antipsychotics and lithium

PSYCHOSIS

variety of mental disorders that are characterized by the inability to distinguish between what is real and what is not, which should be clinically and medically diagnosed by a healthcare professional

Antipsychotic Drugs

• able to reduce the psychotic symptoms in varying conditions like 

  • Schizophrenia

  • bipolar disorder

  • psychotic depression

  • psychoses related to dementia 

  • drug-induced forms of psychoses

Antipsychotic Drugs

able to reduce the psychotic symptoms in varying conditions like:

• Schizophrenia

• bipolar disorder

• psychotic depression

• psychoses related to dementia 

• drug-induced forms of psychoses

Neuroleptic

subtype of antipsychotic agents that produce a high incidence of extrapyramidal side effects (EPS) at clinically effective doses which is common with first generation antipsychotic agents

extrapyramidal side effects (EPS) is common with __

first generation antipsychotic agents

Second Generation Antipsychotics (Atypical Agents)

are used for the management of these psychotic conditions and wider range of activities

SCHIZOPHRENIA

most common psychiatric disorder (affecting 1% of the global population) characterized by having a clear sensorium but marked thinking and perceptual disturbances

SCHIZOPHRENIA

is characterized by

having a clear sensorium but marked thinking and perceptual disturbances

SCHIZOPHRENIA is considered as __

a neurodevelopmental disorder related to three hypotheses for its clinical presentation

SCHIZOPHRENIA is considered as a neurodevelopmental disorder related to three hypotheses for its clinical presentation:

• serotonin hypothesis

• dopamine hypothesis

• glutamate hypothesis

Serotonin hypothesis

abnormal transmission in 5-HT2A and 5HT-2C leading to hallucinatory effects in schizophrenia

leading and most accepted hypotheses in schizophrenia

Dopamine hypothesis

Dopamine hypothesis

hyperactivity in mesolimbic dopamine receptor transmission contributes to the positive symptoms of hallucinations

generally, there are __Dopamine receptors, where D1 & D5 are stimulatory in nature and D2, D3, & D4 are inhibitory

5

D1 & D5

are stimulatory in nature

D2, D3, & D4

are inhibitory

Dopamine hypothesis

due to the hyperactivity of the Dopamine receptors,  D2, D3, & D4, which are inhibitory,

may be activated to be excitatory, leading to positive symptoms of hallucinations 

Glutamate hypothesis

hypoactivity of NMDA receptor leading to reduced inhibitory influences contribute to cognitive impairment and psychosis

NMDA receptors

are related to GABA transmission. Therefore, if it involves hypoactivity of GABA receptors, excitation is predominant, which increases mental activity and may manifest psychoses

Schizophrenia may start at

a young age, slowly progressing as the person ages and doesn’t suddenly just occur in a person

SYMPTOMS OF SCHIZOPHRENIA

• positive symptoms

• negative symptoms

Positive Symptoms (present or observable)

• Delusions

• Hallucinations

• Combativeness in terms of their motor activity

• Insomnia due to mental hyperactivity

Negative Symptoms (absent or unobservable)

• Affective flattening (flat effect):  poor eye contact, lack of expression during conversation

• Alogia: poor vocabulary, poor content of speech

• Avolition / Apathy:  indifference, detachment

• Anhedonia / Asociality:  lack of interest

• Attention problems: inattentiveness

TYPES OF ANTIPSYCHOTICS

• typical antipsychotics

• atypical antispychotics

Typical Antipsychotics or the 1st generation

Associated with higher incidence of higher EPS (extrapyramidal side effects)

Typical Antipsychotics or the 1st generation

drug groups

• aliphatic phenothiazines

• piperidine phenothiazines

• piperazine phenothiazines

• thioxanthenes

• butyrophenones

Aliphatic Phenothiazines:

• Chlorpromazine

• Promethazine

• Triflupromazine

Piperidine Phenothiazines:

• Thioridazine

• Mesoridazine

Piperazine Phenothiazines

(most potent in terms of antipsychotic activity):

Piperazine Phenothiazines

• Acetophenazine

• Perphenazine

• Carphenazine

• Fluphenazine

• Prochlorperazine

• Trifluoperazine

Thioxanthenes: 

• Thiothixene

• Chlorprothixene

Butyrophenones

• Haloperidol

• Droperidol

Haloperidol

most widely used

Promethazine

is not typically classified as antipsychotic but it’s structurally related; an antihistamine

Atypical Antipsychotics or the 2nd generation

Less incidences of EPS

Atypical Antipsychotics or the 2nd generation

• Clozapine (prototype)

• Asenapine 

• Olanzapine 

• Quetiapine

• Risperidone

• Paliperidone 

• Ziprasidone

• Sertindole 

• Zotepine

• Brexpiprazole

• Cariprazine

• Lurasidone

• Aripiprazole

Sertindole and Zotepine

are not available or rarely used in certain countries

PHARMACOKINETICS

• Most are___ as they undergo significant first pass metabolism 

readily but incompletely absorbed

PHARMACOKINETICS

most are:

• highly lipid soluble

• highly protein bound

• have large volume of distribution

• mostly excreted in the urine

Recurrence of psychotic symptoms after discontinuation is variable (when you stop taking antipsychotics the symptoms may reappear in an average of six months), except with

Clozapine

Clozapine

– relapse is rapid, severe, which may involve withdrawal symptoms of myocarditis and agranulocytosis, hence it should not be discontinued abruptly unless clinically needed

The metabolism of antipsychotics occurs in the __

liver via CYP450 activity (CYP2D6, CYP1A2 and CYP3A4).

The metabolism of antipsychotics are affected by _

presence of enzyme inhibitors but the antipsychotic drugs do not affect the metabolism of others

First generation or typical antipsychotics

moa

• primarily block the D2-type receptors (D2, D3 and D4) in five dopaminergic systems in the brain leading to antipsychotic activity and ADRs

• bind with D2 receptors to block them so that they cannot contribute to the stimulation of D1 and D5 receptors to prevent hallucinations.

2 MAJOR PATHWAYS

• mesolimbic-mesocortical pathway

• nigrostriatal pathway

Mesolimbic-mesocortical pathway

• most related to antipsychotic activity

• this is where the D2 type blocking happens

Nigrostriatal pathway

• most related to EPS occurrence

• blocking the dopamine receptors in this pathway produces the extrapyramidal side effects associated with antipsychotic drugs.

The binding affinity is correlated with antipsychotic activity and EPS

The most potent first generation antipsychotic will also give you the most EPS occurrences.

Second generation antipsychotics

• have activity towards serotonin receptors (5-HT) like 5HT_2A antagonist and 5-HT_1A partial agonist activity

Other novel drugs

• targets work muscarinic receptors like M1 and M3

CLINICAL USES (antipsychotics)

• Schizophrenia

• Catatonic forms of schizophrenia

• Manic phase of bipolar affective disorder

• Acute bipolar depression

• Unipolar depression

• Agitation in bipolar disorder

• Tourette syndrome, Alzheimer’s disease, Parkinson’s Disease

• Irritability and behavioral dyscontrol in autism spectrum disorder (ASD)

Catatonic forms of schizophrenia

– BZDs (as anxiolytics and muscle relaxant) followed by antipsychotic agents

Catatonic forms of schizophrenia are characterized by

unusual or abnormal motor behavior including immobility or excessive motor activity.

Manic phase of bipolar affective disorder

• used only as an adjunct because the drug of choice for manic phase is lithium

Acute bipolar depression

– antipsychotic monotherapy

Unipolar depression

– antipsychotic + antidepressant

Agitation in bipolar disorder

- specifically Haloperidol

In some cases, antipsychotics, specifically Risperidone and Aripiprazole, are clinically used in

autism spectrum disorder.

OTHER NON-PSYCHIATRIC USES

first gen

except Thioridazine) have strong anti-emetic activity

OTHER NON-PSYCHIATRIC USES

phenothiazines

exhibit anti-HAM activity

OTHER NON-PSYCHIATRIC USES

droperidol

used to produce neuroleptanesthesia

neuroleptanesthesia

- use of sedative and hypnotic drugs for mild to moderately painful treatments either alone or in combination with an analgesic

Anti-H1

beneficial since it produces sedation

Anti- 𝛼1, and anti-M1 

• responsible for many side effects like orthostatic hypotension  for 𝛼1 dry mouth, constipation, blurred vision, among the others for M1

ADVERSE EFFECTS (antipsychotics)

behavioral and neurologic effects

• pseudo depression

• eps (parkinson syndrome, akathisia, acute dystonic rxn)

• Tardive dyskinesia

• Seizures

ADVERSE EFFECTS (antipsychotics)

behavioral and neurologic effects: pseudo-depression

• This is common due to decreased levels of dopamine.

ADVERSE EFFECTS (antipsychotics)

behavioral and neurologic effects: Tardive dyskinesia

• (most important unwanted effect of antipsychotic drugs)

• this is the involuntary repetitive body movement

ADVERSE EFFECTS (antipsychotics)

behavioral and neurologic effects: seizures

•  from Chlorpromazine treatment

ADVERSE EFFECTS (antipsychotics)

ANS and CV Effects

• Anti-HAM effects

• qt prolongation

ADVERSE EFFECTS (antipsychotics)

ANS and CV Effects: anti ham

• sedation (from anti-H1)

• orthostatic hypotension (from anti-α1)

• dry mouth

• constipation

• blurred vision

• urinary retention (from anti-M1).

ADVERSE EFFECTS (antipsychotics)

metabolic and endocrine effects

• weight gain

• Hyperglycemia

• hyperlipidemia

• diabetic ketoacidosis

ADVERSE EFFECTS (antipsychotics)

others

• Retinal deposits leading to brown vision eventually resulting to blindness from Thioridazine treatment

• Neuroleptic Malignant Syndrome manifesting like malignant hyperthermia is a life-threatening ADR from high potency antipsychotic agent

ADVERSE EFFECTS (antipsychotics)

metabolic and endocrine effects : weight gain

• from all antipsychotic especially with Clozapine and Olanzapine, not seen in Molindone

Bipolar Disorder (Manic-Depressive Illness)

– distinct psychotic disorder manifesting as unusual shifts in a person’s mood, energy, activity levels, and concentration making it difficult to carry day-to-day tasks

Traditionally patients with bipolar disorder were assumed to be

under the impression of schizophrenia. However, bipolar disorder is now a distinct and established condition with a separate and specific diagnosis. 

Lithium

the first non-antipsychotic agent

Lithium

used for

• management of the manic phase of bipolar disorder to prevent recurrent manic and depressive episodes

Carbamazepine and Valproic acid

Classified as anti-seizure medications

Other mood stabilizing agents used to manage the acute mania and prevent its recurrence

Carbamazepine and Valproic acid

CLINICAL USES (lithium)

• Bipolar Affective Disorder

• Recurrent depression

• Acute major depression

• Schizoaffective disorder

• Schizophrenia

CLINICAL USES (lithium)

schizophrenia

• with antipsychotic agents as an adjunct for treatment-resistant patients and to synergize their effects

ADVERSE EFFECTS (lithium)

neurologic and psychiatric effects

• Tremor (one of the most common ADRs)

• Neurologic abnormalities (ataxia, motor hyperactivity, dysarthria, aphasia)

• Mental confusion and withdrawal at toxic doses

ADVERSE EFFECTS (lithium)

metabolic and endocrine effects

• Reversible decreased thyroid function

• Polydipsia and polyuria

• Nephrogenic diabetes insipidus due to the alteration of the body’s vasopressin levels

ADVERSE EFFECTS (lithium)

cv effects

• Edema following sodium retention

• Bradycardia-tachycardia (“sick sinus”) syndrome

ADVERSE EFFECTS (lithium)

others

• Lithium toxicity is newborns (lethargy, cyanosis, hepatomegaly)

  • Given that lithium can cross breastmilk

• Transient acneiform eruptions

• Leukocytosis

Bradycardia-tachycardia (“sick sinus”) syndrome

 definite contraindication to Lithium