Comprehensive Study Guide on Antipsychotic Agents and Lithium Pharmacology

Mental Disorders: Definitions and Terminology

• Psychosis: A mental disorder characterized by the disintegration of the personality and a break with reality (loss of contact with reality). It is primarily characterized by the presence of hallucinations and delusional beliefs.

• Neurosis: Refers to any psychological imbalance that causes distress. Unlike psychosis, neurosis does not prevent or affect rational thought. It is typically characterized by phobias, anxiety, and depression.

• Schizophrenia: A specific form of psychosis characterized by a clear sensorium but accompanied by a marked thinking disturbance.

Schizophrenia: Symptomatology and Genetics

• Genetic Predisposition: Schizophrenia has a strong genetic component, specifically involving the gene encoding Neuregulin 1.

• Categorization of Symptoms:

  • Positive Symptoms: Hallucinations and delusions.

  • Negative Symptoms: Characterized by a loss of normal function, including loss of motivation, blunted emotion, or difficulty experiencing pleasure (anhedonia).

  • Cognitive Symptoms: Deficits involving attention and memory.

Pathophysiology of Schizophrenia: Primary Hypotheses

• Dopamine Hypothesis:

  • Schizophrenia is associated with an imbalance or excess of dopamine in the mesolimbic and mesocortical pathways.

  • Positive symptoms (hallucinations/delusions) are linked to the overactivity of dopamine $D_2$ receptors in subcortical areas.

  • Negative and cognitive symptoms are linked to the hypofunction of dopamine $D_1$ receptors in the prefrontal cortex.

  • Supporting Evidence:

    1. Antipsychotic drugs work by blocking postsynaptic $D_2$ receptors.

    2. Drugs that increase dopaminergic activity (e.g., levodopa, amphetamines, and apomorphine) either produce psychosis or aggravate existing schizophrenia.

    3. There is an observed increase in dopamine receptor density in the brains of untreated patients and on PET scans.

    4. There is an increase in homovanillic acid (HVA), which is a metabolite of dopamine.

• Glutamate Theory:

  • Suggests that hypofunction in the N-methyl-D-aspartate (NMDA) receptors contributes to the disorder.

  • An imbalance in glutamate release may lead to excessive excitation in the brain.

  • Evidence: Drugs that block NMDA receptors, such as phencyclidine (PCP) and ketamine, can induce symptoms similar to schizophrenia.

Classification of Antipsychotic Agents

• First Generation (Conventional, Typical, Traditional): Primarily act by competitive blocking of $D_2$ dopamine receptors and are mostly associated with movement disorders.

  • Phenothiazines:

    • Aliphatic: Chlorpromazine.

    • Piperidine: Thioridazine.

    • Piperazine: Trifluoperazine, Fluphenazine, Prochlorperazine.

  • Thioxanthines: Thiothixene.

  • Butyrophenones: Haloperidol, Droperidol, Pimozide.

• Second Generation (Atypical): Exhibit a lower incidence of extrapyramidal symptoms (EPS) but carry a higher risk for metabolic side effects (weight gain, diabetes, hypercholesterolemia). They act on dopamine and serotonin receptors, and may also involve cholinergic, adrenergic, and histaminic receptors.

  • Clozapine, Risperidone, Loxapine, Ziprasidone, Aripiprazole, Olanzapine, Sertindole.

Pharmacokinetics of Antipsychotics

• Absorption and Distribution:

  • Readily absorbed; many drugs undergo significant first-pass metabolism.

  • Highly lipid-soluble and highly protein-bound ($92\% - 99\%$).

  • The high protein binding results in a much longer clinical duration of action.

• Metabolism:

  • Most are completely metabolized via oxidative metabolism.

  • Metabolites are generally of no clinical importance, except for Mesoridazine (the major metabolite of Thioridazine), which is more potent than the parent compound.

Pharmacodynamics and Clinical Effects

• Mechanism of Action:

  • Virtually all agents block $D_2$ dopamine receptors.

  • Some interact with $D_1$ and $D_4$ dopamine receptors, $5HT_{2a}$ and $5HT_{2c}$ serotonergic receptors, and alpha-adrenergic receptors.

• Potency Variations:

  • High Potency: Associated with adverse extrapyramidal symptoms (e.g., Haloperidol).

  • Low Potency: Associated with sedation, hypotension, and autonomic side effects (e.g., Chlorpromazine).

Adverse Effects of Antipsychotic Therapy

• Autonomic Nervous System (ANS):

  • Muscarinic Cholinergic Blockade: Loss of accommodation, dry mouth, difficulty urinating, and constipation.

  • Alpha-adrenoreceptor Blockade: Orthostatic hypotension, impotence, and failure to ejaculate.

• Central Nervous System (CNS):

  • Dopamine Receptor Blockade: Parkinson’s syndrome, akathisia (motor restlessness), and dystonias (sustained muscle contractions leading to twisting/distorted postures).

  • Tardive Dyskinesia: The most important unwanted side effect, characterized by involuntary movements of the tongue, lips, neck, trunk, and limbs. It is caused by the super-sensitivity of dopamine receptors.

  • Toxic Confusional State: Resulting from muscarinic blockade.

• Endocrine Effects:

  • Hyperprolactinemia resulting from dopamine receptor blockade leading to amenorrhea-galactorrhea, infertility, impotence, and loss of libido.

• Cardiovascular (CVS):

  • Prolonged QT interval, specifically associated with Sertindole and Ziprasidone.

• Other Adverse Reactions:

  • Weight Gain: Possibly due to combined $H_1$ and $5-HT$ blockade.

  • Agranulocytosis: An immune reaction specifically linked to Clozapine.

  • Neuroleptic Malignant Syndrome (NMS): Characterized by muscle rigidity, fever, and stress leukocytosis. It is caused by the rapid blockade of postsynaptic dopamine receptors.

Therapeutic Indications

• Psychiatric Indications:

  • Schizophrenia (all reduce positive symptoms; Clozapine reduces negative symptoms).

  • Schizoaffective disorders.

  • Tourette’s Syndrome and Tic syndromes.

  • Disturbed behavior in Alzheimer’s disease.

  • Psychotic depression.

• Non-Psychiatric Indications:

  • Anti-emetic action: Except for Thioridazine.

  • Antipruritic: Phenothiazines like Promethazine.

  • Preoperative sedative: Promethazine.

  • Neuroleptanesthesia: Droperidol.

  • Intractable Hiccups: Chlorpromazine.

  • Chronic pain with severe anxiety: When combined with narcotic analgesics.

Selecting Therapy and Poisoning

• Selection Guide: Selection is based on individual patient response and adverse effect profiles. Older patients often transition from low-potency (Chlorpromazine, Thioridazine) to high-potency (Haloperidol) drugs.

• Poisoning: Rarely fatal, except for Mesoridazine and Thioridazine.

  • Signs and Symptoms: Neuromuscular excitability, convulsions, drowsiness, coma, miosis, decreased deep tendon reflexes, hypotension, and hypothermia.

  • Cardiovascular Crisis: Ventricular tachyarrhythmia (specifically Mesoridazine and Thioridazine).

Lithium and Mood-Stabilizing Drugs

• Lithium: Often called an "anti-manic drug" or "mood-stabilizing agent" due to its ability to prevent mood swings in bipolar affective (manic-depressive) disorder.

• Bipolar Affective Disorder:

  • Defined by cyclic attacks of mania with schizophrenia-like symptoms: grandiosity, bellicosity, paranoid thoughts, and overactivity.

  • Etiology: Unknown; may involve a preponderance of catecholamine-related activity. Genetic studies link it to at least three different chromosomes.

Lithium: Pharmacokinetics and Dosage

• Properties: A small monovalent cation related to sodium.

• Absorption: Virtually complete within $6 - 8$ hours; peak plasma levels occur in $30\text{ mins} - 2\text{ hrs}$.

• Distribution: Distributes in total body water; slow entry into intracellular compartments. Initial volume of distribution is $0.5\,L/kg$, rising to $0.7 - 0.9\,L/kg$. There is no protein binding.

• Excretion: Virtually entirely in urine. Lithium clearance is about $20\%$ of creatinine clearance. Plasma half-life is approximately $20\text{ hours}$.

• Monitoring:

  • Target Plasma Concentration: $0.6 - 1.4\,mEq/L$.

  • Dosage: $0.5\,mEq/kg/d$ in divided doses.

  • Serum levels are measured $10 - 12\text{ hours}$ after the last dose; initial determination occurs $5\text{ days}$ after starting treatment to ensure steady-state.

Lithium: Mechanisms of Action

• Electrolytes and Ion Transport: Lithium can substitute for sodium in generating action potentials. It slows $Li^+ - Na^+$ exchange across the membrane. At therapeutic concentrations ($1\,mmol/l$), it does not significantly affect the $Na^+/K^+$ ATPase pump or $Na^+/Ca^{2+}$ exchange.

• Neurotransmitters: Enhances serotonin actions; affects norepinephrine and dopamine turnover. It blocks the development of dopamine receptor super-sensitivity.

• Inositol Phosphate Depletion (Second Messengers):

  • Lithium inhibits enzymes responsible for recycling membrane phosphoinositides, specifically the conversion of $IP_2$ to $IP_1$ (inositol monophosphate) and $IP_1$ to inositol.

  • This leads to a depletion of phosphatidylinositol-4,5-bisphosphate (PIP2), the precursor of $IP_3$ and DAG.

  • This selectively depresses overactive circuits active in mania.

Adverse Effects and Interactions of Lithium

• Neurologic/Psychiatric: Tremors, motor hyperactivity, aphasia, dysarthria, and choreoathetosis.

• Endocrine: Decreased thyroid function (reversible).

• Renal: Polyuria and polydipsia secondary to loss of responsiveness to ADH (Nephrogenic Diabetes Insipidus). Chronic interstitial nephritis; minimal change glomerulopathy with nephrotic syndrome.

• Edema: Water retention secondary to sodium retention (occurs in $30\%$ of patients).

• Cardiac: Bradycardia-tachycardia ("Sick Sinus") syndrome. Lithium is a definite contraindication as it depresses the sinus node.

• Pregnancy: Transferred via breast milk; causes lethargy, cyanosis, poor suck, abnormal Moro reflex, and hepatomegaly in infants.

• Drug Interactions:

  • Diuretics: Reduce renal clearance by $25\%$.

  • NSAIDs: Reduce renal clearance, except for aspirin or acetaminophen.

  • Neuroleptics: Combined use increases EPS.

Alternative Mood Stabilizers

• Valproate: Used as an antiepileptic with antimanic effects equivalent to lithium. Efficacy is limited only by nausea. Maximum dose is $60\,mg/kg/day$. Recognized as a first-line treatment for mania.

• Carbamazepine: Alternative for acute mania and maintenance ($880 - 1200\,mg/d$). Major adverse effect is blood dyscrasias.

• Lamotrigine: Useful in preventing depression following manic episodes in bipolar disorder.

• Atypical Antipsychotics (e.g., Olanzapine): Approved as anti-manic agents and potential mood stabilizers.