ANTIPSYCHOTICS INTRODUCTION IN PSYCHIATRY

CLASSIFICATION
OF
ANTIPSYCHOTICS
AND THEIR
HISTORICAL
IMPORTANCE
PRESENTED BY:
DR AASHMEEN
JUNIOR RESIDENT 1
DEPARTMENT OF PSYCHIATRY

CONTENT
1. INTRODUCTION
2. HISTORY AND TIMELINE
3. NEUROTRANSMITTERS INVOLVED
4. CLASSIFICATION OF ANTIPSYCHOTICS
5. PHARMACOKINETICS
6. MECHANISM OF ACTION
7. PRINCIPLES OF THERAPY
8. ALGORHYTHM
9. INDICATIONS
10. CONTRAINDIACTIONS
11. ASSOCIATED MEDICAL CONDITIONS
12. SIDE EFFECTS
13. FDA STATUS OF DIFFERENT ANTIPSYCHOTICS
14. NEWER ADVANCES
15. CONCLUSION

INTRODUCTION
• Mental disorder in which the thoughts, affective response , ability to recognize reality , and
ability to communicate and relate to others are sufficiently impaired to interfere grossly with
the capacity to deal with reality.
• Classic characteristics of Psychosis:
1. Impaired reality testing
2. Hallucinations
3. Delusions
• Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily
used to manage psychosis (including delusions, hallucinations, paranoia or disordered
thought), principally in schizophrenia but also in a range of other psychotic disorders. They
are also the mainstay together with mood stabilizers in the treatment of bipolar disorder.

HISTORY AND TIMELINE
• The first truly effective drugs for psychosis other than sedating tranquilizers were
discovered by accident in the 1952 when a drug with antihistamine properties
(Chlorpromazine) was observed to improve psychosis when this putative
antihistamine was tested in schizophrenia patients.
• Once chlorpromazine was observed to be an effective drug for treating psychosis ,
it was tested experimentally to uncover its mechanism of antipsychotic action,
which was identified as dopamine D2 receptor antagonism.
• Other than chlorpromazine, Reserpine was also one of the first drugs found to Be
useful in schizophrenia.
• Little attention was paid to Cade's report in 1949 that Lithium could be
used for excitement and mania. Its effective use started in the 1960s.

NEUROTRANSMITTERS INVOLVED
❑Dopamine
❑Serotonin
❑ Glutamate

➢ Nigrostriatal pathway:
• Deficiencies of DA in these motor pathways cause movement disorders including Parkinson’s disease,
characterized by rigidity, akinesia/bradykinesia (i.e., lack of movement or slowing of movement), and
tremor.
• Hyperactivity of DA in the nigrostriatal pathway can cause various hyperkinetic movement disorders
such as chorea, dyskinesias, and tics (in conditions such as Huntington’s disease, Tourette syndrome,
and others)
➢ The Mesolimbic Dopamine Pathway
• Too much DA in this pathway classically causes the positive symptoms of psychosis as well as Drug
induced high.
• Too little DA in this pathway causes the symptoms of anhedonia, apathy, and lack of energy seen in
conditions such as unipolar and bipolar depression and in the negative symptoms of schizophrenia
➢ Mesocortical dopamine pathway: Hypoactivity in this pathway involved in the cognitive, affective
and negative symptoms of schizophrenia.
➢ Tuberoinfundibular dopamine pathway : Dopamine inhibits prolactin secretion.

CLASSIFICATION OF ANTIPSYCHOTICS
PHENOTHIAZINE CHEMICAL CLASSIFICATION:
• ALIPHATIC SIDE CHAIN : Chlorpromazine,Triflupromazine
• PIPERIDINE SIDE CHAIN: Thioridazine
• PIPERAZINE SIDE CHAIN: Trifluoperazine , Fluphenazine

❑ They are available in the form of tablets as well as depot preparations
LONG ACTING DEPOT PREPARATIONS
1. Flupentixol decanoate: 20-100 mg IM every 2-4 weeks
2. Fluphenazine decanoate: 12.5-100 mg IM every 2-4 weeks
3. Haloperidol decanoate: 25-250 mg IM every 4 weeks
4. Olanzapine pamoate: 150-300 mg IM every 2 weeks
5. Risperidone Consta: 25-75 mg IM every 2 weeks / 40-50 mg every 4 weeks
6. Zuclopenthixol decanoate: 200-400 mg IM every 2-4 weeks

PHARMACOKINETICS
1. Well absorbed from GIT
2. Low potency antipsychotics have wide dosing range{ Chlorpromazine, Thioridazone}
3. High potency antipsychotics have a narrow dose range and need dose
monitoring { Risperidone, Olanzapine}
4. Highly lipid soluble with high albumin bounding capacity.
5. Metabolized by CYP450
6. Undergoes glucuronidation before being excreted in urine.
7. Are slowly released from lipid rich storage sites, thus, metabolites can be detected in
urine even after 3 months of discontinuation of the drug.

• D2 receptor antagonism is the main mechanism of action
• Atypical antipsychotics have a greater 5HT2 antagonism than D2 receptor
antagonism
• Aripiprazole has
1. Partial D2 receptor antagonism
2. Partial 5HT1A agonism and 5HT2A antagonism
Thus weaker D2 blockade causes less EPS side effects.

PRINCIPLES OF THERAPY
1. Combination of 2 antipsychotics is usually of no advantage; can only be used at times in the
form of injectables to control acute violent symptoms.
2. ECG,LFT, FBS and fasting lipid profile should be done before initiation of therapy and
monitored at 3 monthly intervals . BMI should also be monitored.
3. Chronic schizophrenia pts need at least 2-4 months therapy for max. therapeutic response.
4. Dose should be reduced in cases of hepatic insufficiency.
5. Pt should be assessed within 1-2 weeks of starting antipsychotics.
6. After dose titration has been achieved, pt should be monitored every 2-3 months.
7. After a dose change, pt should be followed up within 1 month.
8. Treatment resistance: Non- response to 2 anti-psychotic therapy in adequate dosage.
9. Adjunctive therapy with mood stabilizers should be used to augment partial response.

INDICATIONS
➢ Schizophrenia and Schizoaffective disorders:
• First and second-generation antipsychotics (except clozapine) are indicated for the treatment of an
acute episode of psychoses and maintenance therapy of schizophrenia and schizoaffective disorders.
• First-generation antipsychotics are better for treating positive symptoms of schizophrenia, e.g.,
hallucinations, delusions, among others. They also decrease the risk of a repeat episode of psychosis.
• Second-generation antipsychotics treat both positive symptoms and negative symptoms of
schizophrenia, e.g., withdrawal, ambivalence, among others, and are known to reduce relapse rates.
➢ Acute Mania:
• First-generation antipsychotics are effective in the treatment of acute mania with psychotic symptoms.
• All second-generation antipsychotics except clozapine can also be used as a treatment of symptoms of
acute mania.
• Antipsychotics are used with mood stabilizers like lithium, valproic acid, or carbamazepine initially,
and then after symptoms stabilize can be gradually decreased and withdrawn.

➢ Major Depressive Disorder with Psychotic features:
• First or second-generation antipsychotics, along with an antidepressant, is the
treatment of choice for depression with psychotic features.
• Olanzapine and fluoxetine, as a combination therapy, have FDA approval for
treatment-resistant depression.
➢ Delusional Disorder:
• First-generation antipsychotics are indicated in the treatment of delusional disorder
and paranoia associated with personality disorders.
➢ Generalized anxiety disorder:
• Quetiapine can be used as it is a non-habit forming alternative of Benzodiazepine.
➢ Childhood Schizophrenia:
• Recent studies have shown the benefit of clozapine in treating early-onset
schizophrenia.

➢ Severe Agitation:
• Severely agitated, irritable, hostile, and hyperactive patients can be treated with a short-term course of
first-generation antipsychotics irrespective of the etiology of the behavioral disturbance.
• Second-generation antipsychotics can also be used for treating acute agitation. Antipsychotics can also
be used in children with severe autism exhibiting behavioral disturbances though repeatedly giving
antipsychotics is not preferred.
• Risperidone and olanzapine are useful for controlling aggression in children.
➢ Tourette Disorder:
• Haloperidol and pimozide are the antipsychotics most commonly used for this syndrome.
• Tourette disorder is an off-label indication for second-generation antipsychotics.
➢ Substance-induced psychotic disorder:
• In cases of severe psychosis secondary to substance use, antipsychotics can be used to control agitation
symptoms.

➢ Borderline Personality Disorder:
• This type of personality disorder can have symptoms of psychosis and paranoia.
• Both first and second-generation antipsychotics are used for the treatment of these symptoms.
➢ Dementia and Delirium:
• A low dose of high potency first-generation antipsychotics like haloperidol is recommended for the
treatment of agitation in delirium and dementia.
• Second-generation antipsychotics can also be used for treating behavioral disturbances in dementia.
• Off-Label use of second-generation antipsychotics is acquired immunodeficiency syndrome-related
dementia.

CONTRAINDICATIONS
• History of severe allergy
• Use of central nervous system (CNS) depressants like barbiturates, benzodiazepines, opioids
• With anticholinergic medication like scopolamine or the use of phencyclidine
• Severe cardiac abnormalities
• History of seizure disorder
• Narrow-angle glaucoma or prostatic hypertrophy
• History of or ongoing tardive dyskinesia
• Elderly patients with dementia. { can increase risk of stroke}
• Pregnancy, especially in the first trimester
• Breastfeeding

ASSOCIATED MEDICAL CONDITIONS
CONDITION DOC DRUGS TO AVOID
DIABETES ARIPIPRAZOLE CLOZAPINE, OLANZAPINE
HYPERLIPIDEMIA ARIPIPRAZOLE CLOZAPINE, OLANZAPINE
ORTHOSTATIC HYPOTENSION ARIPIPRAZOLE CLOZAPINE,RISPERIDONE, QUETIAPINE
OBESE ARIPIPRAZOLE
MOLINDONE
CLOZAPINE, OLANZAPINE
GLAUCOMA ARIPIPRAZOLE
RISPERIDONE
QUETIAPINE
CLOZAPINE,THIORIDAZINE
QTc PROLONGATION OLANZAPINE THIORIDAZINE, ZIPRASONIDONE
PARKINSONISM LOW DOSE
CLOAZAPINE;
QUETIAPINE
HALOPERIDOL
DRYNESS OF EYES OR MOUTH ARIPIPRAZOLE
RISPERIDONE
QUETIAPINE
CLOZAPINE,THIORIDAZINE
HYPOMANIA QUETIAPINE
OLANZAPINE
NIL

SIDE EFFECTS
• Anticholinergic adverse effects like dry mouth, constipation, urinary retention
[chlorpromazine, thioridazine]
• Increased Prolactin levels [ more with 1st gen]
• Sedation [Chlorpromazine and clozapine are the most sedating, while fluphenazine,
haloperidol, and pimozide are less sedating.]
• Prolongation of QTc interval [Pimozide,thioridazine, Paliperidone]
• Orthostatic hypotension [chlorpromazine, thioridazine]
• Weight gain and metabolic syndrome [ more common with 2nd gen]
• Blue-gray skin discoloration and benign pigmentation of the lens and cornea
[Chlorpromazine]
• Retinal pigmentation [Thioridazine]
• Medication induced movement disorders [ more common with 1st gen]

F.D.A STATUS OF
DIFFERENT
ANTIPSYCHOTICS

NEWER ADVANCES
Introduction of new antipsychotics:
❑ Cariprazine
❑ Brexpiprazole
❑ Lumateperone
❑ Pimavanserin
Introduction of new delivery methods:
❑ Subcutaneous long-acting risperidone and aripiprazole lauroxil
❑ Transdermal asenapine
❑ Inhaled loxapine
Introduction of new approaches:
❑ Olanzapine/samidorphan for olanzapine-associated weight gain

DRUG FDA APPROVED FOR APPROVED
IN
MOA
CARIPRAZINE • Depressive episodes in adults with bipolar I disorder
• Schizophrenia
2015 D2 and D3 partial
agonist
BREXPIPRAZOLE • Schizophrenia
• Adjunctive treatment for depression
2015 Partial agonist of
the 5HT1A receptor an
d the D2 and D3
receptors
LUMATEPERONE • Schizophrenia
• Bipolar depression { as monotherapy OR Adjunctive
therapy with lithium or valproate}
2019 for
schizophrenia
2021 for
bipolar depress
ion
Antagonist of 5HT2A
receptor and
antagonizes several
dopamine receptors
(D1, D2, and D4) with
lower affinity.
PIMAVANSERIN • Hallucinations and delusions associated with
Parkinson's disease.
2016 Inverse agonist and ant
agonist at serotonin 5-
HT2A

CONCLUSION
1. D2 receptor antagonism is the main mechanism of
action
2. Atypical antipsychotics have a greater 5HT2
antagonism than D2 receptor antagonism
3. Conventional antipsychotics can only be added to
atypical antipsychotics in treatment failure cases.
4. ECG,LFT, FBS and fasting lipid profile should be
done before initiation of therapy and monitored at 3
monthly intervals . BMI should also be monitored.
5. Medication induced movement disorders are more
common with 1st gen antipsychotics.
6. Metabolic syndromes are more common with 2nd
gen antipsychotics.

REFERENCES
• COMPREHENSIVE TEXTBOOK OF
PSYCHIATRY BY KAPLAN AND
SADOCK’S 10th EDITION
• MAUDSLEY PRESCRIBING GUIDELINES
IN PSYCHIATRY 13th EDITION
• STAHLS PSYCHOPHARMACOLOGY 4th
EDITION

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