Classification of Antipsychotic Drugs

Antipsychotic drugs, also known as neuroleptics or major tranquilizers, are primarily used to treat psychotic disorders such as schizophrenia, bipolar disorder, and other conditions associated with psychosis. These drugs work by altering the activity of neurotransmitters, especially dopamine, in the brain. They are broadly classified into first-generation (typical) and second-generation (atypical) antipsychotics.

1. Pharmacological Classification of Antipsychotic Drugs

Antipsychotic drugs can be classified into two main categories based on their mechanism of action, receptor affinity, and side effect profile:

First-Generation Antipsychotics (FGAs) or Typical Antipsychotics: These drugs primarily block dopamine (D2) receptors, which alleviates the positive symptoms of psychosis but can also lead to extrapyramidal side effects (EPS).
Second-Generation Antipsychotics (SGAs) or Atypical Antipsychotics: These drugs block both dopamine (D2) receptors and serotonin (5-HT2A) receptors, which leads to fewer extrapyramidal side effects and better control of both positive and negative symptoms of psychosis.

First-Generation Antipsychotics (FGAs)

First-generation antipsychotics are divided into two subcategories based on their potency at the D2 receptor:

Low Potency FGAs
High Potency FGAs

a) Low Potency First-Generation Antipsychotics

These drugs have a lower affinity for D2 receptors but higher anticholinergic, antihistaminergic, and alpha-adrenergic effects, which lead to more sedation, hypotension, and anticholinergic side effects (dry mouth, constipation, etc.). However, they are less likely to cause severe extrapyramidal side effects.

Chlorpromazine
- Mechanism of Action: Blocks dopamine D2 receptors.
- Indications: Used for schizophrenia, mania, and nausea/vomiting.
- Side Effects: Sedation, orthostatic hypotension, weight gain, and anticholinergic effects (dry mouth, constipation, urinary retention).
- Clinical Use: One of the earliest antipsychotics, it is less frequently used today due to its side effect profile.
Prochlorperazine
- Mechanism of Action: Primarily blocks dopamine receptors in the brain.
- Indications: Mostly used for the treatment of severe nausea and vomiting, but also for psychotic disorders.
- Side Effects: Similar to other low-potency antipsychotics with a notable risk of sedation and hypotension.
Thioridazine
- Mechanism of Action: Dopamine receptor antagonist with strong anticholinergic properties.
- Indications: Previously used for schizophrenia but is less commonly used today due to the risk of cardiac arrhythmias (QT prolongation).
- Side Effects: Sedation, orthostatic hypotension, and significant cardiac side effects (QT prolongation).

b) High Potency First-Generation Antipsychotics

These drugs have a higher affinity for D2 receptors, resulting in more significant dopamine antagonism and a greater likelihood of causing extrapyramidal side effects (EPS), such as tremors, rigidity, and tardive dyskinesia. However, they are less sedating and have fewer anticholinergic effects than low-potency agents.

Fluphenazine
- Mechanism of Action: Potent dopamine D2 receptor antagonist.
- Indications: Schizophrenia and other psychotic disorders.
- Side Effects: High risk of extrapyramidal side effects, such as dystonia, akathisia, and tardive dyskinesia. Can also cause neuroleptic malignant syndrome (NMS).
- Clinical Use: Available in oral and long-acting injectable forms.
Haloperidol
- Mechanism of Action: Strong dopamine D2 receptor antagonist.
- Indications: Schizophrenia, acute agitation, and delirium. Also used in Tourette syndrome to control tics.
- Side Effects: High risk of EPS, NMS, and QT prolongation. Minimal sedation and anticholinergic effects compared to low-potency FGAs.
- Clinical Use: Frequently used due to its potency, particularly in acute settings for controlling agitation or psychosis.
Pimozide
- Mechanism of Action: Dopamine receptor antagonist with some serotonin blocking activity.
- Indications: Primarily used to treat Tourette syndrome and other disorders involving motor tics.
- Side Effects: Similar to other high-potency antipsychotics, with EPS and QT prolongation being major concerns.
Thiothixene
- Mechanism of Action: Potent dopamine receptor antagonist.
- Indications: Used in the management of schizophrenia.
- Side Effects: High risk of EPS, particularly parkinsonism and dystonia, as well as other typical antipsychotic side effects.

Second-Generation Antipsychotics (SGAs)

Second-generation antipsychotics have a broader mechanism of action, as they not only block dopamine receptors but also have significant effects on serotonin receptors (especially 5-HT2A). This results in fewer extrapyramidal symptoms and improved efficacy for both positive and negative symptoms of schizophrenia.

Aripiprazole
- Mechanism of Action: Partial agonist at dopamine D2 and serotonin 5-HT1A receptors, antagonist at 5-HT2A receptors.
- Indications: Schizophrenia, bipolar disorder, depression (adjunctive), and irritability in autism.
- Side Effects: Less risk of EPS and metabolic side effects, but may cause insomnia, restlessness, and akathisia.
- Unique Feature: "Dopamine stabilizer" due to its partial agonist activity.
Asenapine
- Mechanism of Action: Antagonist at dopamine and serotonin receptors.
- Indications: Schizophrenia and bipolar disorder.
- Side Effects: May cause sedation, dizziness, and weight gain, but has a lower risk of EPS.
Clozapine
- Mechanism of Action: Dopamine receptor antagonist, also has strong serotonin receptor blocking activity.
- Indications: Treatment-resistant schizophrenia and schizophrenia with a high risk of suicidal behavior.
- Side Effects: Agranulocytosis (requires regular blood monitoring), weight gain, diabetes, sedation, and drooling.
- Unique Feature: Considered the most effective antipsychotic but is reserved for treatment-resistant cases due to its side effect profile.
Iloperidone
- Mechanism of Action: Antagonist at dopamine D2 and serotonin 5-HT2A receptors.
- Indications: Schizophrenia.
- Side Effects: May cause dizziness, orthostatic hypotension, and weight gain but has a relatively low risk of EPS.
Lurasidone
- Mechanism of Action: Antagonist at dopamine D2 and serotonin 5-HT2A receptors.
- Indications: Schizophrenia and depressive episodes associated with bipolar disorder.
- Side Effects: Relatively low risk of metabolic side effects, but may cause EPS, especially akathisia.
Olanzapine
- Mechanism of Action: Antagonist at dopamine and serotonin receptors.
- Indications: Schizophrenia and bipolar disorder, including manic and mixed episodes.
- Side Effects: Significant risk of weight gain, diabetes, and sedation. Lower risk of EPS compared to FGAs.
- Clinical Use: Effective but often avoided due to its metabolic side effects.
Quetiapine
- Mechanism of Action: Antagonist at dopamine D2 and serotonin 5-HT2A receptors.
- Indications: Schizophrenia, bipolar disorder (including depression), and major depressive disorder (adjunctive).
- Side Effects: Sedation, weight gain, and metabolic syndrome are common. Lower risk of EPS.
- Unique Feature: Also used off-label for sleep disorders due to its sedative properties.
Paliperidone
- Mechanism of Action: Dopamine D2 and serotonin 5-HT2A receptor antagonist.
- Indications: Schizophrenia and schizoaffective disorder.
- Side Effects: Similar to risperidone, with EPS, weight gain, and metabolic effects. Available as a long-acting injectable.
Risperidone
- Mechanism of Action: Antagonist at dopamine D2 and serotonin 5-HT2A receptors.
- Indications: Schizophrenia, bipolar disorder, and irritability associated with autism.
- Side Effects: Higher risk of EPS compared to other SGAs, particularly at higher doses. Also associated with weight gain and hyperprolactinemia.
- Clinical Use: Commonly used due to its availability in oral and long-acting injectable forms.
Ziprasidone

Mechanism of Action: Dopamine D2 and serotonin 5-HT2A receptor antagonist.
Indications: Schizophrenia and bipolar disorder.
Side Effects: Lower risk of metabolic side effects but may cause QT prolongation and sedation.

The mnemonic ISHADE is a helpful tool for remembering the common side effects of antipsychotic medications. Here's how these side effects come about:

1. Impotence

Cause:
Antipsychotic medications, particularly first-generation antipsychotics (FGAs), can cause sexual dysfunction, including impotence, due to their effect on dopamine and prolactin levels. Dopamine blockade in the tuberoinfundibular pathway leads to increased prolactin levels, which can inhibit sexual function.

2. Sedation and Seizures

Cause (Sedation):
Many antipsychotics, especially low-potency FGAs and some second-generation antipsychotics (SGAs) like clozapine, have antihistamine effects due to H1 histamine receptor blockade. This can cause sedation.
Cause (Seizures):
Antipsychotics, particularly clozapine, lower the seizure threshold. This occurs because of their action on GABAergic pathways and dopamine blockade, which can disturb the balance of excitatory and inhibitory neurotransmitters in the brain, leading to an increased risk of seizures.

3. Hypotension

Cause:
Antipsychotics block alpha-1 adrenergic receptors, which leads to vasodilation and a reduction in blood pressure. This can cause orthostatic hypotension, where the patient feels dizzy or light-headed when standing up. Low-potency antipsychotics, like chlorpromazine, are more likely to cause this side effect.

4. Akathisia (Inability to sit still)

Cause:
Akathisia is a type of extrapyramidal symptom (EPS) associated with the dopamine receptor blockade in the nigrostriatal pathway. This leads to motor restlessness, making it difficult for the patient to sit still. Akathisia is more common with high-potency first-generation antipsychotics such as haloperidol.

5. Dermatological Side Effects

Cause:
Some antipsychotics, especially chlorpromazine, can cause photosensitivity and pigmentation changes in the skin due to their chemical structure and interaction with UV light. Long-term use can also result in dermatitis or other skin reactions.

6. Extrapyramidal Reactions

Cause:
Extrapyramidal symptoms (EPS), such as acute dystonias, rigidity, tremor, and tardive dyskinesia, occur due to the dopamine blockade in the nigrostriatal pathway. This pathway is involved in the coordination of movement, and its disruption leads to the motor side effects characteristic of first-generation antipsychotics.
Tachycardia may be a result of anticholinergic activity or compensatory responses to the sedative effects of the drugs.

Summary of ISHADE:

Impotence: Increased prolactin due to dopamine blockade
Sedation/Seizures: Histamine receptor blockade and seizure threshold reduction
Hypotension: Alpha-1 adrenergic blockade
Akathisia: Dopamine blockade in the nigrostriatal pathway
Dermatological effects: Chemical interactions with UV light, leading to skin sensitivity
Extrapyramidal reactions: Dopamine receptor blockade leading to movement disorders

Each of these side effects arises from the broad receptor activity of antipsychotic drugs, particularly their action on dopaminergic, adrenergic, histaminergic, and cholinergic systems.

Antipsychotic medications are divided into first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) based on their mechanisms of action, therapeutic profiles, and side effect profiles. Below is an overview of both types:

First-Generation Antipsychotics (FGAs)

Also known as typical antipsychotics, these medications primarily target dopamine pathways.

Mechanism of Action:

D2 receptor antagonism:
FGAs block dopamine D2 receptors in the mesolimbic pathway, which reduces positive symptoms of schizophrenia (e.g., hallucinations, delusions).
Non-selective receptor activity also impacts other pathways, including:
- Nigrostriatal pathway: Leading to extrapyramidal symptoms (EPS).
- Tuberoinfundibular pathway: Leading to hormonal disturbances like hyperprolactinemia.

Examples of FGAs:

High-potency FGAs: Haloperidol, Fluphenazine
Low-potency FGAs: Chlorpromazine, Thioridazine

Side Effects of FGAs:

Extrapyramidal Symptoms (EPS):
- Akathisia (restlessness)
- Acute dystonia (involuntary muscle contractions)
- Parkinsonism (tremors, bradykinesia, rigidity)
- Tardive dyskinesia (irreversible repetitive movements)
Neuroleptic Malignant Syndrome (NMS):
- Rare but potentially fatal condition involving muscle rigidity, hyperthermia, and altered mental status.
Other Effects:
- Hyperprolactinemia: Breast enlargement, galactorrhea, menstrual irregularities.
- Anticholinergic effects: Dry mouth, constipation, urinary retention (more common in low-potency agents).
- Sedation and weight gain: Due to histamine receptor blockade.
- Orthostatic hypotension: Due to alpha-adrenergic receptor blockade.

Second-Generation Antipsychotics (SGAs)

Also known as atypical antipsychotics, these medications target both dopamine and serotonin pathways.

Mechanism of Action:

D2 receptor antagonism: Similar to FGAs but with less binding affinity, reducing the risk of EPS.
5-HT2A receptor antagonism: Enhances dopamine release in certain brain regions (mesocortical and nigrostriatal pathways), improving negative symptoms and cognitive deficits while minimizing EPS.

Examples of SGAs:

Clozapine: Unique for treatment-resistant schizophrenia and reducing suicide risk.
Risperidone
Olanzapine
Quetiapine
Aripiprazole: Partial dopamine agonist (unique mechanism).

Side Effects of SGAs:

Metabolic Effects:
- Weight gain
- Hyperglycemia (risk of diabetes)
- Dyslipidemia
Sedation: Common with drugs like clozapine and olanzapine due to histamine receptor antagonism.
EPS (less common than FGAs):
- Risperidone at higher doses may cause EPS.
Agranulocytosis:
- Clozapine carries a risk of life-threatening agranulocytosis (requires regular blood monitoring).
Other Effects:
- Prolonged QT interval: Can increase the risk of cardiac arrhythmias (e.g., ziprasidone).
- Orthostatic hypotension: Similar to FGAs but less pronounced.

Key Differences Between FGAs and SGAs:

Feature	FGAs	SGAs
Primary Target	Dopamine D2 receptors	Dopamine D2 + Serotonin 5-HT2A
Effectiveness	Effective for positive symptoms	Effective for positive & negative symptoms
EPS Risk	High	Low
Metabolic Side Effects	Low	High (weight gain, diabetes)
Prolactin Elevation	Common	Less common
Use in Negative Symptoms	Limited	Superior

Clinical Implications:

FGAs are often reserved for cases where SGAs are ineffective or not tolerated due to their higher risk of EPS and other side effects.
SGAs are preferred as first-line therapy for most patients due to their broader efficacy and reduced EPS risk, but their metabolic side effects require careful monitoring.

Nursing Considerations:

Monitor for early signs of side effects (EPS, metabolic changes, NMS).
Educate patients on the importance of adherence despite delayed symptom relief.
Encourage regular follow-up for metabolic screening (e.g., weight, glucose, lipids).
Ensure routine blood monitoring for clozapine to prevent agranulocytosis.

Both FGAs and SGAs play critical roles in managing psychotic disorders, with the choice depending on the patient’s symptoms, side effect profile, and clinical history.

First-Generation Antipsychotics (FGA) – Typical Antipsychotics

Mechanism of Action:

First-generation antipsychotics, also known as typical antipsychotics, primarily work by blocking dopamine (D2) receptors in the brain, specifically in the mesolimbic and mesocortical pathways. This dopamine antagonism is thought to reduce symptoms of psychosis (hallucinations, delusions).
They also block other neurotransmitter receptors to varying degrees, such as serotonin, histamine, acetylcholine, and norepinephrine.

Common First-Generation Antipsychotics:

Chlorpromazine
Haloperidol
Fluphenazine
Perphenazine
Thioridazine

Common Side Effects:

Extrapyramidal Symptoms (EPS):
- Dystonia: Muscle spasms, particularly in the neck, face, and back.
- Parkinsonism: Tremors, rigidity, bradykinesia, and shuffling gait.
- Akathisia: Restlessness and an inability to sit still.
- Tardive Dyskinesia (TD): Involuntary, repetitive movements, often involving the face and tongue. This can be irreversible in some cases.
Sedation and Drowsiness:
- Due to histamine receptor antagonism.
Anticholinergic Effects:
- Dry mouth, blurred vision, constipation, and urinary retention.
Weight Gain and Metabolic Effects:
- These side effects can occur, though less common compared to second-generation antipsychotics.
Cardiovascular Effects:
- Orthostatic hypotension: Sudden drop in blood pressure when standing.
- QT interval prolongation: Can lead to arrhythmias.
Neuroleptic Malignant Syndrome (NMS):
- A rare but life-threatening condition characterized by:
  - Hyperthermia
  - Muscle rigidity
  - Altered mental status
  - Autonomic dysregulation (e.g., labile blood pressure, tachycardia)
  - Elevated creatine kinase (CK) levels (muscle damage)

Second-Generation Antipsychotics (SGA) – Atypical Antipsychotics

Mechanism of Action:

Second-generation antipsychotics, or atypical antipsychotics, also block dopamine D2 receptors but with greater selectivity in the mesolimbic system and less effect on the nigrostriatal pathways, reducing the risk of extrapyramidal side effects (EPS).
They also have a stronger effect on serotonin (5-HT2A) receptors, which is believed to contribute to their mood-stabilizing properties and to the reduction of negative symptoms of schizophrenia.

Common Second-Generation Antipsychotics:

Clozapine
Risperidone
Olanzapine
Quetiapine
Aripiprazole
Ziprasidone
Lurasidone

Common Side Effects:

Metabolic Side Effects:
- Weight gain (especially with clozapine and olanzapine)
- Increased risk of diabetes
- Hyperlipidemia (high cholesterol and triglycerides)
- Hypertension
Sedation and Drowsiness:
- Common with drugs like clozapine and quetiapine due to histamine receptor antagonism.
Extrapyramidal Symptoms (EPS):
- Lower incidence than FGAs but can still occur, especially with risperidone and paliperidone.
Cardiovascular Effects:
- Orthostatic hypotension (more common with clozapine and quetiapine).
- QT prolongation (with ziprasidone and clozapine).
Clozapine-Specific Side Effects:
- Agranulocytosis: A rare but serious side effect that involves a dangerously low white blood cell count, requiring regular blood monitoring.
- Severe sedation, dizziness, and orthostatic hypotension.
- Myocarditis and cardiomyopathy in rare cases.
- Seizures: More common with higher doses.
Hyperprolactinemia:
- Elevated levels of prolactin (more common with risperidone), leading to symptoms such as:
  - Galactorrhea (milk production)
  - Amenorrhea (absence of menstruation)
  - Sexual dysfunction
Neuroleptic Malignant Syndrome (NMS):
- Atypical antipsychotics carry a lower risk of NMS compared to first-generation antipsychotics but still pose a risk.
Anticholinergic Effects:
- Generally milder than with FGAs, but still possible with drugs like clozapine.

Key Differences Between First- and Second-Generation Antipsychotics:

Feature	First-Generation Antipsychotics	Second-Generation Antipsychotics
Primary Mechanism	Dopamine D2 receptor antagonism	Dopamine D2 and serotonin 5-HT2A receptor antagonism
Extrapyramidal Side Effects (EPS)	Common (especially in high doses)	Less common, but still possible
Metabolic Side Effects	Less common (except for weight gain in some)	More common (weight gain, diabetes, hyperlipidemia)
Sedation	More pronounced (especially with chlorpromazine)	Variable (quetiapine and clozapine are more sedating)
Risk of Neuroleptic Malignant Syndrome	Higher risk	Lower risk
Other Side Effects	Anticholinergic effects, orthostatic hypotension, QT prolongation	Agranulocytosis (clozapine), hyperprolactinemia, cardiovascular effects

Conclusion:

Both first- and second-generation antipsychotics are effective for treating psychotic disorders like schizophrenia and bipolar disorder, but they differ in their side effect profiles. Second-generation antipsychotics are generally preferred due to their lower risk of extrapyramidal side effects and better efficacy for mood symptoms, although they come with metabolic risks that need careful monitoring. First-generation antipsychotics still play a role, especially in cases where second-generation drugs are not effective or are contraindicated.

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