NSG 552 Psychopharm Exam 1 Study Guide – Complete Latest 2024/2025

Dopamine belongs to the family of catecholamines. It is a neurotransmitter. • Hormones, Epinephrine and Norepinephrine (other catecholamines) are derived from Dopamine • Dopamine plays a significant role in learning, goal-directed behavior, regulation of hormones, motor control. DOPAMINE SYNTHESIS Phenylalanine (amino acid from diet) - phenyalanine hydroxylase - Tyrosine - Tyrosine hydroxylase - DOPA - Dopa decarboxylase - Dopamine KEY POINT: Dopamine is synthesized directly from tyrosine or indirectly from phenylalanine • Dopamine is packed and stored into synaptic vesicles via the vesicular monoamine transporter (VMAT2) and stored until its release into the synapse. • When dopamine is released during neurotransmission, it acts on 5 types of postsynaptic receptors (D1-D5). • A negative feedback mechanism exists through the presynaptic D2 receptor which regulates the release of dopamine from the presynaptic neuron. • Any excess dopamine is cleared out o Presynaptically by Dopamine transporter (DAT) o VMAT2 will take excess DA and store it in the synaptic vesicles for future neurotransmission • Excess dopamine is broken down within the presynaptic neuron by monoamine oxidase A (MAO-A), MAOB and extracellularly (outside the neuron) by catechol-o methyltransferase (COMT). • All antipsychotic drugs can reduce dopaminergic neurotransmission. DOPAMINE RECEPTORS • Dopamine neurotransmission is perpetuated via G protein-coupled receptors categorized into two broader subtypes • D1 – like family: o Includes subtypes D 1 and D 5 o Activation is coupled to Gs ; activates adenylyl cylcase which leads to increase in concentration of cAMP • D2 – like family: o Includes D 2, D3 and D4 o Activation is coupled to Gi ; inhibits adenylyl cyclase leading to decrease in concentration of cAMP o Also open K channels & closes Ca influx • DAT (dopamine transporter) and VMAT2 are DA receptors that also regulate DA neurotransmission • Presynaptic D2 autoreceptors are “gatekeepers” and provide negative feedback input. When D2 receptors are NOT bound to DA DA release. When D2 receptors bind to DA inhibit DA release o Location: Striatum, substantia nigra, pituitary o Located presynaptic and postsynaptic FGAs and Neurotransmitters • Mesolimbic pathway: involved in pleasure and reward. Blocking D2 in this pathway by FGA’s not only treats positive symptoms, but it blocks the reward mechanism and can cause apathy, lack of motivation, lack of interest and the ability to feel joyful • Negative symptoms of psychosis are due to low dopamine in the mesocortical pathway. When FGA’s block D2 receptors here, negative symptoms such as blunted affect, lack of pleasure, reduced social interaction can worse • Dopamine inhibits prolactin release in the tuberoinfundibular pathway. When FGA’s bind to D2 in this pathway, there is an increase in serum prolactin levels leading to galactorrhea, infertility or low sex drive. 2 • The degree of D2 receptor binding in the mesolimbic pathway needed for antipsychotic effects is close to 80% , while D2 receptor occupancy greater than 80% in the dorsal striatum is associated with EPS and in the pituitary is associated with hyperprolactinemia. This creates a very narrow therapeutic window Between the threshold for antipsychotic efficacy and that for side effects in terms of a D2 binding. • If D2 receptors in the nigrostriatal DA pathway are blocked chronically, it can cause TD. D2 receptors are hypothesized to become super sensitive or to upregulate (ase in number) perhaps in an attempt to overcome drug induced blockade of D2 receptors in the striatum. After long term treatment the D2 receptors apparently cannot or do not reset back to normal even when conventional antipsychotics are discontinued. This leads to tardive dyskinesia that is irreversible, continuing whether conventional antipsychotic drugs are administered or not • In addition to binding to D2 in all pathways, FGA’s also block muscarinic M1 cholinergic receptors, leading to blurry vision, dry mouth, constipation and cognitive blunting (Stahl, p.138). FGAs that caused more EPS are the agents that have weak anti cholinergic properties, whereas those FGAs that cause fewer EPS are the agents that have stronger anti cholinergic properties. Dopamine normally inhibits acetylcholine. If dopamine can no longer suppress acetylcholine release then acetylcholine becomes overly active. Therefore, EPS is a result of dopamine deficiency and excess acetylcholine. Drugs with anticholinergic actions will diminish the excess acetylcholine activity caused by removal of dopamine inhibition when dopamine receptors are blocked by FGAs. Thus, EPS is reduced. This occurs in the nigrostriatal dopamine pathway. • The use of anticholinergic drugs with an FGA does not lessen the ability of the FGA to cause tardive dyskinesia. • Other properties of FGA’s is the blockade of histamine receptors which leads to weight gain and drowsiness (Stahl, 2013). Blockade of alpha1 receptors can have cardiovascular effects, such as hypotension and drowsiness. • An old-fashioned way to sub classify FGAs is low potency versus high potency. Low potency agents tend to have more of the additional properties such as blockade of muscarinic M1-cholinergic receptor, blockade of histamine and alpha1-adrenergic receptors. SEROTONIN SYNTHESIS AND TERMINATION OF ACTION • Serotonin also known as 5- hydroxytryptamine (5HT) is produced from enzymes after the amino acid precursor tryptophan is transported into the serotonin neuron. Tryptophan is converted by the enzyme tryptophan hydroxylase (TRY-OH) into 5-hydroxytryptophan, which is then converted into 5HT by the enzyme, aromatic amino acid decarboxylase (AAADC). • Serotonin is then taken up into synaptic vesicles via the vesicular monoamine transporter (VMAT2), where it stays until released by a neuron impulse. The 5HT neuron also has a presynaptic transport pump for serotonin called the serotonin transporter (SERT) that terminates serotonin's actions by pumping it out of the synapse and back into the presynaptic nerve terminal where it can be restored in synaptic vesicles for subsequent use. SGAs and Neurotransmitters • Second generation antipsychotics are a class defined as serotonin- dopamine antagonists. They have an affinity of blocking serotonin and D2 receptors. SGA's almost always have higher affinity for 5HT2A receptors than they do for D2 receptors (p.154). o Other actions include partial agonism at 5HT1A receptors and partial agonist at D2 receptors. • SGA’s are different in that they bind to both D2 and serotonin receptors in the nigrostriatal pathway. • Therapeutic window: The 5HT2A and 5HT1A properties of SGA's lower the amount of D2 blockade in the dorsal striatum (nigrostriatal) and in the pituitary to 60%. D2 receptor occupancy remains to be up to 80% in the limbic area (nucleus accumbens). • 5HT2A stimulation of cortical pyramidal neurons normally block downstream dopamine release in the striatum. It does this via stimulation of glutamate release in the brainstem that triggers release of inhibitory 3 GABA there. GABA binds to dopamine neurons projecting from the substantia nigra to the striatum, which inhibits dopamine release. • 5HT2A antagonism increases dopamine in the cortex (nigrostriatal pathway), which results in less EPS. 5HT2A antagonism in the cortex stimulates downstream dopamine release in the striatum. It does this by reducing glutamate release in the brainstem, which in turn fails to trigger the release of inhibitory GABA. Results, in the release of dopamine in the striatum, because GABA cannot inhibit dopamine release from the substantia nigra into the striatum. • 5HT2A antagonism decreases negative symptoms by increasing DA in the mesocortical (prefrontal cortex) pathway, and antidepressant effects by increasing DA. • 5HT2A antagonism decreases risk of hyperprolactinemia in the tuberoinfundibular pathway. Dopamine inhibits prolactin release via stimulating D2 receptors, whereas serotonin promotes prolactin release via stimulating 5 HT2A receptors. simultaneous inhibition of 5HT2A receptors in D2 receptors mean the risk of prolactin release is low. Essentially, they cancel out each other (Reciprocal regulatory action). • In the mesolimbic pathway, SGA's have equal efficacy as FGA's, due to regional differences in the way in which 5HT2A receptors can or cannot exert control over dopamine release. Bind more potently to 5HT2A than D2 Bind more potently to D2 than 5HT2A Bind equally at 5HT2A and D2 The “pines” -clozapine, olanzapine, quetiapine, asenapine The “dones” -risperidone, paliperidone, ziprasidone, ilioperidone, lurasidone “Two pips and a rip” -aripiprazole -cariprazine “Two pips and a rip” -brexiprazole Bind more potently to 5HT1A than D2 Bind more potently to D2 and 5HT1A partial agonists Bind equally at 5HT1A and D2 -clozapine, quetiapine -asenapine - all of the “dones” -aripiprazole -cariprazine 1. Olanzapine does not bind to 5HT1A 2. Brexiprazole: 5HT1A binding is its most potent property Presynaptic 5HT1A receptors in raphe and postsynaptic 5HT1A receptors in the PFC stimulation increases dopamine release. Serotonin binding to 5HT1A receptors in the raphe nucleus inhibits serotonin release. In the striatum, reduced serotonin means that 5HT2A receptors on GABA and dopamine neurons are not stimulated. This means dopamine release is NOT inhibited. This causes dopamine release in the striatum, and mitigates EPS. 5HT1B/D receptors: Detected in the synapse by presynaptic 5HT receptors on axon terminals, occurs via 5HT1B/D receptors, also known as a terminal autoreceptor. Drugs that block this receptor can promote 5HT release and could hypothetically result in antidepressant actions. 5HT2c receptors: Postsynaptic, regulate dopamine and norepinephrine release. Stimulating this receptor suppresses dopamine release more so in the mesolimbic than in the nigrostriatal pathways, which results in an antipsychotic without EPS. Example – vabacaserin. Agonism of this receptor is also an experimental approach to the treatment of obesity. Psychopharmacological treatments for obesity, include lorcaserin. -Antagonism of serotonin 2C receptors is associated with increased risk for weight gain, perhaps due to stimulation of appetite regulated by the hypothalamus 4 -Blocking this receptor stimulates dopamine and norepinephrine release in the prefrontal cortex. Has pro cognitive and antidepressant actions. Fluoxetine has 5HT2C antagonist properties it is often used to boost olanzapine's antidepressant actions in treatment resistant and bipolar depression. -All of the “pines” bind more potently to 5HT2C receptors than D2 – esp. clozapine & seroquel 5HT3 receptors: Postsynaptic, regulate inhibitory GABA interneurons in various brain areas. Peripheral 5HT3 receptors in the gut regulate bowel motility. -Blocking 5HT3 receptors in the chemoreceptor trigger zone of the brain stem is an established treatment for N/V caused by chemotherapy. -Blocking this receptor on GABA interneurons increases the release of serotonin, dopamine, norepinephrine, acetylcholine, and histamine in the cortex. This is a new approach to an antidepressant and to a pro-cognitive agent. Only clozapine has 5HT3 binding potency comparable to its D2 binding potency period 5HT6 receptors: Postsynaptic, decrease in inhibitory GABA allows for increases in the release of acetylcholine and glutamate. Blocking this receptor improves learning and memory. Proposed as a new procognitive agent for the cognitive symptoms of schizophrenia when added onto an SGA. Potent 5HT6 antagonists include clozapine, olanzapine, and asenapine. 5HT7 receptors: Postsynaptic, regulator of serotonin release. When blocked, serotonin release is disinhibited. 5HT7 selective antagonists are thought to be regulators of circadian rhythm, sleep, and mood. Several of the “pines” and “dones” are potent 5HT7 antagonists relative to D2 binding (clozapine, quetiapine, asenapine, risperidone, paliperidone, and lurasidone). D2 partial agonism: partial agonists at D2 receptors stabilize dopamine neurotransmission in a state between silent antagonism and full agonism. They bind to 2 receptors that is neither too antagonizing (too cold, no psychosis, but cases EPS) like a conventional antipsychotic, nor too stimulating like a stimulant or dopamine itself (too hot, excess of full agonist, like DA, causes psychosis and N/V). It binds in an intermediary manner. Partial agonists are sometimes called “Goldilocks” if they get the balance “just right” between full agonism and complete antagonism, which results in NO psychosis and NO EPS. A very slight degree of partial agonist property is sometimes called intrinsic activity. D2 partial agonism can make an antipsychotic atypical. Serotonin and/or Norepinephrine reuptake inhibition: only Seroquel has potency greater than its D2 binding Alpha-2 antagonism: Increases NE. several atypical antipsychotics have this action with variable degrees of potency. All the “pines” (higher potency for clozapine and quetiapine) and “dones” (higher potency for risperidone) and aripiprazole. Antidepressant effect (mirtazapine is a alpha-2 blocker). Antimanic actions: All antipsychotics are effective for psychotic mania, but not for nonpsychotic mania. This is due to D2 antagonism/partial agonism combined with 5HT2A antagonism. Anxiolytic actions: Atypical antipsychotic use is controversial for the treatment of anxiety disorders, especially PTSD. Quetiapine has the most evidence for use in anxiety disorders. Sedative-hypnotic and sedating actions: sedation is both good and bad. Good for short-term treatment, especially in early treatment during hospitalization, and when patients are aggressive, agitated or needing sleep induction. Sedation is bad for long-term treatment because diminished arousal, sedation and somnolence can lead to cognitive impairment, which compromises functional outcomes. -M1 muscarinic cholinergic receptors, H1 histamine receptors, and alpha-1 adrenergic receptors are responsible for causing sedation. 5 -Potent anti-histamine actions: clozapine, quetiapine, and ilioperidone. -Potent anticholinergic actions: only the “pines” have high potency for muscarinic receptors -Potent alpha1 adrenergic antagonism: clozapine, quetiapine, risperidone and ilioperidone. -The pines are more sedating than dones -Lurasidone does not bind to H1 or muscarinic receptors -The “rips and a pip” do not bind to muscarinic receptors Evidence suggests that the best long-term outcomes in schizophrenia result when D2/5HT2A/5HT1A receptor occupancy improves positive symptoms of psychosis, rather than from nonspecific sedation resulting from alpha1, M1 and H1 receptor blockade. Cardiometabolic actions -All atypical antipsychotics share a class warning for causing risks for obesity, dyslipidemia, diabetes, accelerated cardiovascular disease, and even premature death. H1 receptor and 5HT 2C receptor blockade is associated with weight gain. • Highest metabolic risk: clozapine, olanzapine • Moderate metabolic risk: risperidone, paliperidone, quetiapine, ilioperidone (weight only) • Low metabolic risk: ziprasidone, aripiprazole, lurasidone, ilioperidone -The metabolic highway has three key stages. First, increased appetite and weight gain can lead to elevated BMI, and ultimately obesity. Second, SGAs can cause insulin resistance by an unknown mechanism which can be detected by measuring fasting plasma triglyceride levels. Finally, SGAs can cause sudden onset of diabetic ketoacidosis or hyper glycemic hyperosmolar syndrome by unknown mechanisms, possibly including blockade of M3 cholinergic receptors. If BMI or fasting triglycerides increased significantly, switched to a different antipsychotic that has low metabolic risk. -The metabolic toolkit includes four parameters: weight, fasting triglycerides, fasting glucose, and BP. Unmanageable factors that may cause insulin resistance includes genetic makeup and age, while modestly manageable include lifestyle (diet, exercise, and smoking). SCHIZOPHRENIA AND DOPAMINE • THOUGHT TO BE DUE TO EXCESSIVE DOPAMINE • Presynaptic dopamine dysfunction results in increased availability and release of dopamine and this has been shown to be associated with prodromal symptoms of schizophrenia. • Schizophrenia is charactered by positive, negative, cognitive, affective and aggressive symptoms Symptom Characteristics Pathway Positive symptoms delusional thoughts, auditory and visual hallucinations, disorganized speech (i.e. “word salad), agitation, disorganized behavior, catatonic (loss of movement and communication; confusion, restlessness) Mesolimbic pathway VTA nucleus accumbens Negative symptoms flat affect, anhedonia, apathy, asociality (social isolation), avolition (dysfunction of motivation; i.e. poor hygiene), poor memory, impaired attention, stereotyped thinking, alogia (dysfunction of communication; poverty of speech) Mesocortical and some mesolimbic pathway (nucleus accumbens is part of the brain’s reward circuitry, thus plays a role in motivation) Cognitive symptoms overall executive dysfunction. Problems maintaining goals, allocational attentional resources, impaired attention, prioritizing, serial learning, verbal fluency, problem solving. Single strongest correlate of real-world functioning (Stahl, p. 84) Mesocortical pathway (dorsolateral prefrontal cortex) Aggressive symptoms related to impulse control. Overt hostility, verbal or physical abusiveness, self-injurious behaviors, assault, arson or property damage, and sexual acting out (Stahl, p. 85) Located in the orbitofrontal cortex and amygdala Affective depressed mood, anxious mood, guilt, tension, irritability, and Mesocortical pathway 6 symptoms worry. (ventromedial prefrontal cortex) CONCEPT OF SALIENCE • Usually, dopamine’s role is to mediate motivational salience and thereby gives a person the ability to determine what stimulus grabs their attention and drives the subsequent behavior. • Schizophrenia is associated with an aberrant attribution of salience due to dysregulated striatal dopamine transmission. • Deregulation of the dopamine system ultimately leads to irrelevant stimuli becoming more prominent which provides a basis for psychotic phenomena such as ideas of reference, where everyday occurrences may be layered with a with a heightened sense of bizarre significance. Furthermore, this misattribution of salience can lead to paranoid behavior and persecutory delusions THE AGONIST SPECTRUM Naturally occurring neurotransmitters stimulate receptors and are thus agonists. Some drugs also stimulate receptors and are also called agonists. It is possible for drugs to stimulate receptors to a lesser degree then the natural neurotransmitter, these are called partial agonists or stabilizers. It is a common misconception that antagonists are the opposite of agonists because they block the actions of agonists. However, although antagonists prevent the action of agonists, they have no activity of their own in the absence of the agonist. For this reason, antagonists are sometimes called “silent”. Inverse agonists, have opposite actions compared to agonists. That is, they block agonists but can also reduce activity below the baseline level when no agonist is present. Thus, the agonist spectrum reaches from full agonists, to partial agonists, through to “silent” antagonists and finally inverse agonists (Stahl, p.35). DOPAMINERGIC PATHWAYS Location Function Effects of Dopamine Implications 7 Mesolimbic pathway Malfunction causes positive symptoms ventral tegmental area (VTA) to the nucleus accumbens in the ventral striatum Nucleus accumbens is part of the brain’s reward circuit -Site of the rewards pathway -Mediates pleasure, motivation and reward, emotion -Goal directed behavior Excess dopamine causes of positive symptoms of schizophrenia. D2 antagonists reduce positive symptoms of schizophrenia. -65% occupancy requirement is the minimum threshold for treatment to be effective. Mesocortical pathway Malfunction causes negative symptoms VTA to the prefrontal cortex -Negative and cognitive symptoms (dorsolateral PFC) -Negative and affective symptoms: emotion and affect (ventromedial PFC) Decreased dopamine causes negative, cognitive and depressive symptoms of schizophrenia. D2 blockade worsens the negative symptoms of schizophrenia Nigrostriatal pathway EPS and TD Substantia nigra (brainstem) to the basal ganglia or striatum (caudate and putamen). Motor function and movement Decreased dopamine in the nigrostriatal pathway caused by antipsychotics cause EPS (dystonia, parkinsonian symptoms and akathisia). When DA is in excess, it can cause hyperkinetic movements like tics and dyskinesias. Contains about 80% of the brain’s dopamine. Long-standing D2 blockade in the nigrostriatal pathway can lead to TD TD is potentially permanent Tuderoinfundibular pathway Hyperprolactinemia hypothalamus (arcuate and periventricular nuclei) to the anterior pituitary Control prolactin release. Dopamine release in the TI pathway inhibits prolactin release D2 antagonism of the TI pathway by drugs such as antipsychotics causes hyperprolactinemia DOPAMINE ANTAGONISTS IN SCHIZOPHRENIA Antipsychotic Typical (1st generation [FGA[) ▪ FGAs are either low or high potency drugs based on their affinity for D2 receptors - influences side effects. ▪ Low potency higher risk of metabolic side effects. High potency higher risk of EPS. ▪ Metabolism: by the following three of the CYP450 enzymes, such as CYP1A2, CYP2D6 and CYP3A4 ▪ Elimination t1/2 is variable (18-30 hr). ▪ Before starting patient on FGA: AIMS, VS, possible ECG 8 Antipsychotic Atypical (2nd generation [SGAs]) ▪ Before starting patient on SGAs: weight, BMI, fasting glucose and lipids, BP, EKG o Recheck weight and BMI at 4, 8, 12 weeks, 6 months, quarterly and annually follow up o Fasting glucose and lipids repeated only at 6 months and annually ▪ If metabolic syndrome does occur switch agents, lower dose if possible or add metformin ▪ SGAs differ from the FGAs by their action on transiently occupying D2 receptors. After binding to the D2 receptors, the drugs dissociate rapidly to allow dopamine neurotransmission. ▪ SGAs have serotonin 5HT2A antagonism and 5HT1A agonism Common side effects: Metabolic syndrome (weight gain, insulin resistance, elevated lipids), Lower seizure threshold, QT prolongation ▪ FGAs are contraindicated in patients with narrow angle glaucoma, seizure disorder, prostatic hypertrophy, severe cardiac issues, and those who use benzodiazepines or barbiturates. Drug Mechanism of action Toxicity Phenothiazines: -chlorpromazine -prochlorperazine -thioridazine -fluphenazine -trifluophenazine Thioxanthenes -thiothixene -flupenthixol -chlorprothixene -clopenthixol Blockade of D2 Also blocker of alpha1, Muscarinic, and H1 recepto