Neurotransmitters PDF

Neurotransmitters Neurotransmitters are signaling molecules released by one neuron to signal another neuron to ultimately elicit a response or outcome. Neurons communicate through electrical currents called action potentials, which are either excitatory or inhibitory. Excitatory currents are those t...

Neurotransmitters Neurotransmitters are signaling molecules released by one neuron to signal another neuron to ultimately elicit a response or outcome. Neurons communicate through electrical currents called action potentials, which are either excitatory or inhibitory. Excitatory currents are those that prompt one neuron to share information with the next through an action potential, while inhibitory currents reduce the probability that such a transfer will take place. Let’s examine each of these neurotransmitters in more detail. Neurotransmitters are relevant in this module because all of these drugs affect neurotransmitters, either by enhancing their levels or decreasing their levels. These neurotransmitters will be important for subsequent CNS modules as well. Gamma-Aminobutyric Acid (GABA) and Glycine GABA and glycine are the major inhibitory neurotransmitters in the CNS. Glycine is present primarily in the spinal cord and brainstem. GABA is present throughout the CNS. Glutamate Glutamate is the major excitatory neurotransmitter in CNS. Glycine interacts with several receptors: AMPA, KA, and NMDA. Of these, the most important pharmacological target of glutamate are the N-methyl-D-aspartate (NMDA) receptors. AMPA: present in all neurons KA: present in the hippocampus, cerebellum, and spinal cord NMDA: present in essentially all neurons in the CNS Serotonin or 5-Hydroxytryptamine (5-HT) Serotonin is a critical neurotransmitter and its effect (excitatory or inhibitory) depends on the receptor activated. It is involved in signaling in many pathways coming from the raphe or midline region of the pons/upper brainstem. This is responsible for a variety of effects, including: Perceptions Mood Anxiety Pain Sleep Appetite Temperature Neuroendocrine control Aggression Because of these effects, serotonin is a target for many antidepressants and antipsychotics. The image below shows the different pathways involved with serotonin signaling. Norepinephrine (NE) Norepinephrine is a neurotransmitter of the sympathetic nervous system that acts as an agonist at α1, α2, and β1, with little activity at β2 receptors. Pathways involving norepinephrine are present in the locus caeruleus (LC) or lateral tegmental area. The effects of norepinephrine include: Vasoconstriction Tachycardia Increased cardiac output Increased peripheral resistance Hypertension Because of these effects, norepinephrine is a target of drugs to improve attention in ADHD.  The image below shows the different pathways involved in norepinephrine signaling. Dopamine (DA) Dopamine is a neurotransmitter that has many pathways primarily involved in movement and reward. Below you will see the different dopamine pathways in the brain. 1. A. Tubero-infundibular pathway. Regulation of prolactin B. Mesocortical pathway. Important for “higher order” cognitive functions (motivation, impulse control, emotion). C. Nigrostriatal pathway. o Regulator of movement o Impairments in this pathway are evident in Parkinson’s disease and underlie detrimental movement side effects associated with dopaminergic therapy, including tardive dyskinesia. D. Mesolimbic pathway. Reward pathway Acetylcholine (ACh) Acetylcholine is a neurotransmitter that interacts with muscarinic and nicotinic receptors, leading to both excitatory and inhibitory effects. Muscarinic receptors affect smooth muscle while nicotinic receptors affect skeletal muscle. Activation of presynaptic nicotinic receptors regulate the release of glutamate, 5-HT, GABA, DA, and NE in the CNS. Acetylcholine is hydrolyzed through acetylcholinesterase (AChE). The metabolism of acetylcholine can be blocked by AChE inhibitors, leading to higher levels of acetylcholine. AChE inhibitors: Neostigmine, physostigmine, donepezil Many indications: Myasthenia gravis, glaucoma, Alzheimer's, and others Cholinergic Effects/Toxidrome of ACh It is important to know the cholinergic effects/toxidrome of activating ACh receptors. A good mnemonic for general effects is DUMBELS: D — Diarrhea U — Urination M — Miosis/muscle weakness B — Bronchoconstriction/bradycardia E — Emesis/excitation of skeletal muscles L — Lacrimation  S — Salivation/sweating SLUDGE is a helpful mnemonic for remembering muscarinic receptor effects: S — Salivation L — Lacrimation U — Urination D — Defecation G — Gastrointestinal cramping E — Emesis The days of the week (M, T, W, T, F) is a helpful mnemonic for remembering nicotinic effects: M — Muscle cramps T — Tachycardia W — Weakness T — Twitching F — Fasciculations Alternatively, many drugs are considered anticholinergics and are going to have the opposite effect of DUMBELS — or the ABCDs: A — Anorexia B — Blurry vision C — Constipation and confusion D — Dry mouth S — Sedation Antidepressants: Part 1 There are many categories of antidepressants, which will be discussed in more detail in this section. These include: Selective serotonin reuptake inhibitors (SSRIs) Serotonin/norepinephrine reuptake inhibitors (SNRIs) Atypical antidepressants Tricyclic antidepressants (TCAs) Monoamine oxidase inhibitor (MAOI) The image below shows the mechanism of action of the main classes of antidepressants as it pertains to the sympathetic nervous system and serotonin neurons. Treatment of Major Depressive Disorder (MDD) It is important to recognize that the treatment of major depressive disorder is not medication therapy alone. Rather it is a combination of: Psychotherapy Pharmacotherapy Somatic therapies: ECT — electroconvulsive therapy TMS — transcranial magnetic stimulation Light therapy Pharmacotherapy of MDD Effectiveness is generally comparable among antidepressant classes and considerations for treatment should be guided by: Comorbidities Anticipated side effects Pharmacologic properties of the medications Half-life, CYP450 activity, drug interactions, and metabolites Previous response to antidepressants Cost Patient preference It is important to note that the maximum effect of any antidepressant will not be seen for four to six weeks! Black Box Warning All antidepressants carry a black box warning (BBW) for increased risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24) with major depressive disorder and other psychiatric disorders in short-term studies. There is no data demonstrating increased risk for suicidal thinking and behavior in adults > 24 years of age. Selective Serotonin Reuptake Inhibitors (SSRIs) SSRIs inhibit presynaptic serotonin reuptake by inhibition of the 5-HT transporter, which ultimately leads to increased 5-HT in the synaptic cleft. The mechanism of SSRIs is demonstrated in the graphic below. Prescribing Considerations General prescribing considerations for SSRIs include: Consideration of unique features to narrow selection. Drug-drug interactions Renal adjustments are generally not necessary Monitor for response and titrate as tolerated. All SSRIs are pregnancy category C. Exception: Paroxetine can cause cardiac defects and is Category D. May require four to six weeks for full antidepressant effect. Citalopram (Celexa®) Initial Dose: 20 mg daily Max: 40 mg Geriatric: 10–20mg Renal: Avoid: CrCl< 20 mL/min Hepatic: Max 20 mg/day Unique Features: Dose-related risk of QT prolongation. Max doses for >65-year-old, hepatic impairment, or with concomitant 2C19 inhibitors. Escitalopram (Lexapro®) Initial Dose: 10 mg daily Max: 20 mg Geriatric: 5–10 mg Renal: Avoid: CrCl< 20 mL/min Hepatic: Max 10 mg/day Unique Features: Dose-related risk of QT prolongation. S-enantiomer of citalopram. Fluoxetine (Prozac®) Initial Dose: 20 mg daily Max: 80 mg Geriatric: 5–40 mg Renal: No change. Hepatic: Decrease dose by 50% Unique Features: 2D6 inhibitor. Active metabolite (norfluoxetine) with long half-life (7-9 days), taper not required. Paroxetine (Paxil®) Initial Dose: 20 mg daily  Max: 50 mg Geriatric: 10–40 mg Renal: Max 40 mg if CrCl < 30 mL/min Hepatic: Max 40 mg/day Unique Features: Dry mouth, drowsiness, fatigue. More anti-cholinergic adverse effects. High risk of discontinuation syndrome with abrupt discontinuation due to short half-life. 2D6 inhibitor. Sertraline (Zoloft®) Initial Dose: 25 mg daily Max: 200 mg Geriatric: 25–150 mg Renal: No change. Hepatic: Decrease dose by 50% Unique Features: GI side effects (diarrhea, nausea, vomiting) common. Therefore, start with lower dose and titrate slowly. Active metabolite N-desmethylsertraline (half-life 60–80 hours). Fluvoxamine (Luvox®) Initial Dose: 50 mg daily Max: 300 mg Geriatric: 50-300 mg Renal: No dose adjustment. Hepatic: Slower titration. Unique Features:  Potent 1A2 enzyme inhibitor. Generally only used in OCD. Antidepressants: Part 2 Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) SNRIs work by inhibiting the 5HT and NE transporters. This leads to an increase of both NE and 5-HT neurotransmitters in the synaptic cleft. The mechanism of SNRIs is demonstrated in the graphic below. Prescribing Considerations General prescribing considerations for SNRIs include: Consider unique features to narrow selection of SNRI. All SNRIs are approved for treatment of depression. Venlafaxine is also indicated for panic disorder/anxiety and neuropathic pain. (Dose-related increases in blood pressure) Duloxetine has evidence in treatment of anxiety, fibromyalgia, and musculoskeletal pain. Non-antidepressant properties may be evident within one to two weeks of starting therapy. Monitor for response and titrate as tolerated. All SNRIs are pregnancy category C. Duloxetine Initial Dose:  60 mg daily Max: 60 mg Geriatric: 20–40 mg Renal: Avoid: CrCl< 30 mL/min Hepatic: Avoid Unique Features: Monitor liver function Venlafaxine IR and ER Initial Dose: IR: 37.5 mg BID Max: 225–375 mg ER: 75 mg daily Max: 225 mg Geriatric: IR: 25–225 mg divided doses ER: 37.5–225 mg QID Renal: CrCl 150 mg required to get dual NE and 5-HT transporter inhibition. Desvenlafaxine Initial Dose: 50 mg daily Max: 400 mg (doses >50 mg show no additional benefit) Geriatric: 50 mg daily Renal: CrCl < 30 mL/min: 50 mg every other day Hepatic: No change. Unique Features: Active metabolite of venlafaxine. Requires 2D6 for metabolism. High cost. Levomilnacipran Initial Dose: 20 mg daily Max: 120 mg Geriatric: Same as adult. Renal: CrCl 5-HT reuptake inhibitor Atypical Antidepressants Atypical antidepressants are medications that have different mechanisms of action. You’ll see that these medications generally still affect 5-HT and NE. Prescribing Considerations General prescribing considerations for atypical antidepressants include: Consider unique features to narrow selection. Mirtazapine supports increased appetite, weight gain, and sedation with possible benefit as an antiemetic. Trazodone is commonly used as a sleep aid, but has increased anticholinergic effects. Newer atypical antidepressants have higher cost with no superior benefit over traditional medications. Non-antidepressant effects may be evident within days of starting therapy. Monitor for response and titrate as tolerated. Mirtazapine (Remeron®) Mirtazapine is a presynaptic α2 antagonist that increases synaptic concentration of 5- HT and NE. Additionally, it is an antagonist at 5-HT2 and 5-HT3 receptors. Given its adverse effects, it is not often used only for its antidepressant effects but also for anorexia or insomnia.  Dose Adverse Effects Unique Features Prescribing Considerations Initial: 7.5 mg Increased Often scheduled at Geriatric: QHS appetite (17%) night for sedating 7.5-45 mg Max: 45 Weight gain and appetite- Renal: mg/day (7.5%: >7% stimulating effects. CrCl < 40 mL/min increase in use caution body weight) Constipation Hepatic: (13%) Titrate slowly. Sedation (54%) Bupropion (Wellbutrin®) Bupropion blocks NE and DA receptors, and has no effect on 5-HT receptors. It is available as immediate release, sustained release, and extended release formulations. Given its action at DA receptors, it can also be used for smoking cessation. Dose Adverse Unique Prescribing Effects Features Contraindications Consideratio ns Maximum Headache Activating History of Geriatric: dose (25–34%) (useful with seizures May require a depends Insomnia fatigue, History of decreased on (11–20%) poor anorexia/buli dose. formulatio Dizziness concentratio mia Renal: n: (6–11%) n) Abrupt Decrease Xerostomi Strong discontinuatio dose. Immediat a (17– CYP2D6 n of EtOH, e release 26%) inhibitor BDZ, Hepatic: (IR): Tachycard No sexual barbiturates, Severe: o Initial ia (11%) dysfunction or IR: max 75 dose: 100 Weight Risk of antiepileptic mg daily mg loss (14– seizures drugs SR: max 100 o Maximum 23%) Also Arteriovenous mg daily single Anxiety approved malformation ER: 150mg dose: 150 (5–7%) for smoking (AVS) in CNS daily mg Dose- cessation related o Maximum seizure Severe head daily (0.1– injury, stroke, dose: 450 0.4%) CNS tumor mg in three divided doses o Dosing schedule: TID Sustained release (SR): o Initial dose: 150 mg o Maximum single dose: 200 mg o Maximum daily dose: 400 mg in two divided doses o Dosing schedule: BID Extended release (XL): o Initial dose: 150 mg o Maximum single dose: 450 mg o Maximum daily dose: 450 mg o Dosing schedule: Once daily Trazodone (Desyrel®) Trazodone is a weak 5-HT reuptake inhibitor, but it significantly blocks H1 and α1 receptors. This is important for its other indications for use. Dose Adverse Effects Unique Features Contraindications Depression: Sedation (46%) Used commonly as History of 150 mg once Headache (33%) a sleep aid, rarely seizures daily (max 450 Dizziness (25%) as an History of mg) Fatigue (15%) antidepressant. anorexia/bulimia Insomnia: 50– Dry mouth Abrupt 100 mg nightly (25%) discontinuation Nausea (21%) of EtOH, BDZ, Constipation barbiturates, or (8%) antiepileptic drugs Arteriovenous malformation (AVS) in CNS Severe head injury, stroke, CNS tumor Nefazodone (Serzone®) Nefazodone is a 5-HT2A antagonist with moderate inhibition of 5-HT and NE reuptake. Dose Adverse Effects Comments Initial: 100 mg BID (max Dry mouth (25%) Not usually prescribed due 600 mg/day) Sedation (25%) to rare incidence of Nausea (22%) hepatotoxicity. Dizziness (17%) Blurred vision (16%) Vilazodone (Viibryd®) Vilazodone causes inhibition of presynaptic 5-HT transporter and is a 5-HT1A partial agonist. Dose Adverse Effects Comments Prescribing Considerations 10 mg once Diarrhea (28%) Pregnancy Geriatric: daily for one Nausea (23%) Category C No change week Vomiting (5%) Should be Renal: 20 mg once Decreased taken with food No change daily for one libido (4.7% in High cost Hepatic: week clinical trial) No change Max: 40 Nausea (21%) mg/day Constipation (8%) Vortioxetine (Trintellix®) Vortioxetine inhibits 5-HT reuptake and is a 5-HT3 antagonist and 5-HT1A agonist. Dose Adverse Effects Comments Prescribing Considerations 10 mg daily Nausea (10– Pregnancy Geriatric: Max: 20 mg 20%) Category C No change daily Diarrhea (7– Metabolized by Renal: 10%) CYP2D6 No change Dry mouth (6– Concomitant Hepatic: 8%) strong 2D6 No change Sexual inhibitors dysfunction reduce dose by (males: 16–29%, 50%. females: 22– 34%) Tricyclic Antidepressants Tricyclic antidepressants are some of the original medications used for depression. They are non-selective inhibitors of both NE and 5-HT reuptake transporters. However, they have additional action at other receptors, which leads to their significant adverse effect profile. Dosing Comparison Below are the available TCA medications and variations in dosing. Adverse Effects The toxicity of TCAs is dose-dependent and it is important to note that TCAs may be fatal in overdose situations. Other adverse effects of TCAs are particularly related to their action at non-therapeutic receptors, which include: Conduction disturbances and EKG changes Decreased seizure threshold α1 receptor = Orthostatic hypotension Muscarinic receptors = Dry mouth, blurry vision, confusion, constipation, urinary retention H1 and 5-HT2C receptors = Weight gain H1 receptor = Sedation QTc Prolongation QTc prolongation refers to the QTc interval on an echocardiogram (EKG). By prolonging the QTc interval, this delayed ventricular repolarization can lead to worsening arrhythmias including Torsades de Pointes. The graphic below demonstrates the risk of QTc prolongation with TCAs from least likely to most likely. Prescribing Considerations General prescribing considerations for TCAs include: Consider unique features to narrow selection. Higher risk of CV and anticholinergic side effects. Non-antidepressant effects may be evident within days of starting therapy.  Antidepressant effects superior to SSRIs in the context of life-threatening depression with quicker onset. Monitor for response and titrate as tolerated. More specific prescribing considerations for available SNRI medications have been outlined in the table below: Medication Considerations Amitriptyline May benefit in treatment of chronic pain, polyneuropathy, and migraines. Additional sedating properties. Nortriptyline May benefit in treatment of myofascial pain and neuralgia. Imipramine, Additional benefit in treatment of neuropathic pain. desipramine Doxepin Low doses may be used as sleep aid. Monoamine Oxidase Inhibitors (MAOIs) Monoamine Oxidase Inhibitors (MAOIs) Monoamine oxidase inhibitors (MAOIs) are antidepressants generally reserved for patients who neither tolerate nor respond to other antidepressant therapy due to their many drug-to-drug and drug-food interactions. MAOIs cause non-specific irreversible inhibition of monoamine oxidase (MAO). MAO is responsible for the metabolism of 5- HT, NE, DA, and tyramine. The mechanism of action of MAOIs is illustrated in the graphic below. Adverse Effects  Sedation Insomnia Weight gain Changes in blood pressure Dietary Recommendations There are significant drug-food interactions that patients taking MAOIs must avoid. It is therefore very important to counsel patients on how to successfully follow a diet that is low in tyramine. Foods to avoid o Aged cheeses, dried meats, red wine, tap beers, sauerkraut, raw yeast, legumes Foods to limit o Caffeinated beverages, chocolate, figs, meat tenderizers, raisins Prescribing Considerations Not commonly used as first-line medication for treatment of depression Many drug-to-drug and drug-food interactions Specific prescribing considerations for available MAOI medications have been outlined in the table below: Medication Dose Comments Phenelzine 15 mg TID Diet restriction required. (Nardil ) ® Max: 90 mg Tranylcypromine 30 mg/day Diet restriction required. (Parnate )® (BID/TID) Max: 60 mg Isocarboxazid 20 mg/day Diet restriction required. (Marplan®) (divided) Max: 60 mg Selegiline patch 6 mg/24 hours Tyramine diet restriction unnecessary (Emsam®) Max: 12 mg unless daily dose > 6 mg. Two active metabolites: amphetamine/ methamphetamine can cause a positive urine tox screen. Hypertensive crisis can occur when patients on MAOIs ingest foods that are high in tyramine. It generally develops 20–60 minutes after ingestion of the interacting food or drug, and can lead to a cardiovascular event or death. Patients may present with nausea, vomiting, sweating, headache, stiff neck, chest pain, hypertension, and/or palpitations. Serotonin Syndrome Serotonin syndrome may result from overactivation of central serotonin receptors when too much serotonin is available. It is rare but can occur with the combination of serotonergic medications, and may be life-threatening. Presentation Abdominal pain Diarrhea Sweating Fever Tachycardia Delirium Hyperreflexia Clonus Irritability Treatment Discontinue suspected causative medication(s). Provide supportive therapy. Symptoms often resolve within 24 hours of discontinuation. Prevention SSRIs (other than fluoxetine) conversion to MAOIs: 2-week washout Fluoxetine conversion to MAOIs: 5-week washout MAOI conversion to SSRI: 2-week washout Examine the below image, which tracks the progression of serotonin syndrome. Types of Neurotransmitters 1. Inhibitory Neurotransmitters: o GABA (Gamma-Aminobutyric Acid): Major inhibitory neurotransmitter. o Glycine: Another inhibitory neurotransmitter. 2. Excitatory Neurotransmitters: o Glutamate: Major excitatory neurotransmitter. 3. Other Neurotransmitters: o Serotonin, Norepinephrine, Dopamine: Critical balance among these is essential for CNS function. Imbalance can lead to CNS disorders. o Acetylcholine: Can be both inhibitory and excitatory. Effects on its receptors contribute to medication side effects. Typical Antidepressants 1. Selective Serotonin Reuptake Inhibitors (SSRIs): o Increase serotonin levels in the synaptic cleft. o Examples: Fluoxetine, Sertraline. 2. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): o Increase both serotonin and norepinephrine in the synaptic cleft. o Examples: Venlafaxine, Duloxetine. Atypical Antidepressants Work to balance serotonin, norepinephrine, and dopamine. Often used for additional benefits beyond depression treatment: o Mirtazapine: Used for sleep or appetite stimulation. o Bupropion: Used for smoking cessation. Increased risk of seizures; avoid in patients with seizure risk. o Trazodone: Often used for sleep. Tricyclic Antidepressants (TCAs) Examples: Amitriptyline, Nortriptyline. Among the oldest antidepressants with anticholinergic side effects (e.g., dry mouth, constipation). May have a quicker onset in patients with severe psychiatric illness. Monoamine Oxidase Inhibitors (MAOIs) Reserved for treatment-resistant patients or those intolerant to other antidepressants. Significant drug-drug and drug-food interactions: o Avoid foods high in tyramine (e.g., aged cheese, dried meat) to prevent hypertensive crisis. Serotonin Syndrome Cause: Overactivation of serotonin receptors due to medication combinations.  Symptoms: Restlessness, agitation, rapid heart rate, sweating, and in severe cases, life-threatening complications. Prevention: Avoid combining multiple serotonergic drugs. First Generation Antipsychotics (FGAs) Antipsychotics are used to treat psychosis and primarily involve the dopamine pathways of the brain. Therapy is divided into First Generation Antipsychotics (FGAs) and Second Generation Antipsychotics (SGAs). First Generation Antipsychotics (FGAs) First generation antipsychotics (FGAs), also called typical antipsychotics, block the post-synaptic D2 receptors in the brain. However, other receptors are also affected, which accounts for differences in side effects. These include histaminergic, muscarinic, and adrenergic effects. The image below shows the mechanism of FGA medications. Black Box Warning Like with antidepressants, there is a black box warning (BBW) for all antipsychotics. Data has indicated that there is an increased risk of death associated with treatment in patients with dementia-related psychosis. It is recommended that the risks and benefits in this patient population are carefully weighed. Adverse Effects By blocking D2 receptors in other areas of the brain, FGAs can cause a variety of adverse effects, including: Nigrostriatal, which causes movement disorders. Tuberoinfundibular, which causes hyperprolactinemia. Mesocortical, which causes worsening negative symptoms. Given the different potencies for D2, it is important to note that these medications do have different adverse effect profiles, even within the same class. More specific adverse effects for available FGA medications have been outlined in the table below: Extrapyramidal Symptoms*, or EPS, are a group of potentially serious adverse effects associated with antipsychotic medications or metoclopramide, specifically due to blockade of D2 receptors in the nigrostriatal pathway (substantia nigra). More information is included in the EPS section. Prescribing Considerations General prescribing considerations for FGA medications include: Monitor for symptoms of EPS. May require use of anticholinergic medication as adjunct, especially for high potency medications, to minimize movement side effects. E.g. benztropine (Cogentin) 0.5 mg BID. Low potency medications do not require additional meds. Generic availability, so relatively inexpensive.  Immediate acting injections (haloperidol, fluphenazine, and chlorpromazine) are an option for hospitalized, agitated patients. More specific prescribing considerations for available FGA medications have been outlined in the table below: Second Generation Antipsychotics (SGAs) SGAs, or atypical antipsychotics, were developed to have a differing mechanism of action and reduce the EPS related side effects associated with FGAs. However, these medications still have a number of adverse effects of concern. SGAs work by blocking postsynaptic D2 and 5-HT2A receptors. The image below shows how SGAs work. CYP450 Primary Pathway SGAs have a number of drug-drug interactions due to their metabolism through the CYP pathway. Other drugs that induce or inhibit enzymes will affect the levels of SGAs. The diagram below indicates which SGAs are metabolized through the 2D6, 1A2, and 3A4 CYP enzymes. *Two-thirds of ziprasidone metabolism occurs via aldehyde oxidase and one-third by CYP450 system (3A4). CYP Enzyme Drug Interactions 2D6  Genetic variations between poor metabolizers, rapid metabolizers, and ultra rapid metabolizers. 2D6 inhibitors: paroxetine, fluoxetine, and bupropion. 1A2 Smoking induces this enzyme by 20–30%. o May need to adjust dose if smoking status changes. 1A2 inhibitors like fluvoxamine. 3A4 Watch for strong inhibitors such as the azole class of antifungals. Class Adverse Effects Although significantly reduced, SGAs still have a number of adverse effects. These are more likely to be metabolic and include: Metabolic abnormalities (lipids and glucose) Weight gain (H1 and 5-HT2C blockade) QTc prolongation Prolactin elevation (D2 blockade in tuberoinfundibular pathway) Sedation Akathisia Anticholinergic effect (muscarinic blockade) Orthostatic hypotension EPS When selecting medications for long-term care, it is important to consider the major adverse effect rankings as detailed in the graphic below. Prescribing Considerations General prescribing considerations for SGA medications include: Risperidone clinical max of 6–8 mg >8 mg begins acting similarly to typical antipsychotics such as haloperidol. Paliperidone Dose adjustment required when CrCl 1500 (general pop) ANC > 1000 (BEN: benign ethnic neutropenia) ANC (total WBC x total % of neutrophils)  B. Orthostatic Hypotension Slowly titrate to minimize. C. Seizure Higher clozapine doses are more likely to cause seizure. D. Death Death in dementia-related psychosis. E. Myocarditis Most cases generally occur in the first eight weeks. Monitor troponins and C-reactive protein (baseline and weekly for first month). Adverse Effects In addition to the black box warnings, Clozapine has a number of adverse effects including: Highly anticholinergic medication Tachycardia Constipation Prescribe sufficient bowel regimen Cholinergic agonist at M4 receptors in mouth Excessive salivation Strong histaminergic effect Sedating Weight gain Prescribing Considerations Consider prescribing to patients who have failed adequate doses and trials of other medications. May not be appropriate in patients with adherence issues. Dose will need to be re-titrated from the initial 25 mg QHS if the patient missed > 48 hours of dose. Patient will need to travel for blood work: Weekly for the first six months; Biweekly for the second six months; then Monthly for life Long-Acting Injectable Antipsychotics Long-acting injectable (LAI) antipsychotics have developed into an excellent treatment option for any patient. This is helpful because noncompliance to antipsychotic medications may lead to relapsing psychiatric illness, including worsening psychiatric symptoms and the need for emergent treatment or admission to inpatient psychiatric units.  The hospital readmission rate for patients with schizophrenia is 20–46% within one year. The monthly or bimonthly administration of LAI antipsychotics may improve treatment adherence, although the data regarding reducing hospital admissions is currently conflicting. Tolerability to oral formulation should be established before the administration of LAI antipsychotics. Currently available LAI antipsychotic medications. First Generation Antipsychotics Fluphenazine decanoate (Prolixin Decanoate®) Haloperidol decanoate (Haldol Decanoate®) Second Generation Antipsychotics Aripiprazole lauroxil (Aristada®) Aripiprazole monohydrate (Abilify Maintena®) Olanzapine pamoate (Zyprexa Relprevv®) Paliperidone palmitate (Invega Sustenna®, Invega Trinza®) Risperidone (Risperdal Consta®) LAI Dosing The table below shows the typical dosing and dosing intervals for LAI antipsychotics. Oral Antipsychotic Overlap Overlap with an oral medication is generally needed and depends on the medication being used. The table below outlines the overlap recommendations for specific LAI medications. Monitoring Recommendations Monitoring LAI antipsychotics is critical. Initial baseline monitoring should be done for each of these effects and then routine screening should continue to monitor adverse effects. The table below outlines these adverse effects and appropriate monitoring and screening. Extrapyramidal Symptoms (EPS) Extrapyramidal symptoms, or EPS, are a group of potentially serious adverse effects associated with antipsychotic medications or metoclopramide, specifically due to blockade of D2 receptors in the nigrostriatal pathway (substantia nigra). detail. Anticholinergics may worsen symptoms of Parkinsonism or tardive dyskinesia. Click on the headings below to learn more about EPS. Dyskinesia Repetitive, involuntary, purposeless body or facial movements. E.g., Lip smacking, tongue movements, finger movements. Tardive Dyskinesia Tardive dyskinesia is a repetitive, involuntary neurological movement disorder caused by DA blockade. Occurs after longer duration of use, may be permanent. Oral, Facial, Lingual Dyskinesia Abnormal movements of the tongue Facial grimacing Lip puckering, smacking, pouting Bulging of cheeks Chewing movements Limbs and Trunk  Twisting, spreading of fingers Foot tapping Dyskinesia of neck Shoulder shrugging Rocking or swaying Tremor (rare) Akathesia Extreme form of internal or external restlessness, inability to sit still, urge to move constantly. Dystonia Muscle tension disorder causing strong muscle contractions; unusual twisting of parts of body, especially the neck. Parkisonism Mask-like faces, resting tremor, cogwheel rigidity, shuffling gait, bradykinesia. EPS Rankings It’s important to understand which antipsychotics will be more or less likely to cause EPS symptoms, especially if a patient needs to be switched from one medication to another for these concerns. EPS Treatment Treating EPS is important for the patient’s quality of life and ability to tolerate medications that may otherwise work for them. Treatment depends on the EPS symptoms the patient is experiencing. General Treatment Diphenhydramine (Benadryl): 25–50 mg PO or IM (PRN or scheduled) Benztropine (Cogentin): 0.5–4 mg PO Typically divided into BID dosing Propranolol may help with treatment of akathisia Tardive Dyskinesia Treatment No standard treatment approach has been established, but there are a few options for treatment. Discontinue or change medication o Not all patients respond well to discontinuing the medication. o Switching to a less potent dopamine antagonist may be helpful for future symptoms. Adjunctive medications o Clonazepam, gingko biloba, amantadine o VMAT2 inhibitor Valbenazine (Ingrezza®) Valbenazine is a VMAT2 inhibitor that has been approved specifically to treat tardive dyskinesia. Class o Vesicular monoamine transporter 2 (VMAT2) inhibitor FDA indications o Tardive dyskinesia Mechanism of action o Reversibly inhibits VMAT2 transporter which regulates uptake of monoamine from cytoplasm to synaptic vesicle for storage/release (decreased monoamine levels in synapse) Dosing o 40 mg PO daily x 1 week then increase to 80 mg daily o CrCl 24 hours Examples: Flurazepam Diazepam Quazepam Clonazepam Alternative Anxiolytics Benzodiazepines are the agents most associated with anxiety, but there are a number of other medications that do not have the same risks that often go hand in hand with their use. These are explored in the table below: Pharmacotherapy Considerations When choosing a medication for anxiety, consider the following general guidelines: Sedation Appetite Type of pain Onset of action Comorbidity Renal/hepatic function Half-life of medication Drug-drug interactions Drug-food interactions Study Guide Questions and Answers Typical Antipsychotics Definition: Also known as first-generation antipsychotics (FGAs). Mechanism of Action: Block postsynaptic dopamine receptors. Common Drugs: Examples include haloperidol and fluphenazine. Key Adverse Effects: o Known for extrapyramidal symptoms (EPS), such as dystonia, akathisia, and tardive dyskinesia. o Less associated with metabolic or cardiovascular side effects compared to second-generation antipsychotics. Atypical Antipsychotics Definition: Also known as second-generation antipsychotics (SGAs).  Mechanism of Action: Also block postsynaptic dopamine receptors, but with additional effects on serotonin receptors. Common Drugs: Examples include aripiprazole and quetiapine. Key Adverse Effects: o Associated primarily with cardiovascular side effects, including QT prolongation. o May cause weight gain, dyslipidemia, and diabetes mellitus (metabolic syndrome). Lithium Use: Primary mood stabilizer for bipolar disorder. Mechanism of Action: Mimics sodium in the body, affecting neurotransmission. Key Characteristics: o Narrow therapeutic index: Requires regular therapeutic drug monitoring. o Toxicity risks: Can result in nausea, tremors, confusion, or renal dysfunction if levels are too high. Monitoring: Requires monitoring of serum levels, renal function, and thyroid function during therapy. Anxiolytics Benzodiazepines: o Enhance the effects of GABA, an inhibitory neurotransmitter. o Used for short-term management of anxiety. o Common Drugs: Examples include lorazepam, alprazolam, and diazepam. o Risks: § Psychological dependence: Patients can become reliant on these medications. § Limited use: Recommended for short-term use only. Buspirone: o Alternative anxiolytic for long-term therapy. o Non-benzodiazepine that does not cause dependence or sedation. Discussion Questions and Answers 1. Clinically Significant Drug Interactions in Psych/Mental Health Medications Examples:  o SSRIs and MAOIs: Combining these increases the risk of serotonin syndrome due to excessive serotonin receptor activation. o Lithium and NSAIDs/Diuretics: These drugs can increase lithium levels, leading to toxicity. o CYP450 Enzyme Interactions: Certain antipsychotics (e.g., aripiprazole, clozapine) are metabolized through CYP pathways. Co-administration with CYP inhibitors (e.g., fluoxetine) can increase drug levels and toxicity risks. o Benzodiazepines and CNS Depressants: Additive sedation and respiratory depression risks when combined with alcohol or opioids. Clinical Application: o Check for potential interactions before prescribing. o Educate patients about over-the-counter medications and supplements that might interact with their prescribed regimen. o Monitor drug levels and adjust dosages as needed. 2. Key Counseling Points and Monitoring Parameters Antidepressants: o Counseling Points: § Therapeutic effect may take 4–6 weeks. § Black box warning for increased risk of suicidal thoughts in young adults aged 18–24. § Avoid abrupt discontinuation (e.g., Paroxetine has a high risk of discontinuation syndrome). o Monitoring: § Assess mental status for suicidal ideation. § Monitor for adverse effects (e.g., weight gain with SNRIs, QT prolongation with citalopram). Antipsychotics: o Counseling Points: § Discuss risk of metabolic syndrome with SGAs (e.g., weight gain, hyperglycemia). § Highlight adherence importance, especially with long-acting injectables. o Monitoring: § Baseline and periodic checks: lipid profile, fasting glucose, weight, and QTc interval. § Monitor for extrapyramidal symptoms (EPS) and tardive dyskinesia.  Mood Stabilizers: o Counseling Points: § Lithium requires consistent hydration and sodium intake to avoid toxicity. § Report symptoms of toxicity: tremors, confusion, GI upset. o Monitoring: § Regular serum lithium levels (therapeutic range: 0.6–1.2 mEq/L). § Monitor thyroid and renal function periodically. 3. Contraindications and Risk-Benefit Considerations Contraindications: o Antidepressants: Avoid bupropion in patients with seizure history or eating disorders. o Antipsychotics: Clozapine is contraindicated in patients with agranulocytosis or uncontrolled epilepsy. o Mood Stabilizers: Lithium is contraindicated in significant renal impairment. Risk-Benefit Analysis: o Evaluate the severity of the mental health condition. o Consider alternatives if risks (e.g., metabolic syndrome, QT prolongation) outweigh benefits. o Use shared decision-making: educate patients on potential side effects and empower them to participate in treatment decisions. Review of Commonly Used CNS Agents 1. Antidepressants: o SSRIs (e.g., fluoxetine, sertraline): Increase serotonin levels; first-line for depression and anxiety. o SNRIs (e.g., venlafaxine, duloxetine): Increase serotonin and norepinephrine; used for depression, anxiety, and neuropathic pain. o Atypical Antidepressants (e.g., bupropion, mirtazapine): Affect various neurotransmitters; often used for additional benefits like smoking cessation or appetite stimulation. o TCAs (e.g., amitriptyline, nortriptyline): Older agents with significant side effects like sedation and anticholinergic effects. o MAOIs (e.g., phenelzine, tranylcypromine): Reserved for treatment- resistant depression due to dietary and drug interaction risks. 2. Antipsychotics:  o Typical (FGAs): (e.g., haloperidol) Block dopamine receptors; high risk of EPS. o Atypical (SGAs): (e.g., quetiapine, aripiprazole) Block dopamine and serotonin receptors; lower EPS risk but higher metabolic side effects. 3. Mood Stabilizers: o Lithium: Gold standard for bipolar disorder; narrow therapeutic index requiring regular monitoring. o Anticonvulsants (e.g., valproate, lamotrigine): Used as mood stabilizers for bipolar disorder. 4. Anxiolytics: o Benzodiazepines: (e.g., lorazepam, diazepam) Enhance GABA activity; used for short-term anxiety management. o Buspirone: Non-sedating, long-term anxiolytic. 5. Stimulants: o (e.g., methylphenidate, amphetamines): Used for ADHD; increase dopamine and norepinephrine. Counseling Points for CNS Agents 1. Antidepressants: o Onset: Therapeutic effects may take 4–6 weeks. o Risks: Increased suicidal ideation in young adults (18–24 years). o Avoid abrupt discontinuation to prevent withdrawal symptoms. 2. Antipsychotics: o Adherence: Stress the importance of consistent use. o Side Effects: Discuss risks of metabolic syndrome (SGAs) and EPS (FGAs). 3. Mood Stabilizers: o Lithium: Maintain consistent hydration and sodium intake; report signs of toxicity (e.g., tremors, confusion). o Monitor weight, thyroid, and renal function. 4. Anxiolytics: o Benzodiazepines: Warn about dependence risk; reserve for short-term use. o Buspirone: Advise that effects may take weeks to become noticeable. 5. Stimulants: o Timing: Take in the morning to avoid insomnia. o Monitor appetite and growth in children. Developing an Optimal Psychotropic Regimen 1. Patient-Specific Characteristics: o Age: Older adults may require lower doses due to metabolic changes. o Comorbidities: Avoid contraindicated drugs (e.g., bupropion in seizure history). o History: Consider past medication responses. 2. Medication-Specific Characteristics: o Pharmacokinetics: Half-life, metabolism (e.g., CYP450 interactions). o Adverse Effects: Tailor treatment to minimize side effects. o Cost: Consider affordability and insurance coverage. Summary of Drug Interactions, Monitoring Parameters, and Contraindications 1. Clinically Significant Drug Interactions: o SSRIs + MAOIs: Risk of serotonin syndrome. o Lithium + NSAIDs/Diuretics: Increased lithium levels, risk of toxicity. o Benzodiazepines + CNS Depressants: Additive sedation and respiratory depression. 2. Key Monitoring Parameters: o Antidepressants: Mood changes, weight, QTc interval. o Antipsychotics: Lipids, glucose, weight, and EPS. o Lithium: Serum levels, thyroid, and renal function. o Stimulants: Blood pressure, heart rate, and growth in children. 3. Contraindications: o Bupropion: Seizure or eating disorder history. o Clozapine: Agranulocytosis, uncontrolled epilepsy. o Lithium: Significant renal impairment.