Psychosis Neurotransmitters Theories

• Psychosis involves three major pathways: dopamine, glutamate, and serotonin.

Dopamine Hypothesis

• The original hypothesis suggested that excess dopamine levels, specifically hyperactivity at D2 receptors in the mesolimbic pathway, led to psychosis and positive symptoms like hallucinations and delusions.
• The revised hypothesis proposes that low dopamine levels in the mesocortical pathway contribute to negative symptoms.
• Dopamine is an excitatory neurotransmitter with similar effects to amphetamines.

Glutamate Theory

• Hypofunction of NMDA receptors (glutamate receptors) can cause both positive and negative symptoms of psychosis.
• NMDA receptor dysfunction can cause excessive glutamate production, leading to dopamine overactivity in the mesolimbic area.
• PCP and ketamine are related to this theory.

Serotonin Theory

• Hyperfunction of 5HT2A receptors in the cerebral cortex is linked to psychosis, particularly visual hallucinations, insightfulness, and mystical delusions.
• Downregulation or desensitization of 5HT1A receptors is crucial for antidepressant action.
• 5HT2A receptors regulate three dopamine pathways.
• Direct innervation of the mesolimbic/mesostriatal pathway by 5HT2A receptors leads to positive symptoms.
• Indirect innervation of the nigrostriatal pathway by 5HT2A receptors results in motor side effects.
• Indirect innervation of the mesocortical pathway by 5HT2A receptors causes negative, cognitive, and affective symptoms.
• 5HT2A receptor activity can lead to hyperactive dopamine activity in downstream mesolimbic pathways.
• Serotonin hyperfunctioning at 5HT2A receptors can result from substance abuse, Parkinson's disease, and dementia.
• Substances like LSD, mescaline, and psilocybin can cause 5HT2A agonism, leading to psychosis, dissociation, and visual hallucinations.
• Loss of serotonin nerve terminals in Parkinson's can cause upregulation of 5HT2A receptors in the cortex.
• In dementia, plaques and Lewy bodies can disrupt cortical neurons, leading to a lack of inhibition of glutamate neurons, which overstimulates 5HT2A receptors and causes psychosis.

Dopamine Pathways

• The mesolimbic pathway projects from dopamine cell bodies in the VTA to the nucleus accumbens (NA).
• Dopamine release in the mesolimbic pathway is associated with motivation, pleasure, reward, and reinforcement.
• Excessive dopamine in this pathway is linked to positive symptoms of psychosis and drug-induced highs.
• Deficient dopamine in the mesolimbic pathway is thought to cause negative symptoms of schizophrenia, such as anhedonia, apathy, and anergia.
• The mesostriatal pathway is correlated with hyperdopaminergic states and motor movement (mesoSTRIDEatial).
• Dopamine projects from the substantia nigra to the dorsal striatum to control upper motor movements.
• Excessive dopamine projection from the VTA and substantia nigra can cause positive symptoms.
• Low dopamine levels in the mesocortical pathway are associated with negative symptoms.
• The nigrostriatal pathway controls motor movements and is often affected by medications rather than the underlying pathophysiology of schizophrenia.
• Too little dopamine in the nigrostriatal pathway can cause dystonia, akathisia, and Parkinson's-like movement.
• Too much dopamine in this pathway can lead to hyperkinetic movements like chorea, dyskinesias, and tics.
• Chronic blockade of D2 receptors in the nigrostriatal pathway can cause tardive dyskinesia (TD).
• The nigrostriatal pathway is also thought to be involved in emotional regulation and the pathophysiology of schizophrenia.
• Dopamine normally inhibits prolactin release in the tuberoinfundibular pathway.
• When dopamine is blocked in this pathway, prolactin levels increase.
• This pathway does not have a direct correlation with schizophrenia.
• Symptoms of hyperprolactinemia include gynecomastia, galactorrhea, amenorrhea, oligomenorrhea, sexual dysfunction, and osteoporosis.

Schizophrenia Symptoms

• Positive symptoms include delusions and hallucinations.
• Negative symptoms include alogia, affective flattening/blunting, asociality, anhedonia, and avolition (the 5 A’s).

5HT2A Antagonists and 5HT1A Partial Agonists

• "-pines" are sedating due to alpha 1 adrenergic, H1, and M1 antagonism, and they can cause weight gain because of 5HT2C and H1 antagonism.
• Examples include clozapine (Clozaril), quetiapine (Seroquel), and olanzapine (Zyprexa).

Clozapine (Clozaril)

• It is the first and most effective atypical antipsychotic and can reduce suicide risk.
• It's indicated for treatment-resistant schizophrenia.
• Side effects include drooling, sedation, weight gain, constipation, orthostatic hypotension, hyperglycemia, hyperlipidemia, benign fever, and tachycardia.
• Do not give with Luvox due to risk for toxicity, seizure, death for drug interactions.
• Serious adverse effects: severe neutropenia (agranulocytosis), myocarditis (1st 6wks tx), cardiomyopathy, paralytic ileus, neuroleptic malignant syndrome (NMS), seizure, PE, CVA in elderly causing death
• It is metabolized by CYP1A2, with smoking speeding up metabolism.
• Monitor labs weekly to prevent agranulocytosis.
• Localized atropine drops can decrease drooling.
• Monitor troponin or CRP for risk of myocarditis.
• Requires annual EKG, CBC prior to initiation and q weekly, BMI, fasting triglycerides, Blood Pressure, A1C, LFT.
• It targets positive, negative, cognitive symptoms, unstable mood, suicidal behavior, and aggression.

Olanzapine (Zyprexa)

• It is the second most effective treatment for psychosis and schizophrenia.
• Other clinical indications include bipolar disorder, agitation, BPD, PTSD, and dementia with behavioral disturbances.
• Side effects include weight gain, sedation, and metabolic syndrome.
• Do not give with benzodiazepines due to the risk of extreme sedation and cardio/respiratory depression for drug interactions.
• Serious adverse effects include agranulocytosis (less than clozapine), DKA secondary to hyperglycemia, seizures, NMS.
• It has a rapid onset for targeting positive, negative, cognitive, mood, and aggression.

Quetiapine (Seroquel)

• Its effects are dose-dependent: 800mg is antipsychotic, 300mg is antidepressant, and 50mg is hypnotic.
• It is used for treatment of non-bipolar depression and bipolar depression.
• Side effects include sedation and weight gain, with a low risk for EPS.
• May cause prolonged QTI, dysphagia, priapism, SI.
• It antagonizes levodopa, dopamine agonists, enhances antihypertensives, and increases INR with warfarin.
• It targets positive, negative, cognitive symptoms, mood, anxiety, and insomnia.

Asenapine

• It's the only antipsychotic that is not swallowed (sublingual, buccal, transdermal).
• It is approved for children and adolescents with schizophrenia and bipolar disorder.
• It carries a risk of type 1 hypersensitivity reaction.
• It has less weight gain, sedation, and drug-induced parkinsonism (akthisia).
• Do not give with thioridazine due to the risk of dangerous cardiac arrhythmias.
• Targets positive, negative, cognitive, unstable mood, aggression.

-DONES and a-RONE

• Caplyta, Geodon, and Latuda must be taken with food (Come Get Lunch).

Risperidone (Risperdal)

• Doses less than 6mg are atypical antipsychotic, over 6mg is like 1st generation.
• Over 6mg carries a risk for EPS and TD, elevated prolactin, sedation, and hypotension.
• Fluoxetine and paroxetine co-administration will increase risperidone concentrations.
• Carbamazepine will decrease level of risperidone.
• The drug compound breaks down into paliperidone.

Paliperidone (Invega)

• It is dosed once a day.
• It is metabolized/excreted in kidneys with few drug/drug interactions.
• It can still increase prolactin and cause weight gain.

Lurasidone (Latuda)

• It is prescribed for schizophrenia, bipolar depression, mania, and children with behavioral disturbances.
• Some risk of EPS effects, less sedation and less weight gain.
• Must be taken with 350 calories.
• Monitor for C3A4 inducers and inhibitors.

Ziprasidone (Geodon)

• It has antidepressant actions.
• It is less likely to cause weight gain and sedation.
• Questionable QT prolongation, EPS, sedation.
• Must be taken with 500 calories and given BID.

Lumateperone (Caplyta)

• It blocks serotonin 2A, enhancing dopamine release in certain brain regions.
• Binds to D1 receptors
• It blocks postsynaptic D2 receptors and acts as a partial agonist at presynaptic D2 receptors
• Clinical indications include schizophrenia and bipolar depression.
• It is taken once daily with unspecified calories.
• Sedation, low risk for EPS and prolactin effects.

Two -pips and a -rip

• In general, this class is non-sedating, and it doesn't cause weight gain or prolactin increase (D2 and 5H21a agonist).

Aripiprazole (Abilify)

• Very effective for depression.
• EPS, primarily akathisia, and does not usually cause weight gain or sedation.

Brexpiprazole (Rexulti)

• Schizophrenia, add on for major depressive disorder, reduces positive and negative symptoms.
• Sedation, HA, ketoacidosis, dysphagia.
• If pt is taking ketoconazole give ½ dose; if pt is taking carbamazepine, double Rexulti dose.
• Possible impulse control problem.

Pimavanserin

• Only antipsychotic that doesn't work on dopamine receptors.
• Used for treatment of psychosis related to Parkinson's disease.
• Selective 5HT2A antagonist.

Targeting/Antagonizing D2 Receptors

• Typical antipsychotics = neuroleptics, conventional, and 1st generation.
• Atypical antipsychotics = seratonin-dopamine receptor antagonist, second generation.

MOA of Treating Psychosis

• D2 antagonist

• 5HT2A/D2 antagonist

• D2/5HT1A partial agonist

• 5HT2A antagonist

• For antipsychotic effect 60-80% of D2 must be occupied.

1st gen. Side effects

• EPS, QTc prolongation, parkinson, TD, metabolic syndrome, agranulocytosis, orthostatic hypotension, NMS

2nd gen.

• Lower risk fo EPS and metabolic side effects

Chlorpromazine (Thorazine)

• Many side effects
• Low potency D2 antagonist
• Risk for photosensitivity (phenothiazine class side effect), multiple side effects due to antagonism for so many receptors, pigmentation changes to skin and eyes (skin will turn blue/gray), lowered seizure threshold, priapism, Akathisia, galactorrhea, amenorrhea, decrease sweating, increase risk irreversible TD
• Wt gain, sedation, Rare jaundice, NMS, hperprexia, muscle rigidity, delirium, autonomic instability with elevated creatinine phosphokinase myoglobinuria,AKI, Rhabdomylosis

VMAT 2 inhibitors

• Tetrabenazine (Xenazine)
• FDA indicated to tx Huntington’s Chorea
• Risk for depression and suicide

Deutetrabenazine (Austedo)

• TD and Huntington’s Chorea
• Must be given BID with food (no specific calorie).

Haloperidol (Haldol)

• High potency D2 receptor
• high risk for EPS/TD, prolonged QTc risk (with IV admin).

Perphenazine (Trilafon)

NMS vs SS

• Neuroleptic Malignant Syndrome -Causes: Dopamine Antagonist (occurs within days-weeks of treatment changes--usually within first 7 days) -Symptoms: Severe Rigidity, Hyporeflexia/Bradyreflexia -Treatment: Bromocriptine, stop the antipsychotic, IV benzo (Lorzepam or Diazepam) rarely ECT -** once has resolved start low and go slow, use low potency
• Serotonin Syndrome -Causes: Serotonergic Agents (occurs within 24 hrs rapid onset) -Symptoms: Hyperreflexia (tremor, clonus, reflexes), myoclononus, ocular clonus -Treatment: Cyproheptadine, Benzodiazepine

Monitoring and Testing

• Before and after starting Clozapine:
  • Requires annual EKG, CBC prior to initiation and q weekly, BMI, fasting triglycerides, Blood Pressure, A1C, LFT.

Hyperprolactinemia

• Normally Dopamine inhibits the release of prolactin in the tuberoinfundibular pathway, however when dompamien is blocked like in antipsychotic medications it causes an increase in prolactin
• Symptoms: Gynecomastia, amenorrhea, gynecomastic, sexual dysfunction

Dopamine 2 receptors and long-term side effects

• After chronic treatment of D2 blockers, the D2 receptors in the indirect pathway become more sensitive and sometimes create more receptors all together. Essentially supersensitivity in the nigrostriatal d2 receptors.
• D2 antagonist block DA from inhibiting the stop pathway then the net result is movement are stopped which leads to TD

Major Receptor Sites Affected by Antipsychotics

• 5HTA2
  • Therapeutic effects: reduced EPS
  • Side effects: sexual dysfunction
• 5HT2C
  • Therapeutic effects: unknown
  • Side effects: weight gain
• D2
  • Therapeutic effects: reduction of positive symptoms
  • Side effects: EPS, parkinsonism, akathisia, TD, prolactin secretion, menstrual changed, sexual dysfunction
• M1
  • Reduced EPS
  • Side effects: cant see, can't pee, cant spit, can't shit, urinary retention, tachycardia, memory dysfunction
• A1
  • Therapeutic Effects: unknown
  • Side effects: orthostatic hypotension, dizziness, reflex tachycardia
• H1
  • Therapeutic effects: Sedation
  • Side Effects: over sedation, increased appetite, weight gain, hypotension

Differences Between D2 Antagonists vs D2/5HT2A Antagonists

D2 Antagonism

• high vs low potency
• Potency is not the same as efficacy; it’s about the affinity for receptor

Low Potency

- Drug Names: “everything else” Promethazine, Thioridazine, Prochlorperazine, Molindone, Mesoridazine, Hydroxyzine, Fluphenazine, Chlorpromazine, etc. etc. 
- High histaminic and muscarinic activity
- Increased sedation and anticholinergic effects
- Lowers risk of EPS

High Potency

- Drug Names: Droperidol, Haloperidol, Loxapine, Pimozide, Thiothixene, Trifluoperazine
- Low activity at histamine and muscarinic receptors
- Low sedation, little weight gain, little anticholinergic activity
- High risk for EPS (due to high attraction for dopamine antagonism)

Terminology and Treatment

• Acute Dystonia

  • Clinical Presentation: facial grimacing, involuntary upward eye movement, muscle spasms of the tongue, face, neck and back, laryngeal spasms
  • Onset: hours to days after starting drug (VERY ACUTE)
  • Treatment: IM injection of anticholinergic such as benztropine or benadryl

• Akathisia

  • Clinical Presentation: Subjective: inter restlessness, mental unease (confused with anxiety). Objective: rocking from foot to foot, pacing, marching in place (confused with agitation)
  • Treatment: beta blockers (propanolol), benzos (lorazepam)

• Drug Induced Parkinsonism (Akinesia)

  • Clinical Presentation: bradykinesia (generalized slowing of movement) tremors, rigidity, masked face (expressionless face) shuffling gait,
  • Tx: anticholinergic M1 blockers- Diphenhydramine and Benztropine

• Tardive Dyskinesia

  • Due to chronic blockade of D2 (onset months to years)
  • Clinical Presentation: involuntary continuous movements- Constant chewing, Jaw clenching, Lip smacking/chewing, Tongue protruding, jerking movements of the body
  • Tx: d/c current antipsychotic, no medication can tx this

Explores revised dopamine hypothesis, glutamate theory's connection to dopamine, and serotonin's 5HT2A receptor role in psychosis. Discusses drug evidence, symptom alleviation via 5HT2A targeting, antidepressant actions, and mesolimbic pathway hyperactivity in psychotic symptoms.