Antipsychotics and Dopamine Pathways
Anti-psychotics (Neuroleptics)
PED2006: Systems Pharmacology, Lecture 11, Dr Christina Elliott (christina.elliott@ncl.ac.uk)
Focus on dopamine
Aims/ILOs
Understand the main dopamine pathways in the brain.
Grasp the basis for the dopamine theory of psychosis.
Know the proposed mechanism of action of antipsychotics.
Recognize the side effects of antipsychotics.
Differentiate between typical and atypical antipsychotics.
Psychosis
Psychosis is a thought disorder characterized by:
Disturbances of reality and perception.
Impaired cognitive functioning.
Inappropriate or diminished mood.
Psychosis encompasses many mental disorders (e.g., dementia, depression, drug use).
Schizophrenia is a specific type of psychosis mainly characterized by:
A clear sensorium.
Marked thinking disturbance.
Schizophrenia
Affects approximately 1% of the population (higher incidence in males).
Onset typically occurs in adolescence, often with prodromal symptoms beforehand.
Likely represents an umbrella term for multiple diseases.
Considered a developmental disorder with early changes.
Two-hit hypothesis model.
Treatment involves long-term neuroleptics and episodic interventions.
Recent genetic studies (genome-wide association studies) are generating new hypotheses regarding its etiology, such as neuroinflammation.
Symptoms of Schizophrenia
Positive Symptoms:
Hallucinations.
Delusions.
Disorganized thoughts.
Grossly disorganized speech.
Catatonia or abnormality in movements.
Negative Symptoms:
Alogia (poverty of speech).
Affective flattening.
Avolition (lack of motivation).
Anhedonia (inability to experience pleasure).
Asociality (lack of social interaction).
Cognitive Symptoms:
Poor memory.
Difficulty in decision making.
Poor judgment & insight.
Poor concentration and attention.
Impaired sensory perception.
Drugs That Can Induce Psychosis
Levodopa.
CNS stimulants.
Cocaine.
Amphetamines.
Khat (cathinone, methcathinone).
Apomorphine.
Phencyclidine (PCP).
All listed drugs increase dopamine levels, while antipsychotics act as D_2 receptor antagonists.
The Dopamine Hypothesis for Schizophrenia
Mesolimbic pathway: implicated in positive symptoms.
Mesocortical pathway: implicated in negative symptoms.
Nigrostriatal pathway: associated with side effects.
Tuberoinfundibular pathway: associated with side effects.
The hypothesis, while compelling, is considered an oversimplification, suggesting that schizophrenia results from an overactive dopamine system in the brain.
Neurotransmitters in Schizophrenia
Dopamine: associated with positive symptoms.
Serotonin: associated with negative symptoms.
Glutamate, GABA, Acetylcholine, and Inflammation are also implicated in cognitive symptoms.
Dopamine Receptors
5 different subtypes of dopamine receptors.
D1 "like" (D1 and D5): G protein-coupled (Gα_s), stimulate adenylyl cyclase.
D2 "like" (D2, D3, D4): G protein-coupled (Gα_{i/o}), inhibit adenylyl cyclase, located pre- and postsynaptically.
Dopamin receptor tissue expression
D1
Substantia nigra
Nucleus accumbens
Olfactory bulb
Lower levels: Cerebellum, Hippocampus, Thalamus, Kidney
Gas coupled
D5
Substantia nigra
Hypothalamus
Kidney
Heart
Sympathetic ganglia
D2
Substantia nigra
Nucleus accumbens
Ventral tegmental area
Lower levels: Heart, Blood vessels, Adrenal glands, Sympathetic ganglia
Gai/o coupled
D3
Olfactory bulb
Nucleus accumbens
Heart
D4
Blood vessels
Substantia nigra
Hippocampus
Amygdala
Gastrointestinal tract
First Generation Anti-psychotics (Typical)
Chlorpromazine (1955) was the first antipsychotic discovered.
D_2 receptor antagonist (high-affinity), with some antimuscarinic effects.
Used in managing schizophrenia, psychoses, mania, severe anxiety, and nausea/vomiting in terminal illness.
Side effects include muscle spasms, restlessness, and agitation.
Other typical antipsychotics: benperidol, flupentixol, and haloperidol.
Antipsychotics: Mode of Action - Typical
All neuroleptics reduce dopaminergic neurotransmission.
Affinity of antipsychotics for dopamine D_2 receptors (particularly) correlates with therapeutic efficacy.
Antipsychotic drugs block D_2 receptors in limbic/cortical areas.
Second Generation Anti-psychotics (Atypical)
Differ from typical antipsychotics by:
Acting as Dopamine-serotonin receptors antagonists (5HT1A agonist, high dissociation from D_2).
Examples: amisulpride, olanzapine, risperidone, and clozapine.
May be more effective but are associated with greater side effects.
Have a higher propensity for metabolic adverse effects (weight gain, diabetes risk).
Second Generation Anti-psychotics (Atypical)
Atypical antipsychotics often act on serotonin receptors in addition to dopamine receptors.
Examples include amisulpride, olanzapine, risperidone, and clozapine.
Atypical antipsychotics may be more effective, but are associated with greater side effects.
They have a higher propensity for metabolic adverse effects (weight gain, diabetes risk).
Response Prediction
Response to antipsychotics is predicted by D2 occupancy. Responders typically exhibit greater than 65% striatal D2 occupancy.
D_2 Selectivity of Anti-psychotics
Various antipsychotics, including Cariprazine, Blonanserin, Brexpiprazole, Asenapine, Paliperidone, Aripiprazole, Risperidone, Ziprasidone, Iloperidone, Lurasidone, Olanzapine, Clozapine, and Quetiapine, exhibit varying binding affinities for D_3 compared to Dopamine (DA).
Affinity of Dopamine Receptors & Clinical Potency
The affinity of dopamine receptors, specifically the D_2 receptor, is related to the clinical potency of antipsychotics.
Summary of Antipsychotics
1st Generation (Typical):
MOA: D_2 antagonism.
Other effects: Antagonism of M1, H1, and alpha-1 receptors (among others).
2nd Generation (Atypical):
MOA: 5-HT2A/D2 antagonism, rapid D2 dissociation, 5-HT1A agonism.
Other effects: Antagonism of M1, H1, 5-HT2C, alpha-1 receptors (among others).
SDA-Type and MARTA-Type Antipsychotics
SDA (Serotonin-Dopamine Antagonists):
Risperidone: 5-HT2 > α1 > D_2 = 5-HT7 = H1.
Perospirone: 5-HT2 > D_2 5-HT1A
Lurasidone: 5-HT7 > 5-HT2 = D_2 > 5-HT1A α2c.
MARTA (Multi-Acting Receptor Targeted Agents):
Clozapine: H1 > mACh > 5-HT2 = 5-HT a1 = 0 > D_2 = 5-HT1A.
Olanzapine: mACh = 5-HT2 H1> 5-HT > D_2 = α1.
Quetiapine: H1 =α1> 5-HT2 > D_2.
D2 Partial Agonist: Aripiprazole (D2> 5-HT1A > 5-HT2).
Neurotransmitter Cross-Talk
Psychotic State: Increased limbic dopamine (DA) activity, altered limbic glutamate (GLU) and limbic GABA activity.
Non-Psychotic State: Balanced limbic DA, GLU, and GABA activity.
NMDA receptor and GABA receptor involvement. GLU -> GABA interaction. Phencyclidine and ketamine disrupt this balance.
Dopamine's role: DA -> mesolimbic dopamine pathway -> increases DA.
Disruption of Dopamine Pathways
Mesocortical Pathway Disruption:
Negative symptoms.
Cognitive impairment.
Depression.
Hypothalamic Disruption:
Prolactin elevation.
Amenorrhea.
Galactorrhea.
Sexual dysfunction.
Nigrostriatal Pathway Disruption:
Dystonia.
Akinesia.
Rigidity.
Tremor.
Dyskinesia.
Mesolimbic Pathway Disruption:
Agitation, psychosis, mania.
Disorganization.
Thrill/drug seeking.
Antipsychotic Classification
Originally based on side effect profiles.
Phenothiazines: Chlorpromazine (group I), Thioridazine (group II), Fluphenazine (group III).
Side effect profile: Group I (sedation, H1 receptor), group II (anti-cholinergic), group III (EPS).
EPS = extrapyramidal side effects.
Extrapyramidal Side Effects of Antipsychotics
Extrapyramidal symptoms (EPS) are associated with the extrapyramidal system in the brain’s cerebral cortex.
Parkinsonism & Dystonia
Tardive dyskinesia
Akathisia – an inability to remain physically still.
Neuroleptic Malignant syndrome – fever, autonomic instability.
D_2 Occupancy and EPS
D_2 receptor occupancy predicts the occurrence of EPS. Signs of motor EPS begin at a certain dose/receptor occupancy level.
Effectiveness of Treatment
Effectiveness = efficacy + tolerability + compliance
Efficacy is the most important factor.
Side Effects of Antipsychotics
Tolerability:
Nuisance (patient comfort) vs life-threatening.
Often time-limited and easily managed.
Examples: Mild-moderate EPS, prolactin elevation, sexual dysfunction, sedation.
Mixed Safety & Tolerability:
Akathisia, weight gain, metabolic risk factors.
Safety:
Life-threatening side effects.
Acute or chronic cardiovascular disease, metabolic syndrome, diabetes, NMS, laryngospasm.
Barriers to Medication Adherence
Stigma, adverse drug reactions, homelessness/substance abuse, forgetfulness, lack of social support, fear of medication, denial of illness, lack of trust in provider, difficulty with regimen.
Side Effect Summary
D_2 mediated nigrostriatal pathway: Extrapyramidal symptoms (Parkinson’s syndrome, Tardive dyskinesia).
D_2 mediated hypothalamic/pituitary pathway: galactorrhea.
H1 mediated: Sedation.
M1 mediated: dry mouth, blurred vision, constipation.
α1 mediated: postural hypotension.
Dopamine/Drug Action Summary
Antipsychotics block dopamine receptors and sometimes serotonin receptors in the nervous system.
Dopamine impacts mesolimbic, mesocortical, nigrostriatal, & tuberoinfundibular pathways.
Antipsychotics manage mental illnesses like schizophrenia, bipolar disorder, and psychosis.
Positive symptoms of psychosis: Hallucinations, delusions, & disorganized thought.
Negative symptoms of psychosis: Lack of emotionality, social withdrawal, & lack of motivation.
Typical (1st Generation) are not selective to D_2 receptors in the mesolimbic pathway, worsening negative symptoms.
Atypical (2nd Generation) block both D_2 receptors & serotonin 5-HT2A receptors, improving negative symptoms.
Side effects vary by generation and potency.
High-potency, 1st generation: Extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome.
Low-potency, 1st generation: Constipation, dizziness, dry mouth, sedation.
2nd generation: Weight gain, drug-induced type 2 diabetes, tiredness.
Dopamine Receptors
D1-like family: Adenyl cyclase ↑. Selective Antagonists: SCH 23390, SCH 39166, SKF83566. Selective Agonists: A 77636, SKF 38393, SKF 81297, Dihydrexidine
D2-like family: Adenyl cyclase↓. Selective Antagonists: Domperidone, Nemonapride, Raclopride, Sulpiride. Selective Agonists: PHNO, Quinpirole, N-0437
Localisation of different D receptors:
D1: Caudate/putamen, Nucleus accumbens, Olfatory tubercule, Hypothalamus, Thalamus, Frontal cortex
D5: Hyppocampus, Thalamus, Lateral mamillary Nucleus, Striatum, Cerebral cortex
D2: Caudate/putamen, Nucleus accumbens, Olfatory tubercule, Cerebral cortex
D3: Nucleus accumbens, Olfatory tubercule, Islands of Calleja, Putamen, Cerebral cortex
D4: Frontal cortex, Midbrain, Amygdala, Hippocampus, Hypothalamus, Medulla, Retina
Anti-psychotics (Neuroleptics)
PED2006: Systems Pharmacology, Lecture 11, Dr Christina Elliott (christina.elliott@ncl.ac.uk)
Focus on dopamine
Antipsychotics, also known as neuroleptics, are a class of medication primarily used to manage psychosis, including schizophrenia, bipolar disorder, and psychotic depression. They work by modulating neurotransmitter activity in the brain.
Aims/ILOs
Understand the main dopamine pathways in the brain.
Grasp the basis for the dopamine theory of psychosis.
Know the proposed mechanism of action of antipsychotics.
Recognize the side effects of antipsychotics.
Differentiate between typical and atypical antipsychotics.
Psychosis
Psychosis is a complex mental condition characterized by:
Disturbances of reality and perception, such as hallucinations and delusions.
Impaired cognitive functioning, affecting memory, attention, and executive functions.
Inappropriate or diminished mood, including emotional blunting or exaggerated emotional responses.
Psychosis encompasses many mental disorders (e.g., dementia, depression, drug use). It can be triggered by various factors, including:
Neurodegenerative diseases like Alzheimer's and Parkinson's.
Mood disorders such as major depressive disorder and bipolar disorder.
Substance-induced psychosis due to drugs like alcohol, cannabis, or stimulants.
Schizophrenia is a specific type of psychosis mainly characterized by:
A clear sensorium (intact sensory and cognitive functions).
Marked thinking disturbance, including disorganized thoughts and speech.
Schizophrenia is diagnosed based on specific criteria outlined in the DSM-5, including the presence of positive and negative symptoms for a significant portion of time during a one-month period.
Schizophrenia
Affects approximately 1% of the population (higher incidence in males).
Onset typically occurs in adolescence, often with prodromal symptoms beforehand. The prodromal phase may include:
Social withdrawal
Unusual perceptual experiences
Decline in academic or occupational performance
Likely represents an umbrella term for multiple diseases, suggesting heterogeneity in its etiology and presentation.
Considered a developmental disorder with early changes, implying disruptions in brain development from early stages of life.
Two-hit hypothesis model, which posits that genetic vulnerability combined with environmental factors leads to the manifestation of the disease.
Treatment involves long-term neuroleptics and episodic interventions, including:
Psychotherapy
Social support
Rehabilitation programs
Recent genetic studies (genome-wide association studies) are generating new hypotheses regarding its etiology, such as neuroinflammation.
Symptoms of Schizophrenia
Positive Symptoms: These are the "added" symptoms not typically present in healthy individuals:
Hallucinations: Sensory perceptions without external stimuli, such as auditory or visual hallucinations.
Delusions: Fixed, false beliefs that are not amenable to change in light of conflicting evidence.
Disorganized thoughts: Incoherence and difficulty organizing thoughts, often manifested as disorganized speech.
Grossly disorganized speech: Derailment, tangentiality, or incoherence in speech patterns.
Catatonia or abnormality in movements: Abnormal motor behavior, ranging from agitation to complete immobility.
Negative Symptoms: These reflect a "deficit" or reduction in normal functions:
Alogia (poverty of speech): Reduced speech output or content.
Affective flattening: Reduction in emotional expression, such as a flat or blunted affect.
Avolition (lack of motivation): Decrease in goal-directed behavior and motivation.
Anhedonia (inability to experience pleasure): Difficulty experiencing pleasure from normally enjoyable activities.
Asociality (lack of social interaction): Reduced social interaction and interest in relationships.
Cognitive Symptoms: These impact cognitive abilities and are often subtle but significant:
Poor memory: Difficulties with working memory, episodic memory, and attention.
Difficulty in decision making: Impaired executive functions affecting the ability to make sound judgments.
Poor judgment & insight: Reduced awareness of one's own mental state and illness.
Poor concentration and attention: Inability to sustain attention and focus on tasks.
Impaired sensory perception: Difficulties processing sensory information, leading to distortions or misinterpretations.
Drugs That Can Induce Psychosis
Levodopa: Used in Parkinson's disease, can increase dopamine levels and induce psychosis.
CNS stimulants: Increase dopamine and norepinephrine, leading to psychosis in vulnerable individuals.
Cocaine: Blocks dopamine reuptake, causing increased dopamine levels and potential psychosis.
Amphetamines: Increase dopamine release and block reuptake, leading to psychosis with chronic use.
Khat (cathinone, methcathinone): Stimulant drugs that increase dopamine release and can induce psychosis.
Apomorphine: Dopamine receptor agonist, can induce psychosis in susceptible individuals.
Phencyclidine (PCP): NMDA receptor antagonist, can produce dissociative and psychotic symptoms.
All listed drugs increase dopamine levels, while antipsychotics act as D_2 receptor antagonists.
The Dopamine Hypothesis for Schizophrenia
Mesolimbic pathway: implicated in positive symptoms. Increased dopamine activity in this pathway is associated with hallucinations and delusions.
Mesocortical pathway: implicated in negative symptoms. Reduced dopamine activity in this pathway is linked to affective flattening and avolition.
Nigrostriatal pathway: associated with side effects, particularly extrapyramidal symptoms (EPS) due to dopamine blockade.
Tuberoinfundibular pathway: associated with side effects, such as hyperprolactinemia, due to dopamine blockade.
The hypothesis, while compelling, is considered an oversimplification, suggesting that schizophrenia results from an overactive dopamine system in the brain. Other neurotransmitter systems and neural circuits are also involved.
Neurotransmitters in Schizophrenia
Dopamine: associated with positive symptoms. Imbalances in dopamine neurotransmission are central to the dopamine hypothesis.
Serotonin: associated with negative symptoms. Serotonin modulation can affect mood, cognition, and social behavior.
Glutamate, GABA, Acetylcholine, and Inflammation are also implicated in cognitive symptoms. These neurotransmitters and inflammatory processes play a role in the broader pathophysiology of schizophrenia.
Dopamine Receptors
5 different subtypes of dopamine receptors.
D1 "like" (D1 and D5): G protein-coupled (Gα_s), stimulate adenylyl cyclase, leading to increased cAMP production.
D2 "like" (D2, D3, D4): G protein-coupled (Gα_{i/o}), inhibit adenylyl cyclase, reducing cAMP production, located pre- and postsynaptically. These receptors are key targets for antipsychotic drugs.
Dopamin receptor tissue expression
D1- Substantia nigra
Nucleus accumbens
Olfactory bulb
Lower levels: Cerebellum, Hippocampus, Thalamus, Kidney
Gas coupled
D5- Substantia nigra
Hypothalamus
Kidney
Heart
Sympathetic ganglia
D2- Substantia nigra
Nucleus accumbens
Ventral tegmental area
Lower levels: Heart, Blood vessels, Adrenal glands, Sympathetic ganglia
Gai/o coupled
D3- Olfactory bulb
Nucleus accumbens
Heart
D4- Blood vessels
Substantia nigra
Hippocampus
Amygdala
Gastrointestinal tract
First Generation Anti-psychotics (Typical)
Chlorpromazine (1955) was the first antipsychotic discovered. It was initially used as an antihistamine but was found to have antipsychotic properties.
D_2 receptor antagonist (high-affinity), with some antimuscarinic effects. It blocks dopamine receptors in the brain, reducing dopaminergic neurotransmission.
Used in managing schizophrenia, psychoses, mania, severe anxiety, and nausea/vomiting in terminal illness. Chlorpromazine has a broad range of applications due to its effects on multiple receptor systems.
Side effects include muscle spasms, restlessness, and agitation. These are primarily due to dopamine blockade in the nigrostriatal pathway.
Other typical antipsychotics: benperidol, flupentixol, and haloperidol. These drugs also primarily act as dopamine D_2 receptor antagonists.
Antipsychotics: Mode of Action - Typical
All neuroleptics reduce dopaminergic neurotransmission. They block dopamine receptors, decreasing dopamine activity in the brain.
Affinity of antipsychotics for dopamine D2 receptors (particularly) correlates with therapeutic efficacy. The higher the affinity for D2 receptors, the more potent the antipsychotic effect.
Antipsychotic drugs block D_2 receptors in limbic/cortical areas. This reduces the positive symptoms of psychosis.
Second Generation Anti-psychotics (Atypical)
Differ from typical antipsychotics by:
Acting as Dopamine-serotonin receptors antagonists (5HT1A agonist, high dissociation from D_2). They modulate both dopamine and serotonin neurotransmission.
Examples: amisulpride, olanzapine, risperidone, and clozapine. These drugs have varying affinities for dopamine and serotonin receptors.
May be more effective but are associated with greater side effects. Atypical antipsychotics can have a different side effect profile compared to typical antipsychotics.
Have a higher propensity for metabolic adverse effects (weight gain, diabetes risk). Regular monitoring of metabolic parameters is important.
Second Generation Anti-psychotics (Atypical)
Atypical antipsychotics often act on serotonin receptors in addition to dopamine receptors. This dual action can improve efficacy and reduce certain side effects.
Examples include amisulpride, olanzapine, risperidone, and clozapine. These drugs have different receptor binding profiles.
Atypical antipsychotics may be more effective but are associated with greater side effects. The choice of antipsychotic should be individualized based on patient characteristics and side effect profiles.
They have a higher propensity for metabolic adverse effects (weight gain, diabetes risk). Monitoring weight, glucose, and lipid levels is crucial.
Response Prediction
Response to antipsychotics is predicted by D2 occupancy. Responders typically exhibit greater than 65% striatal D2 occupancy. PET and SPECT imaging can be used to measure D*2 receptor occupancy.
D_2 Selectivity of Anti-psychotics
Various antipsychotics, including Cariprazine, Blonanserin, Brexpiprazole, Asenapine, Paliperidone, Aripiprazole, Risperidone, Ziprasidone, Iloperidone, Lurasidone, Olanzapine, Clozapine, and Quetiapine, exhibit varying binding affinities for D_3 compared to Dopamine (DA).
Affinity of Dopamine Receptors & Clinical Potency
The affinity of dopamine receptors, specifically the D_2 receptor, is related to the clinical potency of antipsychotics. Higher affinity typically correlates with lower doses needed for efficacy.
Summary of Antipsychotics
1st Generation (Typical):
MOA: D2 antagonism. They primarily block dopamine D2 receptors.
Other effects: Antagonism of M1, H1, and alpha-1 receptors (among others). This can lead to various side effects.
2nd Generation (Atypical):
MOA: 5-HT2A/D2 antagonism, rapid D2 dissociation, 5-HT1A agonism. They modulate both serotonin and dopamine receptors.
Other effects: Antagonism of M1, H1, 5-HT2C, alpha-1 receptors (among others). This can result in a range of side effects.
SDA-Type and MARTA-Type Antipsychotics
SDA (Serotonin-Dopamine Antagonists):
Risperidone: 5-HT2 > α1 > D_2 = 5-HT7 = H1. It has a higher affinity for serotonin receptors compared to dopamine receptors.
Perospirone: 5-HT2 > D_2 5-HT1A
Lurasidone: 5-HT7 > 5-HT2 = D_2 > 5-HT1A α2c.
MARTA (Multi-Acting Receptor Targeted Agents):
Clozapine: H1 > mACh > 5-HT2 = 5-HT a1 = 0 > D_2 = 5-HT1A. It has a complex receptor binding profile.
Olanzapine: mACh = 5-HT2 H1> 5-HT > D_2 = α1.
Quetiapine: H1 =α1> 5-HT2 > D_2.
D2 Partial Agonist: Aripiprazole (D2> 5-HT1A > 5-HT2). It acts as a partial agonist at the D_2 receptor, stabilizing dopamine activity.
Neurotransmitter Cross-Talk
Psychotic State: Increased limbic dopamine (DA) activity, altered limbic glutamate (GLU) and limbic GABA activity. Imbalances in these neurotransmitter systems contribute to psychosis.
Non-Psychotic State: Balanced limbic DA, GLU, and GABA activity. Maintaining balance is crucial for mental health.
NMDA receptor and GABA receptor involvement. GLU -> GABA interaction. Phencyclidine and ketamine disrupt this balance. These drugs can induce psychosis by disrupting glutamate and GABA neurotransmission.
Dopamine's role: DA -> mesolimbic dopamine pathway -> increases DA.
Disruption of Dopamine Pathways
Mesocortical Pathway Disruption:
Negative symptoms
Cognitive impairment
Depression
Hypothalamic Disruption:
Prolactin elevation
Amenorrhea
Galactorrhea
Sexual dysfunction
Nigrostriatal Pathway Disruption:
Dystonia
Akinesia
Rigidity
Tremor
Dyskinesia
Mesolimbic Pathway Disruption:
Agitation, psychosis, mania
Disorganization
Thrill/drug seeking
Antipsychotic Classification
Originally based on side effect profiles.
Phenothiazines: Chlorpromazine (group I), Thioridazine (group II), Fluphenazine (group III).
Side effect profile: Group I (sedation, H1 receptor), group II (anti-cholinergic), group III (EPS).
EPS = extrapyramidal side effects.
Extrapyramidal Side Effects of Antipsychotics
Extrapyramidal symptoms (EPS) are associated with the extrapyramidal system in the brain’s cerebral cortex.
Parkinsonism & Dystonia
Tardive dyskinesia
Akathisia – an inability to remain physically still.
Neuroleptic Malignant syndrome – fever, autonomic instability.
D_2 Occupancy and EPS
D_2 receptor occupancy predicts the occurrence of EPS. Signs of motor EPS begin at a certain dose/receptor occupancy level.
Effectiveness of Treatment
Effectiveness = efficacy + tolerability + compliance
Efficacy is the most important factor.
Side Effects of Antipsychotics
Tolerability:
Nuisance (patient comfort) vs life-threatening
Often time-limited and easily managed
Examples: Mild-moderate EPS, prolactin elevation, sexual dysfunction, sedation
Mixed Safety & Tolerability: Akathisia, weight gain, metabolic risk factors
Safety:
Life-threatening side effects
Acute or chronic cardiovascular disease, metabolic syndrome, diabetes, NMS, laryngospasm
Barriers to Medication Adherence
Stigma, adverse drug reactions, homelessness/substance abuse, forgetfulness, lack of social support, fear of medication, denial of illness, lack of trust in provider, difficulty with regimen.
Side Effect Summary
D_2 mediated nigrostriatal pathway: Extrapyramidal symptoms (Parkinson’s syndrome, Tardive dyskinesia).
D_2 mediated hypothalamic/pituitary pathway: galactorrhea.
H1 mediated: Sedation.
M1 mediated: dry mouth, blurred vision, constipation.
α1 mediated: postural hypotension.
Dopamine/Drug Action Summary
Antipsychotics block dopamine receptors and sometimes serotonin receptors in the nervous system. This modulation helps manage psychotic symptoms.
Dopamine impacts mesolimbic, mesocortical, nigrostriatal, & tuberoinfundibular pathways. These pathways are critical in the pathophysiology and treatment of psychosis.
Antipsychotics manage mental illnesses like schizophrenia, bipolar disorder, and psychosis. They are essential for symptom management and preventing relapse.
Positive symptoms of psychosis: Hallucinations, delusions, & disorganized thought. These symptoms are often the primary target of antipsychotic treatment.
Negative symptoms of psychosis: Lack of emotionality, social withdrawal, & lack of motivation. Atypical antipsychotics are often used to address these symptoms.
Typical (1st Generation) are not selective to D_2 receptors in the mesolimbic pathway, worsening negative symptoms. These drugs can exacerbate negative symptoms due to their non-selective dopamine blockade.
Atypical (2nd Generation) block both D_2 receptors & serotonin 5-HT2A receptors, improving negative symptoms. This dual action provides a broader therapeutic effect.
Side effects vary by generation and potency.
High-potency, 1st generation: Extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome.
Low-potency, 1st generation: Constipation, dizziness, dry mouth, sedation.
2nd generation: Weight gain, drug-induced type 2 diabetes, tiredness.
Dopamine Receptors
D1-like family: Adenyl cyclase ↑. Selective Antagonists: SCH 23390, SCH 39166, SKF83566. Selective Agonists: A 77636, SKF 38393, SKF 81297, Dihydrexidine
D2-like family: Adenyl cyclase↓. Selective Antagonists: Domperidone, Nemonapride, Raclopride, Sulpiride. Selective Agonists: PHNO, Quinpirole, N-0437
Localisation of different D receptors:
D1: Caudate/putamen, Nucleus accumbens, Olfatory tubercule, Hypothalamus, Thalamus, Frontal cortex
D5: Hyppocampus, Thalamus, Lateral mamillary Nucleus, Striatum, Cerebral cortex
D2: Caudate/putamen, Nucleus accumbens, Olfatory tubercule, Cerebral cortex
D3: Nucleus accumbens, Olfatory tubercule, Islands of Calleja, Putamen, Cerebral cortex
D4: Frontal cortex, Midbrain, Amygdala, Hipp