Schizophrenia (SZ) Symptoms

• Schizophrenia (SZ) is a psychiatric disease where important psychological functions are split apart.
• It is a type of psychosis and a chronic condition characterized by episodic relapses.
• SZ does not have a defined or consistent neuropathology, nor a definite genetic cause, as neuropathology and psychological disturbances vary between patients.
• The term "psychosis" refers to a disruption and distortion of thought and perception.
• SZ onset usually occurs in the late teens or early twenties, after puberty and development are complete.
• SZ is considered a developmental disorder caused by maldevelopment during both periods of development.

Three Symptom Categories of SZ

• Positive symptoms
• Negative symptoms
• Cognitive deficits

Positive Symptoms

• Hallucinations
• Delusions
• Paranoia
• Disconnected and illogical speech
• These are symptoms present in patients with SZ, but not seen in healthy individuals.
• The combination of symptoms varies among individuals with SZ.

Negative Symptoms

• Reduced speech
• Flat or inappropriate affect
• Avolition (loss of motivation and initiative)
• Social withdrawal
• Anhedonia (loss of pleasure)
• Lack of personal hygiene
• These are things that healthy individuals do or have, but patients with SZ do not.

Cognitive Deficits

• Impaired working memory
• Impaired executive function
• These deficits are linked to less activity in the prefrontal cortex.

Impaired Working Memory

• Interferes with the ability to function, as working memory is a type of short-term memory mainly located in the prefrontal cortex.

Impaired Executive Function

• Executive function involves the ability to follow and understand societal rules, as well as strategy and planning.
• Dysfunction in executive function in SZ is due to decreased prefrontal cortex activity.

Risk Factors

• Genetics
• Environment, specifically the prenatal environment
• Prenatal environment: SZ is a disorder of brain development, making in-utero development very sensitive.
• Complications during pregnancy or delivery increase the risk of developing SZ.

Neurochemical Basis Hypotheses

• Dopamine (DA) hypothesis
• Glutamate (Glu) hypothesis
• Serotonin hypothesis

DA Hypothesis

• SZ, especially positive symptoms, is due to excessive DA in the brain.
• This is an important rationale for antipsychotic treatment, as all antipsychotics, except one, block D2 receptors.
• Some negative symptoms and cognitive deficits are due to decreased DA function, specifically in the prefrontal cortex.
• There is a positive linear correlation between clinical potency and D2 affinity, meaning that as affinity for the D2 receptor increases, less drug is needed to cause an effect.

Glu Hypothesis

• Glutamate receptors are dysfunctional in SZ.
• No drugs are currently based on this hypothesis.

Serotonin Hypothesis

• Increased serotonin activity is present in SZ.
• Second-generation (SG) antipsychotics block both D2 and 5HT2A receptors.
• Both first-generation (FG) and SG antipsychotics treat positive symptoms, but SG antipsychotics are more effective for negative and cognitive symptoms.

Key DA Pathways

• Nigrostriatal pathway
• Mesolimbic pathway
• Mesocortical pathway
• Tuberoinfundibular (or tuberohypophyseal) pathway

Nigrostriatal Pathway

• Substantia Nigra (SN) sends dopaminergic input to the striatum, modulating movement.
• Associated with motor side effects of antipsychotics.

Mesolimbic Pathway

• Tegmentum (midbrain) to Accumbens (striatum/ventral striatum, limbic areas).
• Increased activity in this pathway is seen in SZ, associated with positive symptoms.

Mesocortical Pathway

• Tegmentum to Cortex.
• Decreased activity in this pathway is seen in SZ, associated with negative symptoms and cognitive deficits.

Tuberoinfundibular Pathway

• Hypothalamus to Pituitary.
• Sends dopaminergic input to the pituitary and is associated with neuroendocrine side effects of antipsychotics.

Important DA Systems

• Ventral Tegmental Area: Mesolimbic and Mesocortical
• Substantia Nigra
• Tuberohypophyseal (Tuberoinfundibular) Pathway

DA Pathway Associations

• Mesolimbic: Increased activity causes positive symptoms.
• Mesocortical: Decreased activity causes negative symptoms and cognitive deficits.
• Nigrostriatal: DA receptor blockade leads to motor side effects
• Tuberoinfundibular: Blockade causes increased prolactin release.

Antipsychotics (APs)

• Typicals (1st generation)
• Atypicals (2nd and 3rd generation)

Typical Antipsychotics

• Phenothiazines: Aliphatic, Piperidine, or Piperazine
• Thioxanthenes
• Butyrophenones

Potency

• Low potency: Aliphatic and Piperidine Phenothiazines
• High potency: Piperazine Phenothiazines, Thioxanthenes, and Butyrophenones

Mechanism of Action

• D2 antagonists that competitively block DA D2 receptors.

Therapeutic Effect

• Relieve positive symptoms.
• When adjusted for potency, all typical antipsychotics have the same efficacy; selection is based on side effect profile.
• Typicals are not effective against negative symptoms.

Therapeutic Effects in Specific Pathways

• Mesolimbic: DA antagonists decrease excessive DA signaling, treating positive symptoms.
• Dorsolateral Prefrontal Cortex (DLPFC) portion of the Mesocortical: Blockade worsens or does not improve negative symptoms due to DA deficiency.
• Ventromedial Prefrontal Cortex (VMPFC) portion of the Mesocortical: Blockade worsens or does not improve negative symptoms due to DA deficiency.

Side Effects

• Due to DA antagonism.
  • Extrapyramidal motor symptoms (EPS)
  • Thermoregulatory effects
  • Endocrine changes (prolactin)
  • Tardive Dyskinesia
• Sedation
• Autonomic side effects

Extrapyramidal Motor Symptoms (EPS)

• Due to blockade of DA signaling in the nigrostriatal pathway, leading to motor side effects.
• In untreated SZ: the nigrostriatal tract is unaffected.
• With Typical APs: DA receptors in the striatum are blocked, decreasing DA signaling and causing EPS.

DA/ACh Balance

• Untreated SZ: DA from nigral neurons inhibits striatal cholinergic interneurons, maintaining normal balance.
• DA antagonists: Block the D2 inhibitor in the striatum, increasing ACh release, which acts at muscarinic receptors causing tremor.
• DA antagonists with muscarinic antagonist: Prevent tremor by blocking muscarinic receptors, without interfering with AP effects.

EPS Side Effects

• Acute Dystonia
• Akinesia/Parkinsonism/Bradykinesia
• Akathisia

Acute Dystonia

• Onset: 1-5 days
• Bizarre contractions of face, trunk, and limbs.
• Cause: Sudden DA/ACh imbalance.
• High-potency typical APs, especially when given parenterally, have a higher risk.

Parkinsonism

• Akinesia/Bradykinesia/Pseudo-Parkinsonism: all refer to PD-like symptoms.
• Onset: 5-30 days
• Difficulty initiating movement, tremor at rest, stooped posture, and drooling.
• Cause: Imbalance between DA/ACh; AP blocks DA in the nigrostriatum.
• Primarily seen with high-potency group due to decreased anticholinergic activity.
• Treatment: Decrease DA blocker dose or use an anticholinergic (e.g., Benztropine).

Akathisia

• Onset: 5-60 days
• Uncontrolled restlessness and fidgeting.
• Cause: DA receptor blockade in the striatum.
• Treatment: Decrease DA blocker dose or use a B-blocker.

Thermoregulatory Effects

• Due to DA antagonism.
• The hypothalamus regulates body temperature via the tuberoinfundibular DA pathway.
• Blockade of DA receptors decreases the body's ability to regulate temperature, often seen in elderly patients in the summer.

Endocrine Effects

• Due to DA antagonism.
• Prolactin release is normally inhibited by DA from the tuberoinfundibular pathway.
• Blockade of DA receptors allows prolactin to be released, leading to gynecomastia and galactorrhea.
• Untreated SZ: The tuberoinfundibular pathway is normal.
• Typical APs: Block DA receptors in the pituitary, removing DA's basal inhibition of prolactin.

Tardive Dyskinesia (TD)

• Involuntary, repetitive movements of the face, tongue, and lips.
• Occurs due to long-term use of DA antagonists, caused by DA receptor supersensitivity and upregulation.
• High potency APs have a higher risk.
• Risk increases with the number of years on therapy.

Management of TD

• Removing, or decreasing, the AP worsens TD.
• Increasing dose only temporarily delays TD.
• Anticholinergics worsen TD.
• The best therapy is to avoid developing TD by reserving long-term therapy for dire cases only.
• VMAT-2 inhibitors can be used to treat TD.

Function of VMAT

• VMAT-2, the most prevalent subtype in the nigrostriatal tract, stores DA in synaptic vesicles, protecting it from metabolism.

VMAT-2 Inhibitors

• Reversible and selective for VMAT-2 in the nigrostriatal tract.
• Names: Tetrabenazine, Deutetrabenazine, Valbenazine
• Deutetrabenazine and Valbenazine are approved for TD.

Tetrabenazine

• VMAT-2 inhibitor, inactive prodrug.
• Used for HD, not TD.
• Decreases DA signaling by inhibiting VMAT-2, preventing storage of DA.
• Carbonyl reductase converts it to 4 enantiomers, with the +B enantiomer having the most affinity and selectivity for VMAT-2.
• All enantiomers are metabolized by CYP2D6.

Deutetrabenazine

• VMAT-2 inhibitor, inactive prodrug.
• Deuterated Tetrabenazine with a longer half-life.
• The same as Tetrabenazine in every other aspect

Valbenazine

• VMAT-2 inhibitor, inactive prodrug.
• Most common agent for TD.
• Valine linked to its +a enantiomer, with the most specificity for VMAT-2.
• Rapidly converted to active compound +a-dihydrotetrabenazine by carbonyl reductase.
• Slow hydrolysis to elimination causes a long half-life.

Sedation

• Due to ability to antagonize H1, a1, and M1 receptors.
• Low-potency groups have a higher risk because they have more affinity for receptors other than D2.
• Sedation subsides in 1-2 weeks, as tolerance develops.

Autonomic Side Effects

• Muscarinic antagonism: Anti-SLUDGE effects
• Alpha blockade: Decreased BP and orthostatic hypotension
  • Low-potency groups have a higher risk because they have less affinity for D2.

Typical AP Names

• Chlorpromazine
• Thioridazine
• Fluphenazine
• Thiothixene
• Haloperidol

Chlorpromazine

• Aliphatic Phenothiazine
• Low potency
• Affinity for a1, H1, and M1: more prone to cause sedation and orthostatic hypotension.

Thioridazine

• Piperidine Phenothiazine
• Low potency

Fluphenazine

• Piperazine Phenothiazine
• High potency
• Decreased risk of sedation and autonomic SEs due to being high potency.
• Relatively high a1 affinity: some orthostatic hypotension.
• Some H1 blockade.
• Very little M1 affinity.

Thiothixene

• Thioxanthine
• High potency

Haloperidol

• Butyrophenone
• High potency
• Less common side effects due to being high potency.
• Less sedating, but still has some sedating effects due to a1 and M1 affinity.
• Some a1 affinity: some orthostatic hypotension.

Atypical Antipsychotics (2nd and 3rd Generation)

• Distinguished from typicals by side effect profile and efficacy.
• Less likely to cause motor side effects and TD.
• Effective at treating negative symptoms.

Receptor Blockade Side Effects

• Dopaminergic (D2): EPS
• Muscarinic (M1): Anticholinergic
• Histamine (H1): Sedating
• Cholinergic (a1): Cardiovascular
• Muscarinic (M2, M4): Cardiovascular

MOA

• Block 5HT-2A in addition to D2: Higher 2A to D2 binding ratio than typicals.

Mesolimbic Pathway

Untreated SZ:

• Excessive DA causes positive symptoms.
• Serotonin stimulates 5HT-2A receptors, stimulating cortical neurons, which release Glu, increasing DA.

Therapy Opportunity

• Blocking 5HT-2A receptors to prevent excessive DA in the mesolimbic pathways.

Effect of Atypical AP

• 2A antagonist blocks 5HT-2A receptor, decreasing activity of cortical (Glu) neurons, decreasing DA in the emotional (ventral) striatum, and decreasing positive symptoms.

Nigrostriatal Tract

Effect of Pure D2 Antagonist

• Serotonin stimulates 5HT-2A receptors on cortical neurons, which stimulate GABAergic SN neurons.
• GABA release inhibits the nigrostriatal tract, decreasing DA and causing drug-induced parkinsonism (DIP).

Therapy Opportunity

• Block 5HT-2A receptors to prevent inhibition of the nigrostriatal tract, decreasing DIP.

Effect of Atypical AP

• 2A antagonist blocks 5HT-2A receptors, inhibiting Glu neurons and preventing GABA release, decreasing inhibition of the nigrostriatal tract.
• This increases DA in motor striatum and decreases the ability of the AP to cause DIP.

Mesocortical Pathway

Untreated SZ

• Decreased DA activity causes negative and cognitive symptoms.

Effect of Untreated SZ (or D2 Antagonism)

• Serotonin stimulates 5HT-2A receptors on cortical neurons.
• Cortex (Glu) neurons release Glu in VTA, which stimulates the release of GABA, which inhibits the mesocortical pathway.
• Low DA in this pathway causes negative and cognitive symptoms.

Therapy Opportunity

• Block 5HT-2A receptors to prevent inhibition of the mesocortical pathway, improving negative and cognitive symptoms.

Effect of Atypical AP

• When SZ is untreated (or when D2 antagonism is occurring):
• 2A antagonist blocks 5HT-2A receptors, inhibiting Glu neurons and preventing GABA release, decreasing inhibition of the mesocortical pathway.
• This increases DA in cortex which improves negative and cognitive symptoms.

Benefits of Blocking 5HT-2A

• Decreased EPS symptoms (motor SEs).
• Decreased TD.
• Effective against negative symptoms.

2nd Generation Atypical AP Names

• Clozapine
• Risperidone
• Olanzapine
• Quetiapine
• Ziprasidone

3rd Generation Atypical AP Names

• Aripiprazole
• Brexpiprazole
• Cariprazine

Clozapine

• D4 blocking in addition to D2 and 5HT-2A.
• Affinity: 5HT-2A > D4 > D2 (dirty drug).
  • Strong antimuscarinic action, but also salivation.
  • Weight gain due to 5HT-2C and H1 blockade.
  • Prolonged QTC.
  • Dose-related seizure risk.
  • Agranulocytosis
  • Few EPS SEs and TD.
  • No effect on prolactin.

Used: For patients that don't respond to typical APs. Used only when other therapies, at least 2 therapy options, fail. Use limited by SEs, especially agranulocytosis.

Olanzapine

• Very similar to Clozapine.
• High 5HT-2A and H1 affinity.
• Weight gain, but no agranulocytosis risk

Side Effects: -Weight gain due to 5HT-2C and H1 blockade. -Sedation

Used: -Oral or injectable.

• Avoid in patients with diabetes due to weight gain.

Quetiapine

• Metabolite; active metabolite binds 5HT-2C (weight gain), metabolite H1 affinity.
  • Not as effective for negative symptoms as other atypicals, but the same efficacy for positive symptoms.
  • Beneficially treats depression Active Metabolite (Norquetiapine):
  • Blocks NE-T, can be used for treatment of depression caused insomnia.

Avoid in patients with diabetes

• Sedation due to H1 receptor blockade.
• Weight gain due to 5HT-2C and H1 blockade.

Used:

• Treats insomnia

Ziprasidone

- Most dopaminergic out of all the atypical

Very "Clean" drug

• Has no effect on weight/ blood glucose "clean" drug.

Contraindicated: -Hx Prolong QT interval/ MI/Arrhythmia: -Can cause QT prolongation and cardiac events

Risperidone

  ( "Most typical of the Atypical")

• Dopaminergic
• Orthostatic hypotension. -Minimal anticholinergic effects

Side effects: -Motor SEs at higher doses.

Can be given as tablet/ inj / Oral

3rd Generation, Atypical, APs ( "-pips and a rip")

• partial agonists with increased 2A over D2
• Minor SEs: headache agitation, anxiety etc... -Weight gain. Have partial agonist activity

Benefits:

1. Can be able to help symptoms in parts of the brain with increased DA. Dec. DA activity in mesolimbic region ( help+ symptom)
2. Can also help alleviate symptoms in parts DA with decreased DA in mesocortical region (+ symptoms )

Aripiprazole

• D2 and D3 receptor partial agonist
• Side effects: -Minor SEs: headache agitation, anxiety etc... 3rd gen atyp.

Brexpiprazole

Partial D2 and partial D3 receptor Side effects: -Weight gain -Akathisia

Cariprazine

• Selective for D3
• less EPS Selectivity for ventral striatum "2 pips and a rip. -3rd gen atyp. Side effects: Weight gain -Akathisia

Pimavanserin (Inverse Agonist - 5HT2A/2C)

• Inverse Agonist

Used:

• Used for rare cases of psychosis caused by parkinsons ""Clean drug""

AP Agent Selection

• Determined mainly by ADRs Typicals/Atypicals have the same efficacy in treating positive symptoms

1st gen AP

-Limited use to EPS/ Endocrine side effects -Atypical

• More effective at targeting Negative and Cognitive symptom -Limited by metabolic effects

First line agent

• Any atypical option (other than clozapine)

Drug - Chem

Ionic bonding in active states

-All Aps contain amine groups ( ionizable @ normal ph)

• The amines give activity and binding activity on transmembranes
• Positively charged amines form a bond with the carboxylate on Asparatine (D2 receptors)

Distrubtion

-Aps must by lipophillic Log P value Lipophillic : > 3 Facilitate across BBB: distribution to CNS

Metabolism:

All heavily metabolized via CYP 450 Substrates: 1A3/ 2D6/ 3A4 Substrates and Inhibitors ( Inducers/ Inhibitors) Some metabolites have activity

Design an antagonist

Design chemicals to mimic the endogenous ligand Mimic DA to treat ( reduce) positive symptoms

Phenothyazine Ring

3 (6- memebers rings, N /S are on the central memberring Structure = Side chain linked to Nitro Alphanumeric ( has low-potency + many SE) Pipperzine (Has hig-potency)

Subsitions to the 10-position

1. Nitrogen side chain: Essential @ N-10 position has Alkyl side chain

2. Side chains must have 3C (between the N @ ring

• Affects binding affinity + selectivity for reception CNS/ PNS

Piperazines rings, can promontent cis to trans (conformatons ) 3) Piperazines increases the ability of conformations to be cis -Ring is preferred N is ionizable, with an ionic bond, Piperazines (N+ is ioniziable)

• 2nd N ( increase binding affinity. over aliphatic ( has only 1 n + ionizing

Halidols:

• Buryophenome: have planer side chain + structure mimimcs structure of DA
• Side effects: + activity: Bind easily receptors with ( non - D2+ H2A)

Substitution @ position 2:

• Ewg ( Electron Withdrawing ( 1)Essential for: Ap activity (Asymmetric favored binding conformations)

2. Halogens ( Cl, F, BR. are used most often

Chlorphromzine- Alliphatic

-Planter structure - Planer structure helps bind ( CNS + recptors

How does theis compete w DA?

• phenothzainze ring + size mimics DA structure
• Cis pheno mimics DA for bindings

How is the affinity and dose correlated

• Affnity corresponds with daily dose Hig affinity -> lower dose
• lower affinity = higher dose" Why increased AD vs non DOM"

1. Higher dose

• increased % of druch available bound
• higher chance the molecules and ( bind 2 receptor +ADR)

What most popular: buyrophenome ( halloperidol) Butyro ( chain 4 C) Phenone ( phenyl ring)

What chrtacertix butyron binding: - similar

Diarylazepines- struct

Planer- Chemistry " "promis" ( CNS Drugs) -Aspenip ring 2 Ary rings SGAPS PIN"ES ( structure) -Decre D-2 binding affinity -less DPEs

• Great binding affinity - Greater affint - HT 5 TH 2c/ 1 H- gain in the weight

Benzi + Benji structures

• 3 rings ( NO +S
• Benji + 5THHTS- ( gain weight an

Less activity -Sedat(

• Les activity- glu increased EPS

Phenylperiazine

Phenyl conects 3rd and 2P2P. RIPPPP Less ES

Long Acting Formulations

• improve adherence for injection

Ester produrgs - with chain to increases SOil Slowly release for oil depot

• Administered VIA IM- No IM or Death

Metabolism

-APS HEAVILY METABOLIZED

• CYP 134 ( heavily meta Inactv Some active SUSCEPT TO AVERSE EVETS from THE 1AB CYp""""

CYP INOS FOR MOTO Inact"

134"