4.4 | Antipsychotics & Drugs for Bipolar Disorder (Lithium)

Psychosis

- mental disorders

- inability to distinguish between what is real & what is not

Antipsychotic drugs

reduce the psychotic symptoms in varying conditions

Antipsychotic drugs: Varying conditions (4)

1. Schizophrenia

2. Bipolar disorder

3. Psychotic depression

4. Psychoses related to dementia & drug-induced forms

Neuroleptic

- subtype of antipsychotic agents

- high incidence of EPS at clinically effective doses which is common with first generation

2nd Generation Antipsychotic

- atypical agents

- Mx of psychotic conditions

Schizophrenia

- most common psychiatric disorder; neurodevelopment disorder

- clear sensorium

- but marked thinking & perceptual disturbances

Schizophrenia: Etiology (2)

may be:

1. Idiopathic

2. Genetic

Schizophrenia: Hypotheses for its Clinical Presentation (3)

1. Serotonin

2. Dopamine

3. Glutamate

Serotonin hypothesis

abnormal transmission in 5-HT-2A and 5-HT-2C

- leading to hallucinatory effects in schizophrenia

Dopamine hypothesis

hyperactivity in mesolimbic dopamine receptor transmission

- contributes to the positive symptoms of hallucinations

Glutamate hypothesis

hypoactivity of NMDA receptor leading to reduced inhibitory influences

- contribute to cognitive impairment and psychosis

Schizophrenia: Types of Symptoms (2)

1. Positive: present, observable

2. Negative: absent, unobservable

Positive Symptoms (4)

1. Delusions

2. Hallucinations

3. Combativeness

4. Insomnia

Negative Symptoms (5)

1. Affective flattening

2. Alogia

3. Avolition

4. Anhedonia

5. Attention problems

Affective flattening

- flat effect

- poor eye contact

- lack of expression

Alogia

- poor vocabulary

- poor content of speech

Avolition: AKA

Apathy

Avolition

- indifference

- detachment

Anhedonia: AKA

Asociality

Anhedonia

lack of interest

Attention problems

inattentiveness

Antipsychotics: Types (2)

1. Typical

2. Atypical

Typical Antipsychotics: Drug Classes (5)

1. Aliphatic Phenothiazines

2. Piperidine Phenothiazines

3. Piperazine Phenothiazines

4. Thioxanthenes

5. Butyrophenones

Typical Antipsychotics: MOST POTENT Drug Classes

Piperazine Phenothiazines

Aliphatic Phenothiazines (3)

1. Chlorpromazine

2. Promethazine

3. Triflupromazine

(-azine)

Piperidine Phenothiazines (2)

1. Thioridazine

2. Mesoridazine

(-oridazine)

Piperazine Phenothiazines (6)

1. Acetophenazine

2. Perphenazine

3. Carphenazine

4. Fluphenazine

5. Prochlorperazine

6. Trifluoperazine

(-phenazine, -perazine)

Thioxanthenes (2)

1. Thiothixene

2. Chlorprothixene

(-thixene)

Butyrophenones (2)

1. Haloperidol

2. Droperidol

(-peridol)

most widely used antipsychotic

Haloperidol

Other Typical Antipsychotics (2)

structurally different from aforementioned drug classes:

1. Pimozide

2. Molindone

Atypical Antipsychotics (13)

1. Clozapine

2. Asenapine

3. Olanzapine

4. Quetiapine

5. Risperidone

6. Paliperidone

7. Ziprasidone

8. Sertindole

9. Zotepine

10. Brexpiprazole

11. Cariprazine

12. Lurasidone

13. Aripiprazole

(-apine, -idone, -piprazole)

Atypical Antipsychotics: Rarely Used

not available or rarely used:

1. Sertindole

2. Zotepine

Comparisons Between Antipsychotic Classes (5)

1. Receptor Blockade

2. Positive Symptoms

3. Negative Symptoms

4. EPS

5. Tardive Dyskinesia

Receptor Blockade

TYP: Dopamine

ATYP: Dopamine and Serotonin

Positive Symptoms

BOTH Effective

Negative Symptoms

TYP: Effective

ATYP: MORE Effective

EPS

TYP: more frequent

ATYP: less frequent

Tardive Dyskinesia

TYP: High incidence

ATYP: Low incidence

Given the comparisons, the preferred class of antipsychotics is?

Atypical antipsychotics

Antipsychotics: Pharmacokinetics (5)

1. Distribution

2. Metabolism

3. Excretion

4. Recurrence of psychotic symptoms after discontinuation

5. CYP450

Antipsychotics: Distribution

- highly lipid-soluble

- highly protein-bound

- large volume of

distribution

Antipsychotics: Metabolism

- Most are readily but incompletely absorbed

- undergo significant first-

pass metabolism

- affected by the presence of enzyme inhibitors, but do NOT affect other drugs' metabolism

Antipsychotics: Excretion

in the urine

Antipsychotics: Recurrence of psychotic symptoms after discontinuation

- variable

- average of six months

Antipsychotic EXCEPTION in Recurrence of psychotic symptoms after discontinuation

Clozapine

- relapse is rapid, severe

- may involve withdrawal symptoms of myocarditis and agranulocytosis

- should NOT be discontinued abruptly unless clinically needed

Antipsychotics: CYP450 enzymes (3)

1. 1A2

2. 2D6

3. 3A4

1st Gen (Typical) Antipsychotics: Pharmacodynamics

primarily block the D2-type receptors (D2, D3 and D4)

- in 5 dopaminergic systems in the brain

- leads to antipsychotic activity & ADRs

D2-type receptors (5)

D1 & D5 - stimulatory

D2, D3, D4 - inhibitory

1st Gen: Pathways (2)

1. Mesolimbic-mesocortical pathway

2. Nigrostriatal pathway

Mesolimbic-mesocortical pathway

- most related to antipsychotic activity

- D2 blocking happens

Nigrostriatal pathway

most related to EPS occurrence

1st Gen: Binding Affinity

- correlated with antipsychotic activity & EPS

- ↑ potency = ↑ EPS

2nd Gen Antipsychotics: Pharmacodynamics

activity towards serotonin receptors (5-HT):

- 5HT-2A antagonist

- 5-HT-1A partial agonist activity

Antipsychotic Pharmacodynamics: Other Novel Targets

work [on] muscarinic receptors like M1 and M3

Antipsychotic: Clinical Uses (10)

1. Schizophrenia

2. Schizophrenia: Catatonic forms

3. Bipolar affective disorder: Manic phase

4. Acute bipolar depression

5. Unipolar depression

6. Agitation in bipolar disorder

7. Tourette syndrome

8. Alzheimer's disease

9. Parkinson's Disease

10. Autism spectrum disorder (ASD): Irritability & behavioral dyscontrol

Schizophrenia — Catatonic forms

unusual or abnormal motor behavior

- immobility or excessive motor activity

Schizophrenia — Catatonic forms: Drug

BZDs (as anxiolytics & muscle relaxant) followed by antipsychotic agents

Bipolar affective disorder: Manic phase

- as adjunct only

- DOC: Lithium

Agitation in bipolar disorder: Drug

Haloperidol

Autism spectrum disorder (ASD): Drugs (2)

1. Risperidone

2. Aripiprazole

1st Gen: Non-Psychiatric Use

anti-emetic

1st Gen EXCEPTION for Non-Psychiatric Use

Thioridazine

Phenothiazines: Non-Psychiatric Use

anti-HAM activity

- anti-H1

- anti- α1

- anti-M1

anti-H1

beneficial since it produces sedation

anti- α1 & anti-M1

many side effects

Droperidol: Non-Psychiatric Uses

produce neuroleptanesthesia

Neuroleptanesthesia

neuroleptic/antipsychotic (neurolept-) + analgesic (anesthesia)

Antipsychotic: ADRs (4)

1. Behavioral & Neurologic Effects

2. ANS & CV Effects

3. Metabolic & Endocrine Effects

4. Others

Behavioral & Neurologic Effects

1. Pseudo-depression

2. EPS

3. Tardive dyskinesia

4. Seizures

Behavioral & Neurologic Effect: EPS (3)

1. Parkinson syndrome

2. Akathisia

3. Acute dystonic reactions

Acute dystonic reactions are observed from which Antipsychotic Type?

Typical Antipsychotics

most important unwanted effect of antipsychotic drugs

Tardive dyskinesia

Behavioral & Neurologic Effect: from Chlorpromazine

Seizures

ANS & CV Effects (2)

1. Anti-HAM effects

2. QT Prolongation

ANS & CV Effect: Anti-HAM effects (6)

1. Sedation

2. Orthostatic hypotension

3. Dry mouth

4. Constipation

5. Blurred vision

6. Urinary retention

Metabolic & Endocrine Effects (4)

1. Weight gain

2. Hyperglycemia

3. Hyperlipidemia

4. Diabetic ketoacidosis

Metabolic & Endocrine Effect: Weight gain

from all antipsychotics

- especially with Clozapine and

Olanzapine

Metabolic & Endocrine Effect: Weight gain NOT SEEN WITH?

Molindone

Antipsychotics: Other Effects (2)

1. Retinal deposits → brown vision → blindness

2. Neuroleptic Malignant Syndrome

Retinal deposits → brown vision → blindness: Drug

Thioridazine

Neuroleptic Malignant Syndrome

- manifesting like malignant hyperthermia

- life-threatening ADR

- from high potency antipsychotic agent

Bipolar Disorder: AKA

Manic-Depressive Illness

Bipolar Disorder

- distinct psychotic disorder

- unusual shifts in a person's mood, energy, activity levels,

and concentration

- difficult to carry day-to-day tasks

the first non-antipsychotic

Lithium

Lithium: Uses (2)

1. Mx: Bipolar disorder: Manic phase

2. Mx: acute phase of the illness to prevent recurrent manic and depressive episodes

Carbamazepine & Valproic Acid

- classified as antiseizures

- mood stabilizing agents

- Mx: acute mania & prevent its recurrence

Lithium: Clinical Uses (5)

1. Bipolar Affective Disorder

2. Recurrent depression

3. Acute major depression

4. Schizoaffective disorder

5. Schizophrenia

Lithium: Schizophrenia

with antipsychotic agents (as an adjunct) for treatment-resistant patients

Lithium: TI

narrow therapeutic index

Drugs for Bipolar Disorder: ADRs (4)

1. Neurologic & Psychiatric Effects

2. Metabolic & Endocrine Effects

3. CV Effects

4. Others

Neurologic & Psychiatric Effects

1. Tremor

2. Neurologic abnormalities

3. Mental confusion and withdrawal

BD: one of the most common ADRs

Tremor

Neurologic abnormalities (4)

1. Ataxia

2. Motor hyperactivity

3. Dysarthria

4. Aphasia

BD: at toxic doses

Mental confusion & withdrawal

Metabolic & Endocrine Effects (3)

1. Reversible decreased thyroid function

2. Polydipsia & polyuria

3. Nephrogenic diabetes insipidus

CV Effects (2)

1. Edema after sodium retention

2. Bradycardia-tachycardia Syndrome

Bradycardia-tachycardia Syndrome: AKA

Sick sinus

Bradycardia-tachycardia Syndrome

definite contraindication to Lithium

BD: Other ADRs (3)

1. Lithium toxicity

2. Transient acneiform eruptions

3. Leukocytosis