SECOND & THIRD GENERATION ANTIPSYCHOTIC

mechanism of actionmechanism of side effectmanagment of side effect

BY DR WASIMUNDERGUIDANCE OF

DR SANJAY JAIN

First generation=typical antipsychoticaka conventional

primary pharmacological property of D2 antagonist

Second generation=atypical antipsychoticlow EPS and good for negative symptoms

Third generation=aripiprazolemetabolic friendly

1) serotonin dopamine antagonists2) D2 antagonist with rapid dissociation3) D2 partial agonist4)serotonin partial agonist

MECHANISM OF ACTION

Serotonin receptors:Presynaptic (5HT1A and 5HT1B/D) and several are

postsynaptic ( 5HT1A, 5HT1B/D as well as 5HT2A, 5HT2C, 5HT3, 5HT4, 5HT5,5HT6 and 5HT7)

5HT1A and 5HT2A receptors have opposite actions in regulating dopamine release:

5HT1A receptors act as accelerator for dopamine release, whereas 5HT2A receptors act as brake on dopamine release.

1) serotonin dopamine antagonists

Receptors influence dopamine (DA) release, either directly or via gamma aminobutyric acid (GABA) neurons.

When 5HT binds to 5HT2A receptors on postsynaptic DA neurons, this inhibits DA release (bottom left).

5HT binding to 5HT2A receptors on GABA interneurons causes GABA release, which in turn inhibits DA release (also bottom left).

5HT1A somatodendritic autoreceptors, on the other hand, act as DA accelerators. That is, when 5HT binds to these receptors, it inhibits 5HT release; thus, 5HT is unable to inhibit DA release, and dopamine release is thus disinhibited,

and therefore increased .

5HT2A antagonists stimulate dopamine release

Atypical antipsychotics are antagonists at the 5HT2A receptor as well as at the D2 receptor. The actions of these antipsychotics at 5HT2A receptors as antagonist actions. 5HT2A antagonism can cause dopamine release in certain brain areas, and this pharmacological actionhypothetically explains the clinical properties of these agents that distinguish them from conventional antipsychotics, namely "low EPS" and "good for negative symptoms." Thus, the 5HT2A receptor "brake" on dopamine release is disrupted by a 5HT2A antagonist.

5HT2A antagonists stimulate DA release. Serotonin (5HT) inhibits dopamine (DA) release viastimulation of 5HT2A receptors (left); when this action is blocked by a 5HT2A antagonist, this leads to anincrease in DA release, either by blocking 5HT2A receptors on postsynaptic DA neurons or by blocking 5HT2Areceptors on gamma aminobutyric acid (GABA) interneurons (on the right).

5HT-DA interactions. Serotonin-dopamine interactions in the nigrostriatal dopamine

pathway. 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.

How does 5HT2A antagonist action reduce EPS?

How does 5HT2A antagonism reduces negative symptoms ?

How does 5HT2A antagonism may improve positive symptoms?

•Ascending serotonin (5HT) projections from the raphe to the cortex stimulate release of glutamate from descending glutamatergic cortical pyramidal neurons via postsynaptic 5HT2A receptors. Because descending cortical pyramidal neurons synapse directly with dopaminergic neurons in the ventral tegmental area (VTA), serotonergic actions at 5HT2A receptors can indirectly modulate activity of the mesolimbic dopamine pathway.

•Thus stimulation of 5HT2A receptors increases glutamate release, which in turn increases dopamine release in the mesolimbic pathway, possibly leading to positive symptoms of psychosis.

•On the other hand, blockade of 5HT2A receptors would reduce glutamate release, which in turn would reduce mesolimbic dopamine release (B). 5HT2A antagonism is therefore a possible mechanism for reducing positive symptoms of psychosis.

How does 5HT2A antagonist actions reduce hyperprolactinemia?

•Serotonin and dopamine have reciprocal roles in the regulation of prolactin secretion from the pituitary lactotroph cells. That is, dopamine inhibits prolactin release by stimulating D2 receptors, whereas serotonin promotes prolactin release by stimulating 5HT2A receptors. • In the case of an atypical antipsychotic, there is simultaneous inhibition of 5HT2A receptors, so serotonin can no longer stimulate prolactin release. This tends to mitigate the hyperprolactinemia of D2 receptor blockade.

2) D2 antagonist with rapid dissociation

.

Atypical antipsychotic binds to D2 postsynaptic receptors & have the ability to rapidly dissociate from D2 receptors.S

.

It stabilizes dopamine neurotransmission in a state between silent antagonism and full stimulation. This is due to partial agonist actions at the D2 receptor. Dopamine partial agonists (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. Instead, a partial agonist binds in an intermediary manner.

3) D2 partial agonist

4)serotonin partial agonist

Agonism of serotonin 1 A receptors can increase dopamine release, which could improve affective, cognitive, and negative symptoms while also reducing the riskof extrapyramidal symptoms (EPS) and prolactin elevation. Serotonin 1 A agonism can also decrease glutamaterelease, which could indirectly reduce positive symptoms of psychosis.

•Agonist actions at 5HT1A receptors would be expected to increase dopamine release and reduce glutamate release.

•Enhanced dopamine release by SPA action in the striatum would theoretically improve extrapyramidal actions.

•Enhanced dopamine release by SPA action in the pituitary would theoretically reduce the risk of hyperprolactinemia.

•Enhanced dopamine release by SPA action in the prefrontal cortex would theoretically improve negative, cognitive, and affective symptoms of schizophrenia.

•Reduced glutamate release by SPA action in prefrontal cortex could theoretically reduce positive symptoms.

MECHANISM OF SIDE EFFECTSerotonin-2C, muscarinic-3, and histamine-1 receptors as well as receptors X

identified are all hypothetically linked to cardiometabolic risk.

antagonism of serotonin-2C and histamine-1 receptors is associated with weight gain, while antagonism atmuscarinic-3 receptors can impair insulin regulation.An unknown receptor X may be involved in the rapid production of insulin resistance and may also rapidly cause elevated fasting plasma triglyceride levels in some patients who experience increased cardiometabolicrisk on certain atypical antipsychotics

At first, weight gain and obesity were clearly linked to atypical antipsychotics but more recently, increased risk for dyslipidemia, diabetes, accelerated cardiovascular disease, and premature death have been linked to certain drugs in this class as well.

The "metabolic highway" begins with increased appetite and weight gain and progresses to obesity, insulin resistance, and dyslipidemia with increases in fasting triglyceride levels. Ultimately, hyperinsulinemia advances to pancreatic beta cell failure, prediabetes, and then diabetes. Oncediabetes is established, risk for cardiovascular events is further increased, as is the risk of premature death.

Receptors associated with increased weight gain are the HI histamine receptor and the 5HT2 C serotonin receptor; when these receptors are blocked, particularly at the same time, patients can experience weight gain. Such weight gain is at least in part due to enhanced appetite in hypothalamic eating centers , although peripheral factors unrelated to appetite may also be involved in antipsychotic-induced weight gain.Antipsychotics associated with the greatest degree of weight gain are those that have themost potent antagonist actions simultaneously at HI and 5HT2 C receptors .

Such weight gain can lead to obesity, obesity to diabetes, and diabetes to cardiac disease along the metabolic highway .

Histamine 1 (HI ) combined with serotonin-2C antagonism may stimulate appetite. Antagonism of serotonin-2C and/or HI receptors can lead to weight gain, perhaps at least in part due to stimulation of appetite regulated by the hypothalamus.

Metabolic highway. The metabolic highway depicts stages of metabolic changes and illnesses that progressively increase risk of cardiovascular disease and premature death. The "entrance ramp" for themetabolic highway may be increased appetite and weight gain that leads to a body mass index (BMI) greater than 25. This can progress to obesity, insulin resistance, and dyslipidemia, with increases in fasting triglyceride levels. Ultimately, hyperinsulinemia advances to pancreatic beta cell failure, prediabetes, and then diabetes.Diabetes in turn increases risk for cardiovascular events as well as premature death

Insulin resistance, elevated triglycerides, and antipsychotics: caused by tissue actions at anunknown receptor? Some atypical antipsychotics may lead to insulin resistance and elevated triglycerides independently of weight gain, although the mechanism is not yet established. This figure depicts a hypothesized mechanism in which antipsychotic binds to receptor X at adipose tissue, liver, and skeletal muscle to cause insulin resistance.

Blocking M3-cholinergic receptors reduces insulin release. (A) Insulin secretion is regulated in part by parasympathetic cholinergic neurons that synapse with pancreatic beta cells. (B) Whenacetylcholine (ACh) binds to muscarinic-3 (M3) receptors on pancreatic beta cells, this causes insulin secretion.(C) Thus, agents that block M3 receptors - such as certain atypical antipsychotics like olanzapine and clozapine may reduce insulin release.

Which receptors hypotheticallymediate sedation? Antagonism of D2 receptors, as well as of muscarinic-1 , histamine-1 , and alpha-1 adrenergic receptors, could hypothetically mediate sedation.

Dopamine, acetylcholine, histamine, and norepinephrine are all involved in arousal pathways.

The neurotransmitters acetylcholine (ACh), histamine (HA), and norepinephrine (NE) are all involved in arousal pathways connecting neurotransmitter centers with the thalamus (T), hypothalamus (Hy), basal forebrain (BF), and cortex. Thus, pharmacological actions at their receptors could influence arousal. In particular, antagonism of muscarinic M l , histamine H I , and alpha-1 adrenergic receptors are all associated with sedating effects.

Atypical antipsychotic and risk for weight gain.FDA and experts agree on three tiers of risk

Atypical antipsychotic and cardiometabolic risk.FDA and experts disagree on one versus three teirs of

risk

Metabolic friendly antipsychotic.Low- risk agents for weight gain and cardiacmetabolic illness.

Monitoring and Managment

Baseline investigations : Family h/o diabetes

BMI

Fasting TG levels (also monitored throughout treatment)

If raised : consider switching to another agent +/- lifestyle changes

For obese/ prediabetic/ diabetic pts :

Monitor BP

Fasting glucose

Waist circumference (before and after Rx)

Be vigilant for DKA/HHS

Approach to prevention and

treatment

Take personalized family history of obesity, cardiovascular

disease, diabetes.

Establish good exercise and dietary regiments.

Avoid weight-gain prone antidepressants, mood stabilizers

and atypical antipsychotics.

Monitor weight, waist circumference, and assay random

blood sugars and blood pressure at baseline, 3 months and

yearly.

Recommend intervention when BMI increases by one unit.

Assay fasting lipids every 5 years, more often if abnormal.

Replace weight-gain prone medications with agents with

lower liability and equal efficacy, if possible, in each class.

Consider adjunctive use of drugs with a positive side-effects

profile of weight loss i.e., zonisamide or topiramate.

Checkpoints on the metabolic highway

Weight and BMI : Increased appetite and weight gain can lead to elevated BMI and ultimately obesity.

1. Fasting plasma triglyceride : helps to detect insulin resistance caused by atypical antipsychotics by unknown mechanism.

2. Fasting glucose :

1. AA can cause sudden onset of DKA/HHS by unknown mechanisms.

2. This can be detected by informing patients of the symptoms and by FBG.

Sedation

Strategies to avoid sedation and enhance long-term outcome. Achieving the best long-term outcomes in schizophrenia may require avoiding long-term sedation. For patients whose treatment was initiated with a nonsedating antipsychotic but who received an adjunct benzodiazepine, this may mean discontinuing the benzodiazepine. Some patients initiated on a sedating antipsychotic may develop tolerance to the sedating side effects and not require treatment adjustment; however, others may need to be switched to a nonsedating agent.

weight gain

• switching drugs

• switching to aripiprazole or ziprasidone

• other drugs with a low propensity for weight gain

• add aripiprazole to existing

behavioural methods

• calorie restriction,

• low glycaemic index

diet.

• Weight Watchers and

• diet/exercise

programmes.• initial options involve switching drugs or instituting behavioural

programmes (or both).

• Pharmacological methods :- above methods have failed or obesity

presents clear, immediate physical risk.

• metformin is now probably considered the drug of choice for

antipsychotic-induced weight gain.

Dyslipidaemia

• If moderate to severe hyperlipidaemia develops

during antipsychotic treatment :-

• a switch to another antipsychotic less likely to

cause this problem should be considered in the

first instance.

• not recommended as a strategy in patients with

treatment-resistant illness,

• Aripiprazole seems at present to be the

treatment of choice in those with prior

antipsychotic-induced dyslipidaemia.33

When triglycerides alone are raised

diets low in saturated fats and

the taking of fish oil and

fibrates are effective treatments.

Such patients should be screened for impaired

glucose tolerance and diabetes

Patients with raised cholesterol may benefit from

dietary advice, lifestyle changes and/or treatment with

statins.

Evidence supports the treatment of cholesterol

concentrations as low as 4 mmol/l in high-risk patients

and this is the highest level recommended by NICE for

secondary prevention of cardiovascular events .

Coronary heart disease and stroke risk can be reduced

by a third by reducing cholesterol to as low as 3.5mmol/l.

Insulin Resistance

Several factors influence whether or not an individual develops insulin resistance, some of which are manageable by a psychopharmacologist and some of which are not. Unmanageable factors include genetic makeup and age, while items that are modestly manageable include lifestyle (e.g., diet, exercise, smoking). Psychopharmacologistsexerttheir greatest influence on managing insulin resistance through selection of antipsychotics that either do or do notcause insulin resistance.

ARIPIPRAZOLE KNOWN AS THIRD GENERATION ANTIPSYCHOTIC

Aripiprazole differs from most other antipsychotics in that it is a partial agonist at D2 receptors rather than

an antagonist.

Additional 5HT2A antagonist actions and 5HT1A partial agonist actions.

Aripiprazole lacks the pharmacological actions usually

associated with significant sedation and also seems to lack the

pharmacologic actions associated with weight gain and increased

cardiometabolic risk, such as increasing fasting plasma triglyceride levels or increasing insulin resistance

Mechanism of action

46

•Decreased propensity for orthostasis, sedation & weight gain)

•No antimuscarinicside-effects such as dry mouth, thirst, blurred vision, dry skin, increased heart rate)

• Improves positive and negative symptoms

• Reduced risk of EPS

•Functional antagonist under conditions of dopamine hyperactivity control positive symptoms)

•Functional agonist under conditions of dopamine hypoactivity control negative, cognitive & causes minimal motor effects

Partial agonist at

D2 receptors

High-affinity

binding to 5-HT1A and

5-HT2A

Low-to-moderate affinity at α1 and H1 receptors

No affinity for

muscarinicreceptors

Unique Receptor binding profile

Unique MechanismDopamine serotonin system stabilizerImproves positive & negative symptoms of schizophrenia

Good EfficacyEffective for schizophrenia maintenance & bipolar disorder treatment

Effective in mania unresponsive to Li/VPA

Effective at treating episodes of mania or mixed episodes

Helps prevent relapse of bipolar disorder

Quick response in treatment resistant depression

Effective in low doses in Major Depressive Disorder (MDD) patients withinadequate response to prior antidepressant therapy

Good SafetyMinimal extrapyramidal side effects (EPS)

Negligible anticholinergic, sedative, hematologic, QTc prolongation siFewer side-effects such as cholesterol increase, weight gain, sedationand prolactin associated side-effectsReverses antipsychotic induced hyperprolactinemia

Easy switch over from other antipsychotic drugsControls withdrawal symptoms from previous medication

Good ComplianceOnce daily dosing

aripiprazole can be activating in some patients, causing mild agitation or akathisia, which diminishes over time or is often decreased by dose reduction or by administering an anticholinergic agent or a benzodiazepine.

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