Antipsychotics and Schizophrenia

• Antipsychotics

Objectives of Antipsychotic Medications:

• Describe the characteristics symptoms of schizophrenia and indicate the effects of antipsychotic medications on these symptoms
• Describe the "catecholamine theory" of psychosis
• Explain the proposed mechanisms of action and therapeutic uses of antipsychotic drugs
• Describe the adverse effects of antipsychotic drugs and how to manage them
• Describe the important drug interactions of the antipsychotic agents
• Compare and contrast the mechanisms of action, adverse effects, and efficacy of classical and atypical antipsychotic drugs

Psychosis:

• Schizophrenia, a common type of psychosis, leads to marked thought disturbance
• Schizophrenia affects mood, emotion, behavior, and cognitive processes
• Approximately 1% of the US population has schizophrenia
• Schizophrenia onset typically occurs during adolescence or early adulthood and is often chronic
• Most patients alternate between acute psychotic episodes and stable phases with full or partial remission
• An estimated ~1/3 of homeless single adults suffer from severe mental illness, largely schizophrenia

Positive and Negative Symptoms of Psychosis:

• Positive symptoms include delusions, hallucinations, agitation, and insomnia
• Negative symptoms include restricted range of emotional expression (affective flattening), poverty of speech (alogia), lack of pleasure (anhedonia), apathy (avolition), social isolation, and catatonia
• Positive symptoms respond better to antipsychotics

Etiology of Psychosis:

• Organic psychoses are associated with definable toxic, metabolic, or neuropathologic changes
• "Psychotomimetics" or drug-induced substances produce a psychotic-like syndrome
• Cocaine and Amphetamines leads to excessive dopamine
• LSD is an agonist at 5-HT2 receptors
• PCP blocks NMDA receptors

Dopamine Hypothesis of Schizophrenia:

• Psychosis results from excessive dopamine activity in the brain, particularly in the mesocortical and mesolimbic pathways
• The mesocortical pathway goes from the VTA to the cerebral cortex
• The mesolimbic pathway goes from the ventral tegmental area (VTA) to the nucleus accumbens and regulates goal-directed and reward behavior

Evidence Supporting the Dopamine Hypothesis:

• Drugs that increase dopaminergic activity like Levodopa, Amphetamines, and Apomorphine aggravate schizophrenia or produce psychosis
• Brains of schizophrenics not treated with antipsychotics show increased dopamine receptor density (post-mortem)
• PET and MRI scans show increased dopamine receptor density in schizophrenics (treated and non-treated compared to non-schizophrenics)
• Potency of antipsychotic drugs correlates with blocking D2 receptors in mesolimbic and mesocortical pathways

Other Neurotransmitter Systems Implicated in Psychosis:

• Antipsychotic drugs are partially effective or ineffective in some patients
• Antipsychotic drugs immediately block dopamine receptors, but it takes a week or two to reduce psychosis symptoms
• The hypoglutamate hypothesis suggests diminished NMDA activity also plays a role in the disease, and NMDA receptor blockers like PCP produce severe schizophrenia-like symptoms
• Newer antipsychotic drugs block slightly less dopamine in the brain than older drugs while also affecting serotonin (5-HT2), cholinergic, histaminergic, and GABA function

Classes of Antipsychotics:

• Classic "typical” antipsychotics
• Atypical antipsychotics

Typical Antipsychotic Agents

• Phenothiazines include Chlorpromazine (Thorazine), which was introduced in the 1950s as a prototype, Thioridazine (Mellaril), and Fluphenazine (Prolixin)
• Thioxanthenes: Thiothixene (Navane)
• Butyrophenones: Haloperidol (Haldol)
• Dihydroindolone: Molindone (Moban)
• Dibenzoxazepines: Loxapine (Adasuve)

Pharmacology of Chlorpromazine:

• Chlorpromazine is a non-selective drug, and has many adverse effects
• It binds to α1-adrenergic receptors, H1-histamine receptors, 5-HT2-serotonin receptors, D2-dopamine receptors, mAChRs, α2-adrenoceptors and interferes with NE and DA reuptake

Pharmacokinetics of Antipsychotics

• Absorption is erratic and unpredictable after oral administration
• Parenteral doses are typically much lower than oral doses
• Metabolism is complex and complete, with some active metabolites formed, such as Thioridazine becoming mesoridazine
• Elimination half-life ( T_{1/2} ) is 10-20 hours
• Decanoate esters like Fluphenazine and Haloperidol provide effects for two to four weeks
• Tranquilization effects are seen quickly
• Antipsychotic onset is variable, taking days to weeks, but improvements are often seen in the first week of treatment with more improvements in following weeks

Acute Adverse Effects from DA Receptor Blockade:

• Acute Dystonia: Abnormal muscle tension and spasms of the tongue, face, neck, and back occur within 4 hours and are treated with mAChR blockers such as Benztropine
• Akinesia (Pseudo-Parkinsonism): Bradykinesia, rigidity, tremor, mask faces, and shuffling gait onset occurs within 4 days and are treated with mAChR blockers
• Akathisia: Motor restlessness without anxiety or agitation can occur within 4 weeks can be treated with a reduced dose, change of medicine or mAChR blockers or Benzodiazepines medicines

Chronic Adverse Effects from DA Receptor Blockade:

• Tardive dyskinesia involves repetitive, involuntary, purposeless movements such as grimacing, tongue protrusion, lip smacking, and rapid eye blinking, develops over the course of months to years and worsens after medicine withdrawal
• Perioral tremor presents as a "rabbit" syndrome with a time of months to years and may be helped by mAChR blockers,

Vesicular Monoamine Transporter Type 2 (VMAT2) Inhibitors

• Valbenazine (Ingrezza) and Deutetrabenazine (Austedo) are VMAT2 inhibitors
• They have been approved for the treatment of tardive dyskinesia
• These medications are thought to work on the principle that tardive dyskinesia results from post-synaptic dopamine hypersensitivity
• These drugs inhibit the VMAT2 transporter to reversibly deplete dopamine stores
• They are more selective for dopamine than other monoamines
• Of patients tested, 40-60% showed improvements in their tardive dyskinesia, using these medications:
• Most common side effects include fatigue, somnolence, and headaches
• GI side effects and akathisia also have been reported
• Less commonly, there is QT prolongation

Neuroleptic Malignant Syndrome (NMS):

• This is a rare dose-independent disorder that may develop within hours of exposure to a drug because of an excessive decrease in dopaminergic transmission
• Main characteristics are hyperpyrexia, muscle rigidity, and autonomic dysfunction
• Death occurs unless treated
• Treatments include Diazepam to relax muscles, the enhancement of DA transmission (Amantadine, levodopa, or bromocriptine), and Dantrolene, which blocks ryanodine receptors to decrease Ca2+ release from the sarcoplasmic reticulum in skeletal muscle

Other Adverse Effects from DA Receptor Blockade:

• Hyperprolactinemia occurs due to the blockade of DA receptors in the pituitary
• Dopaminergic projections in the tuberoinfundibular system project from the hypothalamus to the anterior pituitary and inhibit prolactin release
• The effects of hyperprolactinemia include galactorrhea (inappropriate milk secretion), amenorrhea, infertility, impotence, and loss of libido
• Weight gain (metabolic syndrome) results from blocking inhibitory D2 receptors in the pancreas, causing increased release of insulin and glucagon

Adverse Effects Due to Non-DA Receptors:

• ( \alpha_1 ) adrenoceptor blockade leads to orthostatic hypotension, dizziness, reflex tachycardia, and impaired ejaculation
• H1 blockade causes drowsiness
• H1 and 5-HT2 block lead to weight gain and increased appetite from blocking receptors in the hypothalamus
• mAChR blockade results in dry mouth, urinary retention, blurred vision, constipation, and confusion
• Ocular deposits can occur such as corneal deposits with chlorpromazine and retinal deposits with thioridazine

Acute Poisoning:

• Poisoning is seldom fatal
• Usually, drowsiness progresses to coma, and convulsions may occur
• Exceptions include Thioridazine and mesoridazine, which can produce life-threatening ventricular tachyarrhythmias, and a prolonged Q-T interval apparently by blocking K+ channels

Drug Interactions of Antipsychotics:

• Pharmacodynamic additive effects occur with sedatives (ethanol, opiates, barbiturates), mAChR blockers, ( \alpha_1 )-adrenergic blockers, and antihistamines

Atypical Antipsychotics:

• Examples of atypical antipsychotics include Clozapine (Clozaril), Olanzapine (Zyprexa), Risperidone (Risperdal), Aripiprazole (Abilify), Brexpiprazole (Rexulti), Cariprazine (Vraylar), Lurasidone (Latuda), Quetiapine (Seroquel), and Ziprasidone (Risperdal)
• These are very effective antipsychotics that are atypical because
• They have less affinity for D2 dopamine receptors
• They produce less EPS and other side effects, with a low to absent risk of tardive dyskinesia
• They may produce effects through blocking 5-HT2A, ( \alpha_2 ), or histamine receptors, as well as acting as partial agonists at the 5-HT1A receptor
• Clozapine and Olanzapine are better at treating negative symptoms than Haloperidol

Toxicities of Atypical Antipsychotics:

• Agranulocytosis can occur, especially with clozapine (2%), which requires mandatory weekly blood counts, this medicine is a reserver for "treatment resistant cases"
• Increased cases of de novo Seizures (2-5%) with clozapine
• Some medicines are associated with large increases in weight and lipids
• Aripiprazole (Abilify) blocks 5-HT2A receptors and acts as a partial agonist at D2 receptors and has the least side effects

Comparison of Antipsychotics:

• See chart in provided document

Therapeutic Uses of Antipsychotics:

• They improve positive symptoms, such as tension, hyperactivity, combativeness, hostility, negativism, hallucinations, delusions, insomnia, poor self-care, and anorexia; atypical antipsychotics improve positive and negative symptoms

Other Therapeutic Uses of Antipsychotics:

• Other neuropsychiatric diseases include Tourette's syndrome (Haloperidol), mania episodes of bipolar disorder (olanzapine and risperidone), bipolar depression, obsessive-compulsive disorder (olanzapine), anxiety disorder (olanzapine), and depression (olanzapine)
• They can reduce the risk of suicide (clozapine)
• As an antiemetic, it is useful through Dopamine receptor blockade in the chemoreceptor trigger zone of the medulla & in the stomach
• Relief of pruritus is seen via H1 blockade
• They can be used in neuroleptanesthesia along with Droperidol + fentanyl (opioid) + nitrous oxide and it is used for uncontrollable hiccups

Recurrence of Psychotic Symptoms:

• Recurrence is highly variable after discontinuing antipsychotic drugs
• The average time for relapse in stable patients with schizophrenia who discontinue their medication is 6 months
• Clozapine is an exception because relapse after discontinuation is usually rapid and severe

Treatment of Psychotic Symptoms in Parkinson’s Disease:

• Pimavanserin (Nuplazid) reduces visual hallucinations and delusions
• It functions as an antagonist/inverse agonist at serotonin 5HT2A receptors and has less potent antagonist/inverse agonist actions at 5HT2C receptors
• This is not a dopamine antagonist and not associated with EPS
• Side effects may include peripheral edema, confusional state, hallucinations, constipation, nausea and gait disturbances)

Xanomeline and Trospium Chloride (Cobenfy):

• The first drug for schizophrenia does not target the D2 dopamine receptor (2024)
• There is a significant reduction in positive symptoms
• Xanomeline is an M1/M4 muscarinic agonist
• It activates muscarinic receptors in the brain to decrease acetylcholine release in the VTA, leading to reduced dopamine release in areas associated with psychosis
• Trospium chloride is A peripheral muscarinic antagonist, it has several benefits:
  • It reduces adverse effects like nausea and vomiting in the periphery
  • It is a Quaternary amine so has limited CNS penetration
• It reduces positive psychotic symptoms with less weight gain, movement disorders, and drowsiness than traditional antipsychotic medications
• Some adverse effects may include nausea, indigestion, constipation, vomiting, abdominal pain, diarrhea, GERD, tachycardia, hypertension, and dizziness

Glutamatergic Antipsychotics:

• The bitopertin is a glycine transporter 1 inhibitor (GlyT1)
• Glycine is a required co-agonist with glutamate at NMDA receptors
• Phase 2 studies using bitopertin adjunctively with standard antipsychotics significantly improved negative symptoms of schizophrenia
• The hypothesis is that patients with schizophrenia, the glycine site of the NMDA receptor is not fully saturated