antipsychotics and update

1. ANTIPSYCHOTICS: An Update
PRESENTOR JYOTI SHARMA

2. CONTENT
 Introduction
 History
 Schizophrenia
 Classification of drugs
 MOA of drugs
 Safety of drugs
 Newer anti-psychotics
 Summary

4. INTRODUCTION
 Schizophrenia, Bipolar Disorder, Psychotic Depression, Psychosis associated with
Dementia, Parkinsons, Huntingtons, Alzheimers and Tourette syndrome.
 Improve mood, reduce anxiety and sleep disturbance .
 A Typical NEUROLEPTIC produces a high incidence of EPS .
 2nd generation or “atypical” antipsychotics drugs most widely used .

5. HISTORY
 EMIL KRAEPELIN-DEMENTIA PRAECOX.
 EUGEN BLEULER –SCHIZOPHRENIA (1911).
 KURT SCHEIDER-first rank symptoms.

6.  In 1950s, Reserpine and chlorpromazine 1st drugs.
 Reserpine was extracted from dried root of Rauwolfia serpentine (Indian snakeroot). Reserpine no
longer used. chlorpromazine, related to dopamine receptor blockade.
 In 1959, clozapine with fewer EPS led to shift from typical to atypical. Brief instead of lifelong
hospitalization. It helped in studying pathophysiology of psychosis.

7. PSYCHOSIS-loss of insight

8. SCHIZOPHRENIA
According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5), to meet
the criteria for diagnosis of schizophrenia, the patient must have experienced at least 2 of the following
symptoms :
 Delusions
 Hallucinations
 Disorganized speech
 Disorganized or catatonic behavior
 Negative symptoms
 At least 1 of the symptoms must be the presence of delusions, hallucinations, or disorganized
speech.
 Continuous signs of the disturbance must persist for at least 6 months, during which the patient
must experience at least 1 month of active symptoms (or less if successfully treated), with social or
occupational deterioration problems occurring over a significant amount of time.

9. Positive symptoms
hallucinations, auditory;
delusions; and disorganized
speech and behavior
Negative symptoms -
Decrease in emotional
range, poverty of speech,
and loss of interests and
drive
Cognitive symptoms -
Neurocognitive deficits
(eg, deficits in working
memory and attention
and in executive functions,
such as the ability to
organize and abstract);
patients also find it
difficult to understand
nuances and subtleties of
interpersonal cues and
relationships
Mood symptoms - cheerful
or sad
Thought disorder - the
person may jump from one
subject to another for no
logical reason. The speaker
may be hard to follow or
erratic.
Social withdrawal
Cognitive difficulties - the
patient's ability to
concentrate, recall things,
plan ahead, and to organize
their life are affected.
Communication becomes
more difficult.

10. Hallucinations
Unawareness of illness
Delusions delusions
of persecution, or
delusions of
grandeur
Lack of motivation
(avolition)
Poor expression of
emotions
Social withdrawal

11. DOPAMINERGIC SYSTEMS

12. DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA

15. SEROTONIN HYPOTHESIS OF SCHIZOPHRENIA
 5HT 2A Receptor blocks (2nd generation antipsychotics) clozapine , melperone ,risperidone, zotepine
,blonanserin, olanzapine, quetiapine, ziprasidone, aripiprazole, sertindole ,paliperidone , iloperidone ,
asenapine ,lurasidone , cariprazine and brexpiprazole. Inverse agonist of 5HT 2A receptor. Block
constitutive activity of these receptor .
 Modulate release of dopamine, norepinephrine , glutamate , GABA and acetylcholine in cortex , limbic
region and striatum .
 Stimulation of 5HT 2A receptor leads to depolarization of glutamate neurons and stabilisation of NMDA
receptors on post synaptic neuron.
 Stimulation of 5HT 2C Receptors leads to inhibition of cortical and limbic dopamine release . Drugs like
clozapine, asenapine and olanzapine are 5HT 2C inverse agonist.

21. CLASSIFICATION

22. FIRST GENERATION
ANTIPSYCHOTICS
LOW POTENCY D2
ANTAGONISTS
AVERAGE DAILY DOSES
MG/DAY
Half lives
hrs
CHLORPROMAZINE 150-800 8-35
FIRST GENERATION
ANTIPSYCHOTICS
MEDIUM AND HIGH POTENCY
D2 ANTAGONISTS
HALOPERIDOL 2.5-20 12-35
FLUPHENAZINE 2.5-20 14-24
TRIFLUOPERAZINE 5-40 4
THIOTHIXENE 2.5-40 34
PERPHENAZINE 12-60 8-21
LOXAPINE 15-60 4

23. SECOND GENERATION
ANTIPSYCHOTICS
5HT 2A AND D2 ANTAGONIST
AVERAGE DAILY DOSES
MG/DAY
Half life
hrs
ASENAPINE 10-20 24
CLOZAPINE 200-900 8-12
ILOPERIDONE 8-24 18-37
LURASIDONE 40-160 18
OLANZAPINE 7.5-30 21-54
PALIPERIDONE 3-15 23
QUETIAPINE 200-900 6-7
RISPERIDONE 2-8 3-20

24. SECOND GENERATION
ANTIPSYCHOTICS
5HT 2A AND D2 ANTAGONIST
AVERAGE DAILY DOSES
MG/DAY
Half life
hrs
SERTINDOLE 4-32 53-102
ZIPRASIDONE 80-200 7
SECOND GENERATION
ANTIPSYCHOTICS
D2 PARTIAL AGONISTS
ARIRIPRAZOLE 10-30 75
BREXPIPRAZOLE 2-4 91
CARIPRAZINE 3-6 48-96
SECOND GENERATION
ANTIPSYCHOTICS
D2 AND D3 ANTAGONIST
AMISULPRIDE 200-1200 12
5HT 2A INVERSE AGONIST
WITHOUT D2 BINDING
PIMAVANSERIN 17-34 57

26. PK - ADME
 Absorption - Readily but incompletely absorbed, Significant first pass metabolism.
 Distribution – Highly lipid soluble, Larger Vd, Longer clinical action as compared to T1/2.
 Metabolism - Metabolised by oxidation or demethylation , catalysed by liver microsomal
cytochrome P450 enzymes.CYP2D6, CYP1A2 and CYP3A4 are the major isoforms involved .

27.  Excretion –
1. renal excretion weeks after last dose of chronic drug.
2. Long acting injectable cause receptor blockade after 3-6 months.
3. Average time for relapse in stable patients is 6 months. Exception clozapine ,relapse on
discontinuation is rapid and severe . Hence should not be discontinued abruptly unless
clinically needed because of adverse effects such as myocarditis and agranulocytosis (true
medical emergencies)

28. Psychological effects
 low doses of some of these drugs, particularly quetiapine, are used to promote sleep onset and
maintenance, although there is no approved indication for such usage.
 A pseudodepression due to drug-induced akinesia responds to antiparkinsonism drugs and sometimes by
dose reduction.
 Toxic-confusional states (high doses of drugs with antimuscarinic actions).

29. EEG effects
 Antipsychotics produce shifts in the pattern of EEG frequencies , usually slowing them and increasing
their synchronization.
 The slowing (hypersynchrony) is sometimes focal or unilateral, which may lead to erroneous diagnostic
interpretations.
 Some of the neuroleptic agents lower the seizure threshold and induce EEG patterns typical of seizure
disorders.
 With careful dosage titration , most can be used safely in epileptic patients.

31. ADVERSE EFFECTS
NEUROLOGICAL
ADVERSE EFFECTS
FEATURES TIME OF ONSET
AND RISK INFO
MECHANISM TREATMENT
Acute dystonia Spasm of muscles
of tongue, face ,
neck,back
1-5 days
Young ,
antipsychotic naïve
patients at highest
risk
Acute DA
antagonism
antiparkinsonian
akathisia Subjective and
objective motor
restlessness not
anxiety or agitation
5-60 days unknown Reduce or change
drug/clonazepam ,
propranolol
parkinsonism Bradykinesia ,
rigidity , tremors ,
mask facies ,
shuffling gait
5-30 days
Elderly at high risk
DA antagonism Dose reduction,
Change medication
Antiparkinsonian
drugs

35. NEUROLOGICAL
ADVERSE EFFECTS
FEATURES TIME OF ONSET
AND RISK INFO
MECHANISM TREATMENT
Neuroleptic malignant
syndrome
Extreme rigidity,
fever, unstable
blood pressure,
myoglobinemia,
can be fatal
Weeks-months.
Can persist for days
after stopping
antipsychotic
DA antagonism Stop drug,
Supportive care,
Dantrolene,
bromocriptine
Perioral tremor
Rabbit syndrome
Perioral tremor Months or years unknown Antiparkinsonian
drug
Tardive dyskinesia Orofacial
dyskinesia ,
choreoathetosis
or dystonia.
Months or years.
Elderly at 5 fold
greater risk
Risk propotional to
potency of D2
Blockade.
Postsynaptic DA
Receptor
supersensivity
Drug
disconituation,
VMAT2 inhibitors
valbenazine and
deutetrabenazine

37.  SS and NMS are rare, serious medication-induced disorders with certain overlapping
features.
 SS can present with restlessness, agitation, HTN, tachycardia, diarrhea, tremor,
myoclonus, hyperreflexia, diaphoresis, hyperthermia, and tachypnea.
 Symptoms of patients presenting with NMS include: HTN, tachycardia, tachypnea,
diaphoresis, stupor, hyperthermia, lead pipe rigidity, hyporeflexia, and decreased
bowel sounds.
 The similarities in presentation can make diagnostic decisions problematic. Prompt
recognition and discontinuation of the causative agents is imperative in preventing
serious complications in both disorders, since each condition is treated differently.

38. RABBIT syndrome ( perioral tremors )

40.  Urinary retention ( significant
antimuscarinic action).
 Orthostatic hypotension or impaired
ejaculation( chlorpromazine or
mesoridazine)due to marked
adrenoceptor-blocking actions.
AUTONOMIC NERVOUS SYSTEM
EFFECTS
METABOLIC AND ENDOCRINE EFFECTS
 Weight gain (clozapine, olanzapine).
 Hyperglycemia
 Hyperlipidemia
 Insulin resistance
 Hyperprolactinemia (amenorrhea, galactorrhea,
infertility, loss of libido,impotence, osteoporosis)

41. Ocular Complications
 Chlorpromazine (Deposits
in cornea and lens).
 Thioridazine (Retinal
deposits) .
 Maculopathy
TOXIC OR ALLERGIC REACTIONS
 Agranulocytosis
 Cholestatic jaundice
 Skin eruptions

42. CARDIAC TOXICITY
 Clozapine (myocarditis),risperidone,
fluphenazine,haloperidol,ziprasidone,pimozide,droperidol,quetiapine.
 Overdoses of thioridazine(removed in 2005)causes torsades de pointes, cardiac
conduction block, sudden death(arrythmia)
 Mean arterial pressure, peripheral resistance, and stroke volume are decreased.
 Orthostatic hypotension , tachycardia ,dizziness, reduced S T interval and longer QTc
interval.
 Metabolic syndrome (risk of coronary artery disease, stroke, and hypertension).

44. Pimavanserin
 Medications such as levodopa that treat the symptoms of Parkinson’s disease can also exacerbate
psychotic symptoms.
 Antipsychotics that can treat the psychotic symptoms can significantly worsen the other symptoms
of Parkinson’s disease.
 In 2016, Pimavanserin is a selective serotonin inverse agonist. It has no dopamine antagonist
properties and is not associated with EPS.

45. IONOTROPIC GLUTAMATE RECEPTORS as targets
AMPA
 AMPAkine CX516 was tested in a RCT as an adjunct
to antipsychotics – no advantage.
 Ampakines are drugs that potentiates currents
mediated by AMPA-type(α-amino-3-hydroxy-5-
methyl-4-isoxazolepropionic acid) glutamate
receptors .
 They protect neurons against neurotoxic insults ,in
part by mobilizing growth factors such as BDNF.
KAINATE
 Topiramate as an adjunct to antipsychotics – 1
positive RCT ,1 equivocal RCT bt associated
with cognitive dulling.

46. GLUTAMATERGIC ANTIPSYCHOTICS
No glutamate specific agents are currently approved but several are in late clinical testing :
 BIOPERTIN GlyT1 (glycine is required co agonist with glutamate at NMDA receptor )used adjunctively
with standard antipsychotics, improved negative symptoms of schizophrenia but subsequent trials have
been disappointing.
 SARCOSERINE (N- methylglycine) GlyT1 , in combination with standard antipsychotic has improved
positive and negative symptoms of schizophrenia in both acute and chronic patients.
 METABOTROPIC GLUTAMATE RECEPTOR AGONISTS: 8 are divided into 3 groups, 1(mGluR1,5) , 2
(mGluR2,3) and 3(mGluR4,6,7,8). mGluR2,3 inhibit glutamate release presynaptically and are being
investigated in treatment of schizophrenia. pomaglumetad methionil showed antipsychotic efficacy in
early phase 2 trials but subsequently failed to show benefit in both positive and negative symptoms.

47.  The antibiotic minocycline inhibit the effects of NMDA receptor antagonism by MK-801 on rats
,and to reverse PCP-induced cognitive deficits. Minocycline as add-on treatment in patients with
early phase schizophrenia revealed a significant effect on negative and cognitive symptoms .
 Cannabidiol (CBD), have a modulatory effect on glutamatergic transmission, as it inhibit ketamine
and MK-801-induced effects in animal models , and in humans .
 Topiramate, (AMPA antagonist)effective as an adjunctive therapy in TRS patients , and to reduce
the effects of MK-801 in rats, effects of topiramate through enhancement of GABA transmission, as
AMPA antagonism only occurs at higher concentrations.

49. SUMMARY
 Although all currently available antipsychotics agents have atleast some degree of antagonism at the
dopamine D2 receptors , some experimental agents reduce psychotic symptoms in the absence of
dopamine D2 receptor antagonism .
 Glutamate receptor dysfunction upstream of dopamine can be an explanation for the symptoms of
schizophrenia.
 Several novel therapeutic targets involving glutamate receptors are under active investigation, including
NMDA (N-methyl-D-aspartate) agonists, Glycine transporters inhibitors and metabotropic glutamate
receptor agonist.