NURS 660 Exam 1 Study Guide - PMHNP

NURS 660 Exam 1 Study Guide - PMHNP Exam 1 Review Pathways in schizophrenia • Brain imaging shows cerebral atrophy and enlarged fluid filled ventricles, as well as shrinkage in prefrontal cortex, temporal, basal ganglia, and limbic regions like hippocampus. • Five dopamine pathways in the brain. The neuroanatomy of dopamine neuronal pathways in the brain can explain the symptoms of schizophrenia as well as the therapeutic effects and side effects of antipsychotic drugs. Know different pathways in the brain • The nigrostriatal dopamine pathway, which projects from the substantia nigra to the basal ganglia or striatum, is part of the extrapyramidal nervous system and controls motor function and movement. When dopamine is deficient, it can cause parkinsonism with tremor, rigidity, and akinesia/bradykinesia. When DA is in excess, it can cause hyperkinetic movements such as tics and dyskinesias. In untreated schizophrenia, activation of this pathway is believed to be “normal.” • The mesolimbic dopamine pathway projects from the midbrain ventral tegmental area to the nucleus accumbens, a part of the limbic system of the brain thought to be involved in many behaviors such as pleasurable sensations, the powerful euphoria of drugs of abuse, as well as delusions and hallucinations of psychosis. Hyperactivity of dopamine neurons in the mesolimbic dopamine pathway theoretically mediates the positive symptoms of psychosis such as delusions and hallucinations. This pathway is also involved in pleasure, reward, and reinforcing behavior, and many drugs of abuse interact here. • The mesocortical dopamine pathway also projects from the midbrain ventral tegmental area but sends its axons to areas of the prefrontal cortex, where they may have a role in mediating cognitive symptoms (dorsolateral prefrontal cortex, DLPFC) and affective symptoms (ventromedial prefrontal cortex, VMPFC) of schizophrenia. Expression of these symptoms is thought to be associated with hypoactivity of this pathway. • The tuberoinfundibular dopamine pathway projects from the hypothalamus to the anterior pituitary gland and controls prolactin secretion into the circulation. Dopamine inhibits prolactin secretion. In untreated schizophrenia, activation of this pathway is believed to be “normal.”. • The thalamic dopamine pathway arises from multiple sites, including the periaqueductal gray, ventral mesencephalon, hypothalamic nuclei, and lateral parabrachial nucleus, and it projects to the thalamus. Its function is not currently well known but may be involved in sleep and arousal mechanisms by gating information passing through the thalamus to the cortex and other brain areas. There is no evidence at this point for abnormal functioning of this dopamine pathway in schizophrenia. GLUTAMATE • Excitatory NT, can excite and turn on all virtually ALL CNS neurons. Known as the master switch • Glutamate is released from synaptic vesicles, interacts with neighbor cells (glia) is taken up into glia VIA excitatory amino acid transporters (EAATs), it is converted to glutamine inside glia by enzyme glutamine synthetase, glutamine is released and SNAT (specific neutral amino acid transporters) takes it back into presynaptic neuron where its converted back to glutamate, then goes back into synaptic vesicles by vGluT transporters to be stored. • NMDA receptors are glutamate receptors and requires cotransmitter glycine or d-serine, made by neighboring glial cells (some neurons make glycine to put in synaptic vesicle but most comes from glial cells). Glial cells convert l-serine to d-serine Glutamate receptors: • NMDA, AMPA, and kainite- these are all ionotropic. So glutamate is released, attaches to receptor, sodium channels open and depolarize the cell, glutamate flows in, then Gaba is released. Glutamate pathways: • Cortico-brainstem-descending projects from cortical pyramidal neurons to brainstem NT centers including raphe for serotonin, VTA and substantia nigra for dopamine, ad locus coeruleus for NE. These excitatory cortico brainstem neurons stimulate NT release. • Corticostriatal-descending from cortical pyramidal neurons to striatal complex. AKA cortico-accumbens when project to NA. These neurons terminate on GABA neurons. • Hippocampal accumbens-projects from hippocampus to NA-this path is linked to schizo. • Thalamo-cortical pathways-brings info from thalamus back to cortex to process sensory info. • Corticothalamic-projets back to thalamus • Cortico-cortical-glutamate pathways in cortex • Indirect cortico-cortico-one neuron inhibit another neuron via interneurons that release GABA. Positive and negative symptoms of Schizophrenia • Positive symptoms: these are psychotic behaviors that are not generally seen in healthy individuals. Those with positive symptoms may lose touch with some aspects of reality. Symptoms: delusions, hallucinations, thought disorders (unusual or dysfunctional ways of thinking), movement disorder (agitated body movements) (Arising from the mesolimbic dopamine pathway) i. Positive symptoms of schizophrenia are hypothetically modulated by malfunctioning mesolimbic circuits. 1. Delusions, Hallucinations, Distortions or exaggerations in language and communication, Disorganized speech, Disorganized behavior, Catatonic behavior, and Agitation • Negative symptoms: disruptions to normal emotions and behaviors. Characterized by: flat affect, reduced feelings of pleasure in everyday life, difficulty beginning and sustaining activities, decreased communication. (Arising from the mesocortical dopamine pathway) ii. Negative symptoms are hypothetically linked to malfunctioning mesocortical circuits and may also involve mesolimbic regions such as the nucleus accumbens. 1. Alogia – Poverty of speech; e.g., talks little, uses few words 2. Affective blunting – Reduced range of emotions (perception, experience and expression); e.g., feels numb or empty inside, recalls few emotional experiences, good or bad 3. Asociality – Reduced social drive and interaction; e.g., little sexual interest, few friends, little interest in spending time with (or little time spent with) friends 4. Anhedonia – Reduced ability to experience pleasure; e.g., finds previous hobbies or interests unpleasurable 5. Avolition – Reduced desire, motivation, persistence; e.g., reduced ability to undertake and complete everyday tasks; may have poor personal hygiene iii. Affective symptoms of schizophrenia 1. Affective symptoms are associated with the ventromedial prefrontal cortex. a. Depressed mood, Anxious mood, Guilt, Tension, Irritability, and Worry iv. Cognitive symptoms of schizophrenia 1. Cognitive symptoms are associated with problematic information processing in the dorsolateral prefrontal cortex. a. Problems representing and maintaining goals, Problems allocating attentional resources, Problems focusing and sustaining attention , Problems evaluating functions , Problems modulating behavior based upon social cues, Problems monitoring performance , Problems prioritizing , Problems with serial learning, Impaired verbal fluency, and Difficulty with problem solving DSM five: two of the following during one month (one must be 1-3) • delusions • hallucinations • disorganized speech • grossly disorganized or catatonic behavior • negative symptoms Know the following brain regions and what mental health symptoms originate from them: Dorsolateral prefrontal cortex – cognitive symptoms • Nucleus accumbens – negative symptoms/reward circuits • Orbital frontal cortex – aggressive symptoms • Substantia nigra – motor function and movement • Mesolimbic – positive symptoms • Ventromedial prefrontal cortex – affective symptoms ***Suicidal ideation:VMPFC, amygdala Important to note: Negative symptoms can also be linked to mesolimbic system which involves the nucleus accumbens which is part of the brain's reward circuitry and plays a role in motivation. NA may also be involved in substance abuse. Dopamine hypothesis: AKA: dopamine hypothesis of schizophrenia) • The mesolimbic dopamine pathway projects from dopaminergic cell bodies in the ventral tegmental area of the brainstem to axon terminals in one of the limbic areas of the brain, mainly the nucleus accumbens located in the ventral striatum. This pathway is said to have an important functional role in many emotional behaviors (positive symptoms of psychosis - delusions & hallucinations). This pathway also plays a role in motivation, pleasure, and reward. Drugs that increase dopamine will increase or produce positive symptoms of psychosis. The opposite is true for drugs that decrease dopamine - decrease or stop positive symptoms. All antipsychotics that treat positive symptoms are blockers of the dopamine D2 receptor. Ex: stimulants such as cocaine/amphetamines: release dopamine, if taken repeatedly, can cause paranoid psychosis that is hard to differentiate from positive symptoms of schizophrenia. • The dopamine hypothesis or the mesolimbic dopamine hypothesis of positive symptoms of schizophrenia. Since it is believed that hyperactivity in the mesolimbic pathway, mediates positive symptoms of psychosis. Hyperactivity of this path accounts for positive symptoms whether symptoms are a part of schizophrenia or a drug induced psychosis, or psychosis from depression or dementia. IT IS NOT KNOWN what causes dopamine hyperactivity, but they think its consequence of dysfunction in prefrontal cortex and hippocampal glutamate • May also play a role in aggression and hostile symptoms • Evidence of dopamine hypotheses: amphetamine, cocaine increases dopamine levels which can cause symptoms that look like psychosis. Levodopa can do the same. Know the neurotransmitters and their role related to schizophrenia. • Dopamine is the main neurotransmitter in schizophrenia. There are four main dopamine receptors and all are blocked by some atypical antipsychotics. The dopamine 2 receptors are presynaptic and block the release of dopamine into the synaptic cleft. • The mesolimbic dopamine pathway projects from the tegmental area of the brainstem to axons in the limbic system in the nucleus accumbens in the ventral striatum. This area is associated with emotional behaviors including positive symptoms of psychosis, but it also creates motivation, pleasure, and rewards. Stimulants like amphetamine and cocaine increase dopamine which can increase the presence of psychosis. Whereas medications that block dopamine will reduce positive symptoms. • All antipsychotics that can block dopamine can treat the positive symptoms of schizophrenia. Hyperactivity of the mesolimbic dopamine pathway may also play a role in the hostility and aggression found with schizophrenia. The mesocortical dopamine pathway branches into the dorsolateral prefrontal cortex which is thought to regulate cognitive and executive functioning and branches into the ventromedial parts of the prefrontal cortex to regulate emotions and affect. This means that these pathways will produce cognitive, affective, and some negative symptoms with a dopamine deficit. • Another important area affected in the brain by dopamine is the nigrostriatal dopamine pathway stemming from the substantia nigra in the brainstem to the basal ganglia or striatum. This is part of the extrapyramidal nervous system which controls motor movements and deficits of dopamine will lead to movement disorders. Deficiency in the basal ganglia can also cause akathisia and dystonia. If there is too much dopamine in these areas you will see hyperkinetic movements such as chorea, dyskinesia, and tics. • With the tuberoinfundibular dopamine pathway, deficiencies can affect prolactin levels leading to galactorrhea, amenorrhea, and sexual dysfunction. This is often seen when antipsychotics are given and the dopamine is blocked. • Glutamate - is the major neurotransmitter in the central nervous system and sometimes to be considered the “master switch” of the brain, since it can excite and turn on virtually all CNS neurons. • Glutamate is the major excitatory neurotransmitter of the CNS as it can “turn on” nearly all the CNS neurons. There are six pathways of relevance to schizophrenia. The cortico- brainstem glutamate pathway is a regulator or neurotransmitter release where direct innervation of monoamine neurons in the brainstem stimulates release and indirect innervation via GABA interneurons blocks release. • The cortico-striatal glutamate pathway projects to the dorsal striatum terminate on GABA neurons. The hippocampal-accumbens glutamate pathway has specific theories that link this to schizophrenia and also terminate on GABA neurons. The thalamo-cortical glutamate pathway helps to process sensory information by carrying information from the thalamus to the cortex. The cortico-thalamic glutamate pathway projects back into the thalamus and may affect the manner in which neurons react to sensory information. The direct cortico-cortical glutamate pathway allows pyramidal neurons to excite one another. Finally, the indirect cotrico-cortical glutamate pathway allows for one pyramidal neuron to inhibit another via indirect input on the intraneurons releasing GABA. • NMDA hypofunction hypothesis: Research proposes that glutamate activity at NMDA receptors is hypofunctional due to abnormalities in the formation of glutamatergic NMDA synapses and has been shown with the administration of PCP and ketamine. These drugs have produced schizophrenic symptoms in mentally healthy individuals because they are NMDA receptor antagonists. These drugs mimic the cognitive, affective, and negative symptoms of schizophrenia. • Problems with development of glutamate synapses at the GABA interneurons in the cerebral cortex is thought to be linked to schizophrenia. The developed abnormalities mean that they have hypofunctioning NMDA receptors. There are interactions that allow glutamate to determine dopamine release. The mesolimbic dopamine pathway directly innervates specific dopamine neurons and stimulates them, creating positive symptoms. Glutamate neurons regulating mesocortical dopamine neurons indirectly innervate an inhibitory GABA interneuron which inhibits mesocortical dopamine neurons, leading to negative symptoms from dopamine deficit. Know how to cross-taper medications. • Gradually reducing the dose of the first drug (antipsychotic or antidepressant) while starting the second antipsychotic/antidepressant at a low dose and then increasing this dose as the first drug is withdrawn. Cross-tapering is an option when switching between some antidepressants. (Note from Ellen: Again, this is not taken from the book.) • Switching between two agents that have similar pharmacology is generally easiest, fastest, and has the fewest complications namely a -pine to a -pine or a -done to a -done, in over a weeks time. Switching from -pine to -done should be done more slowly. • Pines in general have more anticholinergic, antihistaminic, a1 blockade actions and are more sedating than the -dones, which are less potent binding at these sites. • From -pine to -done - Stop the -pine slowly, over two weeks allowing the patient to readapt to withdrawal of blocking cholinergic, histaminic, alpha 1 receptors • From -done to -pine - titrate the -pine up over two weeks or more, the -done can usually be stopped as quickly as over 1 week. This allows the patient to become tolerant to sedating effects of the -pines. • To and from aripiprazole - arip has a higher affinity/potency for D2. Its administration causes immediate withdraw of the first drug from the D2 receptor. Same principles applied to -pip and -rip (brexpiprazole and cariprazine). Little experience switching in between these drugs. • Switching TO arip- from -pine - start a middle dose building up rapidly over 3-7 days while taper the pine over two weeks. Fast titration because arip- replace the first drug at D2 receptors immediately. Slower titration of the -pine allows readaptation of cholinergic and histaminergic receptors. • Switching TO arip- from -done - start middle dose, build rapidly over 3-7 days. Taper done over 1 week since -dones are less likely to be associated with anticholinergic and antihistamine withdrawal • Switching FROM arip- , stop immediately, due to long half life and strong affinity of D2. Starting a middle, not low doses, of -pines/-dones tapering up 2/1 week respectively. Know the following medications, including their major side effects, drug interactions, starting dose, therapeutic dose, how to taper up, how to taper down, and FDA indications, and lab work that should be monitored while on the medication: Clozapine What is it? This drug is considered the most effective antipsychotic. However, it is never a first line choice because it can cause the fatal side-effect of agranulocytosis Page 180: Clozapine, a serotonin 5HT2A–dopamine D2 antagonist or serotonin-dopamine antagonist (SDA) is considered to be the “prototypical” atypical antipsychotic, and has one of the most complex pharmacologic profiles of any of the atypical antipsychotics. Clozapine was the first antipsychotic to be recognized as “atypical” and thus to cause few if any extrapyramidal side effects, not to cause tardive dyskinesia, and not to elevate prolactin. Despite its complex pharmacology, these atypical properties were linked particularly to the presence of serotonin 5HT2A antagonism added to the dopamine D2 antagonism of conventional antipsychotics, and this has become the prototypical binding characteristic of the entire class of atypical antipsychotics, namely 5HT2A antagonism combined with D2 antagonism. Clozapine, however, is the one atypical antipsychotic recognized as particularly effective when other antipsychotic agents have failed and is thus the “gold standard” for efficacy in schizophrenia. It may have a particular niche in treating aggression and violence in psychotic patients. It is unknown what pharmacologic property accounts for this gold-standard enhanced efficacy of clozapine, but it is unlikely to be simply 5HT2A antagonism since clozapine can show greater efficacy than other atypical antipsychotics that share this pharmacologic property. Major Side Effects: Clozapine is also the antipsychotic associated with the greatest risk of developing a life-threatening and occasionally fatal complication called agranulocytosis, in 0.5– 2% of patients. Because of this, patients must have their blood counts monitored for as long as they are treated with clozapine. Clozapine also has an increased risk of seizures, especially at high doses. It can be very sedating, can cause excessive salivation, has an increased risk of myocarditis and is associated with the greatest degree of weight gain and possibly the greatest cardiometabolic risk among the antipsychotics. Thus, clozapine may have the greatest efficacy but also the most side effects among the atypical antipsychotics. Because of these side-effect risks, clozapine is not considered to be the first-line treatment but is used when other antipsychotics fail. Starting Dose: ● Initial 25 mg at night; increase by 25–50 mg/day every 48–72 hours as tolerated ● Obtain trough plasma level on 200 mg at bedtime ● The threshold for response is 350 ng/mL ● Levels greater than 700 ng/mL are often not well tolerated ● No evidence to support dosing that results in plasma levels greater than 1,000 ng/mL ● Doses greater than 500 mg per day may require a split dose How to taper up: See the Art of Switching from the book--it is below. How to taper down: See the Art of Switching from the book FDA Indications: What does this mean? Lab work: See above for lab testing. ART OF SWITCHING: FROM BOOK: Figure 5-70. Switching from one antipsychotic to another. When switching from one antipsychotic to another, it is frequently prudent to “cross-titrate” – that is, to build down the dose of the first drug while building up the dose of the other over a few days to a few weeks. This leads to transient administration of two drugs but is justified in order to reduce side effects and the risk of rebound symptoms and to accelerate the successful transition to the new medication. THE ART OF SWITCHING Switching from Oral Antipsychotics to Clozapine • With aripiprazole, amisulpride, and paliperidone ER, immediate stop is possible; begin clozapine at middle dose • With risperidone, ziprasidone, iloperidone, and lurasidone, begin clozapine gradually, titrating over at least 2 weeks to allow patients to become tolerant to the sedating effect * Benzodiazepine or anticholinergic medication can be administered during cross-titration to help alleviate side effects such as insomnia, agitation, and/or psychosis. However, use with caution in combination with clozapine as this can Risperidone What is it? Neuroscience-based Nomenclature: dopamine, serotonin, norepinephrine receptor antagonist (DSN-RAn). Atypical antipsychotic (serotonin- dopamine antagonist; second generation antipsychotic; also a mood stabilizer) Commonly Prescribed for (bold for FDA approved) ● Schizophrenia, ages 13 and older (oral, long-acting microspheres intramuscularly) ● Delaying relapse in schizophrenia (oral) ● Other psychotic disorders (oral) ● Acute mania/mixed mania, ages 10 and ● older (oral, monotherapy and adjunct to ithium or valproate) ● Autism-related irritability in children ages 5–16 ● Bipolar maintenance (long-acting ● microspheres intramuscularly, monotherapy ● an adjunct to lithium or valproate) ● Bipolar depression ● Behavioral disturbances in dementia ● Behavioral disturbances in children and adolescents ● Disorders associated with problems with ● impulse control ● How the Drug Works ● Blocks dopamine 2 receptors, reducing positive symptoms of psychosis and stabilizing affective symptoms ● Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognitive and affective symptoms ● Interactions at a myriad of other neurotransmitter receptors may contribute to risperidone efficacy ● Specifically, 5HT7 antagonist properties may contribute to antidepressant actions Major Side Effects: • May increase risk for diabetes and dyslipidemia • Dose-dependent extrapyramidal symptoms • Dose-related hyperprolactinemia • Dose-dependent dizziness, insomnia, • anxiety, sedation Nausea, constipation, abdominal pain, weight gain Tachycardia, dose-dependent sexual dysfunction Rare tardive dyskinesia (much-reduced risk compared to conventional antipsychotics) Rare orthostatic hypotension, usually during initial dose titration Life-Threatening or Dangerous Side Effects • Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking atypical antipsychotics • Increased risk of death and cerebrovascular events in elderly patients with dementia- related psychosis • Rare neuroleptic malignant syndrome (much-reduced risk compared to conventional antipsychotics • Rare seizures • Weight Gain • Sedation Thioridazine • Major side effects: Neuroleptic-induced deficit syndrome; akathisia; priapism; EPS; parkinsonism, TD; galactorrhea, hypotension; weight gain • Drug interactions: Levodopa; dopamine agonists; CNS depressants; CYP450 2D6 inhibitors; antihypertensive drugs • Starting dose: 50-100mg TID with maximum of 800mg/day in divided doses. • Therapeutic dose: 200-800mg daily in divided doses • Tapering up and down: increase gradually and taper slowly over 6-8 weeks • FDA indications: Schizophrenic patients who fail to respond to tx with other antipsychotic drugs • Lab work: Serum potassium levels and possibly magnesium levels Quetiapine • Major side effects: sedation, dizziness, weight gain • Drug interactions: CYP450 3A inhibitors and CYP450 2D6 inhibitors may reduce clearance and raise blood levels. Possible increased INR when combined with warfarin • Starting dose: 25 mg BID, increase 25-50 BID until up to 800 • In acute bipolar mania: 100mg day 1, increasing up to 400mg on day 4 in increments of 100md/day • Bipolar depression: once daily at bedtime titrate to 300 • Schizo - 300mg daily can increase to 800mg/daily XR • Therapeutic dose: 50 IR mg for sedation, 300mg XR for depression, 800mg antipsychotic • Tapering up and down: rapid discontinuation can lead to rebound psychosis • FDA indications: Acute schizophrenia in adults; Acute mania; Bipolar depression and depression • Lab work: Fasting plasma glucose, fasting lipids and CBC if patient has a history of drug- induced neutropenia Haloperidol • Major side effects: neuroleptic induced syndrome, akathisia, EPS, galactorrhea, amenorrhea • Drug interactions: may decrease the effects of levodopa, dopamine agonists • Starting dose: 1-15mg/day, up to 100mg/day. Injection 2-5mg, subsequent doses may be given as often as every hour • Therapeutic dose: • Tapering up and down; slow down titration • FDA indications • Lab work Olanzapine • Major side effects: sedation, dizziness, weight gain, dyslipidemia, insulin resistance, glucose intolerance; dry mouth, constipation • Drug interactions: Anti-hypertensive agents; levodopa; dopamine agonists; CYP450 1A2 inhibitors (fluvoxamine) or inducers (cigarette smoke, carbamazepine) • Starting dose: 5-10mg PO daily • Therapeutic dose • Tapering up and down: Increase by 5mg daily until desired efficacy is reached (max of 20mg/day) • FDA indications: Schizophrenia (>13yrs); Acute mania/mixed mania; treatment resistant depression in combination with fluoxetine; acute agitation • Lab work: Fasting triglycerides, plasma glucose, lipids and LFT for patients with liver disease and CBC for patients with h/o drug-induced neutropenia. LABS for MEDICATIONS • All medications: Baseline and monitor weight gain, monitor and baseline for diabetes, dyslipidemia, BP in elderly, monitor prolactin levels, CBC to monitor WBC in patients with low WBC count or hx of drug induced leukopenia/neutropenia. BMI monthly for 3 months then quarterly; BP, fasting plasma glucose, and fasting lipids in first 3 months then annually, but earlier and more frequently for patients with diabetes and who have gained >5% of initial weight. • Thioridazine: Add baseline and periodic EKG. Baseline serum K+ and magnesium levels. • Quetiapine: Add US manufacturer recommends 6-month eye checks for cataracts, but Stahl says this may not be necessary. • Olanzapine: Add patients with liver disease should have blood tests done a few times a year • Clozapine: Lower ANC threshold for starting clozapine: normal pop. >1500/ul, benign ethnic neutropenia (BEN): >1000/ul. • Testing for myocarditis: myocarditis is rare and only occurs in the first weeks of treatment. Baseline check troponin I/T, c-reactive protein (CRP). Weekly troponin I/T and CRP for the first month. Fever is usually benign and self limited; suspicion of myocarditis should only be raised based on elevated troponin and other features of myocarditis. Clozapine should be stopped is troponin > 2x upper limits of normal and CRP > 100 mg/L. Cardiomyopathy is a late complication; consider annual ECG. • See ANC monitoring on page 181 in Stahl drug book Explain how and why some antipsychotic medications increase prolactin. • Conventional antipsychotic drugs are D2 antagonists and thus oppose dopamine’s inhibitory role on prolactin secretion from pituitary lactotrophs. Thus, these drugs increase prolactin levels.” (Stahl, pg. 153) • 5HT2A antagonism reverses the ability of D2 antagonism to increase prolactin secretion. As dopamine and serotonin have reciprocal regulatory roles in the control of prolactin secretion, one cancels the other. Thus, stimulating 5HT2A receptors reverses the effects of stimulating D2 receptors. The same thing works in reverse, namely, blockade of 5HT2A receptors reverses the effects of blocking D2 receptors.” (Stahl, pg. 153) • Serotonin and dopamine have reciprocal roles in the regulation of prolactin secretion from the pituitary lactotroph cells. Dopamine inhibits prolactin release by stimulating D2 receptors. Serotonin promotes the release of prolactin by stimulating the 5HT2A receptors. When D2 receptors are blocked by certain antipsychotics, this then blocks the actions of dopamine inhibition of prolactin secretion, thereby leading to increased levels of prolactin. Know what akathisia is and how it is commonly treated. • Akathisia is a type of restlessness due to dopamine deficiency in the basal ganglia (Stahl, 2013, p. 95) • Akathisia is a feeling of muscle quivering, restlessness, and inability to sit still, sometimes a side effect of antipsychotic or antidepressant medications (Mayoclinic) • Akathisia — Tardive akathisia refers to late-appearing motor restlessness. Manifestations may include repeated leg-crossing, weight-shifting, or stepping in place (Up to date) Treatment • For akathisia, we suggest treatment with a benzodiazepine or a beta blocker. A benzodiazepine such as lorazepam may be started at 0.5 mg orally twice daily. If the symptoms do not resolve, and the patient has not experienced side effects including ataxia and sedation, the medication can be incrementally raised up to 6 to 10 mg/day.” (Up to date) Explain upregulation of dopamine 2 receptors. • Long-term blockade of D2 receptors in the nigrostriatal dopamine pathway can cause upregulation of those receptors, which may lead to a hyperkinetic motor condition known as tardive dyskinesia, characterized by facial and tongue movements (e.g.,tongue protrusions, facial grimaces, chewing) as well as quick, jerky limb movements. This upregulation may be the consequence of the neuron’s futile attempt to overcome drug- induced blockade of its dopamine receptors.” (Stahl, pg. 136) • If D2 receptors in the nigrostriatal dopamine pathway are blocked chronically, they can produce a hyperkinetic movement disorder known as tardive dyskinesia. These changes can sometimes be irreversible when these receptors become super sensitive or to “upregulate” (increase in number) in an attempt to overcome drug-induced blockade of D2 receptors in the striatum. Explain downregulation of dopamine 2 receptors • Receptors have a lifespan like other cell proteins. Not only is there a normal life span for receptors, but receptors are modified both in number (long-term regulation) and regulation via second messengers). Long-term regulation, called up-regulation when receptors are increased in number or down-regulation when receptors are decreased In number. This reflects a compensatory change following prolonged absence of receptor agonists or chronic activation of the receptor, respectively. Chronic use of receptor antagonist leads to subsequent up-regulation. Drugs that act as agonists cause a reduction in receptor proteins if they are administered repeatedly. It requires 1-2 weeks of altered activity to change the number of receptors (Meyers, p 30; fig 1.11) • Pharmacodynamic tolerance occurs when changes in nerve cell function compensates for continued presence or absence of drug. Chronic receptor activation leads to down- regulation and a given amount of drug will have fewer receptors to act on and therefore will produce less biological effect. Compensatory up-regulation (increased receptor activation is chronically reduced). This is an explanation for withdrawal syndrome that occurs when chronic drug users abruptly stop using the drug. Because the adaptive mechanism produces effects opposite to the initial drug effects, when the drug is no longer present, the adaptive mechanism remains functioning and so causes a rebound withdrawal syndrome, overshooting basal levels. Alcohol, amphetamine, caffeine are 3 drugs for example that produce withdrawal syndrome. See table 1.9 for examples types of tolerance (Meyer, p 36). • Dopamine is a catecholamine which is more broadly a monoamine. The dopamine transporters (VMAT2) which carry dopamine back into the cell is blocked leaving dopamine in the nerve terminal vulnerable to enzymatic breakdown causing temporarily very low levels in the brain causing depressive symptoms in humans. Discovery of the degradation of dopamine causing depressive effects in humans due to low levels of dopamine won a Nobel Prize in 2000. How does dopamine released by 5HT2A reduce EPS? • Normally serotonin REDUCES dopamine release from the striatum by actions of serotonin at the various 5HT2A receptors • Atypical antipsychotic blocks D2 and 5HT2A receptors which then INCREASES dopamine release in the striatum therefore resulting in the elimination of EPS • 5HT2A receptor antagonism theoretically makes an antipsychotic atypical: low hyperprolactinemia How do 5HT2A antagonist actions reduce hyperprolactinemia? • Serotonin and dopamine have reciprocal roles in the regulation of prolactin secretion from the pituitary lactotroph cells • Dopamine INHIBITS prolactin release via stimulating D2 receptors • Serotonin PROMOTES prolactin release via stimulating 5HT2A receptors – so serotonin can no longer stimulate prolactin release • This mitigates the hyperprolactinemia of d2 receptor blockade • 5HT2A receptor antagonism theoretically makes an antipsychotic atypical: comparable antipsychotic actions Why does 5HT2A antagonism reverse antipsychotic actions? • Conventional antipsychotics only decrease dopamine at D2 receptors throughout the brain while atypical with their additional 5HT2A antagonist properties have much more complicated net actions on dopamine activity • Not only do they decrease dopamine activity by BLOCKING D2 receptors, but they can also INCREASE dopamine release and thus increase dopamine activity by indirectly stimulating dopamine receptors Explain serotonin 2c antagonism. • 5HT2C receptors are postsynaptic and regulate both dopamine and norepinephrine release • STIMULATION of 5HT2C receptors is one experimental approach to a novel antipsychotic, as this suppresses dopamine release, curiously more from the mesolimbic than from the nigrostriatal pathways, yielding an excellent preclinical profile: namely an antipsychotic without EPS. • The 5HT2C selective agonist vabicaserin, has entered clinical trials for the treatment of schizophrenia • STIMULATING 5HT2C receptors is also an experimental approach to the treatment of obesity, since this leads to weight loss in both preclinical and clinical studies • Another 5HT2C selective agonist, lorcaserin, is now approved for the treatment of obesity • BLOCKING 5HT2C receptors stimulates dopamine and norepinephrine release in prefrontal cortex, and has pro-cognitive but particularly antidepressant actions in experimental animals. • Several known antidepressant are 5HT2C antagonists, ranging from certain tricyclic antidepressants to mirtazapine to agomelatine. Some atypical antipsychotics have potent 5HT2C antagonist properties, especially the pines including those with known antidepressant action – quetiapine and olanzapine. • Olanzapine is often combined fluoxetine to boost olanzapine’s antidepressant actions in treatment resistant and bipolar depression. • Fluoxetine is not only a well-known SSRI, but also has potent 5HT2C antagonist properties that may not only contribute to its antidepressant effects as monotherapy, but also add to the 5HT2C antagonist actions of olanzapine when given together • 5HT2c are postsynaptic and regulate both dopamine and norepinephrine release. • Stimulation of these receptors suppresses more dopamine from the mesolimbic than nigrostriatal pathways. • Blocking 5HT2c stimulates dopamine and norepinephrine release in prefrontal cortex and has pro-cognitive and antidepressant actions. • Some atypical antipsychotics have potent 5HT2c antagonist properties especially the “pines” (quetiapine and olanzapine) Know what AMPA is and how it is activated. • AMPA receptors are one of the glutamate receptor subtypes coupled to ion channels that modulate cell excitability by gating the flow of calcium and sodium ions into the cell • Regulate ion flow and neuronal depolarization that can lead to NMDA receptor activation • Many modulators of AMPA are under development including those that do not act directly at the glutamate site of the AMPA receptor • Widely distributed in the CNS • AMPA (acid): glutamate receptor subtype; regulate ion flow and neuronal depolarization that can lead to NMDA (N-methyl-D-aspartate) receptor activation. Members of the ligand-gated ion channel family of receptorsMediate fast, excitatory neurotransmission, allowing Na to enter neuron to depolarize it o AKA: ionotropic receptors and ion-channel linked receptors o Activated by glutamate, allowing sodium to enter the neuron to depolarize it • Metabotropic glutamate receptors (linked to G proteins) can occur either pre- or postsynaptically. Three types of postsynaptic glutamate receptors are linked to ion channels, and are known as ligand-gated ion channels: N-methyl-D-aspartate (NMDA) receptors, α-amino-3-hydroxy-5methyl-4-isoxazole-propionic acid (AMPA) receptors, and kainate receptors, all named for the agonists that bind to them. • AMPA and kainate receptors may mediate fast, excitatory neurotransmission, allowing sodium to enter the neuron to depolarize it. NMDA receptors in the resting state are normally blocked by magnesium, which plugs a calcium channel. AMPA and kainate receptors require only glutamate to bind in order for the channel to open. This leads to fast excitatory neurotransmission and membrane depolarization. Sustained binding of the agonist glutamate will lead to receptor desensitization, causing the channel to close and be transiently unresponsive to agonist. • AMPA receptor with its sodium channel in the resting state, allowing minimal sodium to enter the cell in exchange for potassium. When glutamate arrives, it binds to the AMPA receptor, causing the sodium channel to open, thus increasing the flow of sodium into the dendrite and of potassium out of the dendrite. This causes the membrane to depolarize and triggers a postsynaptic nerve impulse. Depolarization of the membrane removes magnesium from the calcmdanium channel. This, coupled with glutamate binding to the NMDA receptor in the presence of glycine, causes the NMDA receptor to open and allow calcium influx. Calcium influx through NMDA receptors contributes to long-term potentiation, a phenomenon that may be involved in long-term learning, synaptogenes, and other neuronal functions.