD & to augment other agents for other anxiety disorders. Side effects and cost consideration and the lack of regulatory approval have tended to restrict this application of the atypical antipsychotics. Antihistaminic and anticholinergic sedative properties of some of these agents are responsible for anxiolytic action. Quetiapine is having maximum anxiolytic activity.

21. Sedative –hypnotic and sedating agent: Blocking any among M1, H1 & alpha 1 receptors are responsible for sedation. Potent antihistaminic actions: clozapine,quetiapine,olanzapine and ilioperidone . Potent anticholinergic: only pines clozapine, quetiapine and olanzapine. potent alpha 1 adrenergic antagonism: clozapine, quetiapine , resperidone and iloperidone .

22. Current place of atypical antipsychotics in treating Schizophrenia & bipolar disorder Atypical antipsychotics are first line treatment for schizophrenia Clozapine is used in drug of choice for refractory schizophrenia Olanzapine,risperidone,quetiapine,aripiprazol & asenapine have been most robustly evaluated and are licensed in many countries for the treatement of mania. Quetiapine , robust efficacy in all aspect of BPAD Risperidone & aripiprazol LAI are also effective for prophylaxis & maintenance

23. Clozapine The relatively low affinity for D 2 receptors may explain clozapine's lack of extrapyramidal side effects. In clinically effective doses, clozapine only occupies 40 to 50 percent of D 2 receptors. Differential antipsychotic effect of clozapine is related to its low D 2 to 5-HT 2 ratio. Clozapine's affinity for the 5-HT 2 receptor is among the highest for antipsychotic agents. An alternative hypothesis proposes that clozapine is effective because it has a selective preference for the mesolimbic dopamine system. Clozapine has stronger 5-HT 3 blockade and stronger α 1 - and α 2 -adrenergic receptor blockade. It has stronger affinities for histamine type 1 (H 1 ) receptors and acetylcholine muscarinic receptors.it induces hypersalivation despite anticholinergic properties probably due to central ACIONS. Clozapine also has a tenfold higher affinity for the D 4 receptor than do other antipsychotics.

24. Risperidone High affinity for dopamine D 2 receptors and for serotonin 5-HT 2A receptors. High affinity for adrenergic α 1 - and α 2 -receptors and histaminergic H 1 receptors . Moderate affinity for serotonin 5-HT 2C , 5-HT 1D , and weak affinity for dopamine D 1 receptors. Risperidone has no affinity for cholinergic muscarinic receptors or adrenergic β 1 and β 2 receptors. Risperidone blocks 65 percent of D 2 receptors (the lowest threshold percentage for antipsychotic efficacy) at an average dose of 2 mg per day. At an average of 6 mg per day, 80 percent of D 2 receptors are blocked, and EPS may occur.

25. Olanzapine Olanzapine is a high affinity antagonist at 5-HT 2A / 2C, 5-HT 6 , D 1 - 4 , H 1 , and adrenergic α 1 -receptors and a moderate affinity antagonist at M 1 - 5 and 5-HT 3 receptors. PET studies indicate that typical doses of olanzapine such as 10 to 20 mg result in 68 to 84 percent D 2 occupancy. Compared with risperidone, quetiapine, and ziprasidone, olanzapine has greater M and H receptor antagonism . This histamine activity may explain its tendency to cause weight gain. Adding together the 5HT2C antagonist actions of both fluoxetine and olanzApine could theoretically lead to enhanced DA and NE release in cortex to mediate antidepressant actions in bipolar depression .

26. cariprazine Another D2 partial agonist. Cariprazine is more of an antagonist at D2 receptors than aripiprazole. In theory, cariprazine may be preferred at higher doses for mania and schizophrenia,to emphasize its antagonist actions, and at lower doses for depression, to emphasize its agonist actions and potentially its uniquely D3-preferring properties. At low dosage greater affinity for D3 than D2 partial agonist properties. Cariprazine so far shows a low incidence of EPS in clinical testing, perhaps because it has potent 5HT1A partial agonist actions and lesser 5HT2A antagonism. At higher doses cariprazine could potentially block 5HT7 and 5HT2C receptors for hypothetical antidepressant actions.

27. Quetiapine It has a high affinity for 5-HT 2 , histamine H 1 , α 1 , and α 2 receptors ; a moderate affinity for 5-HT 1A receptors; a moderate affinity for D 2 and a low affinity for D 1 receptors. Quetiapine has a very low affinity for cholinergic M 1 and D 4 receptors . Quetiapine's low incidence of EPS may be explained by its relatively high 5-HT 2A binding compared to its activity at D 2 receptors. PET study demonstrated that 2 hours after a single clinical dose, quetiapine occupies 44 percent of D 2 receptors and 72 percent of 5-HT 2 receptors. Other PET studies demonstrate rapid dissociation of quetiapine from the D 2 receptor. In one study, D 2 receptor occupancy 2 hours postdose ranged from 58 to 64 percent, and fell to 20 to 0 percent 12 to 24 hours postdose for single doses of 400 and 450 mg, respectively. This supports the hypothesis of quetiapine's “ fast dissociation

28. Ziprasidone Strong D 2 antagonist, it is an even more potent antagonist at the 5-HT 2A receptor, with a very high 5-HT 2A to D 2 ratio of 11. Ziprasidone also has potent affinity for the D 3 receptor and moderate affinity for the D 4 receptor, similar to haloperidol; Ziprasidone is an agonist at the 5-HT 1A receptor and a potent antagonist at 5-HT 2C (five times greater than clozapine and 19 times greater than risperidone) and 5-HT 1D receptors. Ziprasidone has only moderate affinity for the α 1 receptor and low affinity for the H 1 receptor. With twice-daily administration of oral ziprasidone, estimates based on systemic exposure and PET scan data predict that 5-HT 2 and D 2 receptor occupancy ranges from 80 to 90 percent and 45 to 75 percent, respectively.

29. Aripiprazole For aripiprazole, D 2 partial agonism could translate into an agent that acts as a functional antagonist under hyperdopaminergic conditions and as an agonist under hypodopaminergic conditions. An advantage of this mechanism is that it could address concerns that schizophrenia may be an illness that is associated with excessive dopamine activity at sites in limbic areas and decreased dopamine activity in frontal and prefrontal areas. Aripiprazole also appears to be a partial agonist at 5-HT 1A receptors (like buspirone ). Aripiprazole also binds with high affinity to D 3 , 5-HT 2A , 5-HT 2C , and H 1 receptors.

30. Amisulpride Novel substituted benzamide with a high affinity for the presynaptic dopamine D 2 and D 3 receptor subtypes at low doses. However, it lacks affinity for other dopamine receptor subtypes (D 1 , D 4 , D 5 ) (fortunately, D 1 blockade is not good for cognition) and other neurotransmitter receptors. Without affinity for 5-HT 2A / c receptors, it is, therefore, not a true serotonin dopamine antagonist.

31. Adverse effects of SGA ( 1) Metabolic side effects ( Because of 5HT2c & H1 receptor blocking) weight gain Increase risk of obesity Dyslipedemia Diabetes Accelerated cardiovascular disease Premature death High metabolic risk : clozapine, olanzapine Moderate metabolic risk : risperidone , paliperidone , quetiapine , iloperidone Low metabolic risk : ziprasidone , aripiprazole , lurasidone , asenapine , brexpiprazole , cariprazine (2) Anticholenergic effects (3) Drowsiness (4) Decrease sex drive [risperidone > olanzapine > quetiapine> aripiprazole] (5) Sun sensitivity (6) seizures

32. All cause discontinuation : Haloperidol,quetiapine,aripiprazol,risperidone,clozapine ,olanzapine, Amisulpride Weight gain :olanzapine, clozapine, quetipine , risperidone EPS: Haloperidol, Lurasidone , Risperidone,Amisulpride,Aripiprazol Hyperprolectinemia : Amisulpride,Paliperidone , Risperidone , olanzapine, quetiapine , aripiprazol QTcprolongation: Amisulpride,Asenapine,Risp.,olanzapine,quetiapine,paliperidone,aripiprazol,lurasidone Sedation :Clozapine,quetiapine , olanzapine,Risperidone , aripiprazol , paliperidone , Amisulpride

33. General principle of prescribing Use lowest possible dose. For each patient, the dose should be titrated to the lowest known to be effective(Minimum effective doses). Dose increases should then take place only after 2 weeks of assessment during which the patient is clearly showing poor or no response. Antipsychotics should not be used as necessary sedatives Asses response using recognized rating scale. Reduce dose slowly to avoid withdrawl and rebound psychosis. Tests before starting an atypical antipsychotic: weight,BMI,BP , waist circumference, fasting Lipid profile,fasting plasma glucose. Above mention parameters should me monitor in every 3 months initially and then annually, but earlier and more frequently for patients with diabetes or who have gained more than >5% of initial weight

34. For the large majority of patients, the use of a single antipsychotic (with or without additional mood stabiliser or sedatives) is recommended. Apart from exceptional circumstances (e.g. clozapine augmentation) antipsychotic polypharmacy should generally be avoided because of the risks associated with QT prolongation and sudden cardiac death Combinations of antipsychotics should only be used where response to a single antipsychotic (including clozapine) has been clearly demonstrated to be inadequate. In comparison with oral antipsychotics, there is strong evidence that depots/long‐acting injectable (LAI) are associated with a reduced risk of relapse and rehospitalisation . With regular dosing of depot medication, plasma levels rise for at least 6–12 weeks after initiation, even without a change in dose. The preferred method is to establish efficacy and tolerability of oral medication at a particular dose and then give the equivalent dose of that drug in LAI form.

35. References: KAPLAN & SADOCK’S COMPREHENSIVE TEXTBOOK OF PSYCHIATRY, 10TH EDN KAPLAN & SADOCK’S SYNOPSIS OF PSYCHIATRY 11TH EDN Stahls essential psychopharmacology 6 th edition The maudsley,prescribers guidelines in psychiatary . Second gen.v /s first gen. antipsychotic drugs for schiz .( stefan Leucht )

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