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General Psychiatry j. Paliperidone i. The major active metabolite of risperidone. Paliperidone’s pharmacologic profile is similar to that of the parent drug (see the text that follows). ii. Paliperidone palmitate is also available as an LAI in monthly (Invega Sustenna), 3-month (Inv...

General Psychiatry j. Paliperidone i. The major active metabolite of risperidone. Paliperidone’s pharmacologic profile is similar to that of the parent drug (see the text that follows). ii. Paliperidone palmitate is also available as an LAI in monthly (Invega Sustenna), 3-month (Invega Trinza), and 6-month (Invega Hafyera) formulations. As with other LAI formulations, oral tolerability should be established before changing to the LAI. No overlap with oral medication is needed for either LAI formulation; however, both Trinza and Hafyera require onetime pretreatment with Sustenna before switching formulations. iii. Adjustment for renal function is required. k. Pimavanserin i. Currently indicated only for psychosis associated with Parkinson disease, but is being studied as an adjunctive treatment for patients with schizophrenia who have predominantly negative symptoms ii. Lacks affinity for D2 receptors. Is an inverse agonist at serotonin-2C receptors. Although classified as an SGA, it is structurally different from any other member of this class. iii. Has a large volume of distribution and a long half-life (55–60 hours), with an active metabolite with a half-life of 200 hours iv. The most common adverse effects include headache, dizziness, nausea, peripheral edema, and confusion. v. The dose is 34 mg once daily. It is metabolized by CYP3A4. The dose must be tapered when given with a strong 3A4 inhibitor. Pimavanserin should be avoided with strong CYP3A4 inducers. l. Quetiapine i. In addition to antagonism at the D2 and serotonin-2C receptors, quetiapine has a high affinity for histamine-1 receptors. Therefore, quetiapine has a high incidence of somnolence and weight gain. May also cause OH ii. Unlike other antipsychotics, quetiapine has a low incidence of EPS. Hence, quetiapine is often used for psychosis associated with Parkinson disease, despite the lack of strong evidence for efficacy. m. Risperidone i. This drug is a potent dopamine D2 antagonist and a serotonin-2C antagonist with limited anticholinergic activity. ii. At doses of up to 6 mg/day, the incidence of EPS has been no higher than with placebo in clinical studies. However, EPS is a dose-related phenomenon that may occur in patients taking the drug even at usual doses. iii. Patients often tolerate risperidone better than haloperidol. However, this increase in tolerability compared with haloperidol is lost at high doses of risperidone (i.e., adults, 6 mg/day or more or seniors, 4 mg/day or more). iv. Adverse effects include sedation, OH, weight gain, sexual dysfunction, and hyperprolactinemia. v. Dose must be tapered for CrCl less than 30 mL/minute/1.73 m 2 and severe hepatic impairment (Child-Pugh class C). vi. An LAI formulation that is administered intramuscularly (Risperdal Consta) is available and requires refrigeration. This formulation is administered every 2 weeks and requires a 3-week bridge therapy with oral risperidone. vii. Risperidone is also now available as a monthly LAI that is administered subcutaneously (Perseris). This injection does not require oral overlap. viii. Like with other LAIs, tolerability with oral therapy should be established before initiating either of the long-acting formulations of risperidone. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-427 General Psychiatry n. Ziprasidone i. Has a low incidence of metabolic syndrome, but can prolong the QTc interval. Use caution if combining it with other drugs (e.g., tricyclic antidepressants [TCAs] or antiarrhythmics) that can also increase the QTc interval. ii. Ziprasidone is also available in a parenteral formulation for acute agitation. iii. Ziprasidone must be taken with food (at least 500 kcal) to increase absorption. iv. Ziprasidone carries a warning for drug reaction with eosinophilia and systemic symptoms (DRESS), which can be fatal. It consists of three or more cutaneous reactions (including rash or exfoliative dermatitis), eosinophilia, fever, and lymphadenopathy and one or more of the following systemic complications: hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis. J. Treatment Goals 1. Acute a. Reduce acute symptoms. b. Return patient to baseline level of function. 2. Maintenance a. Prevent recurrence of symptoms. b. Maximize functioning and quality of life. K. Nonpharmacologic Treatment of Schizophrenia 1. A comprehensive, person-centered treatment plan should be developed and documented. Elements should include treatment setting, plans for addressing risks of harm to self or others, barriers to adherence, and goals of treatment. 2. Psychosocial interventions that benefit patients include cognitive behavioral therapy (CBT) for psychosis, psychoeducation, supported employment services, cognitive remediation, social skills training, and supportive psychotherapy. 3. Patients with schizophrenia with a history of poor engagement with services that lead to frequent relapse or social disruption, such as homelessness and legal difficulties including imprisonment, should be offered assertive community treatment. 4. Patients with schizophrenia should receive interventions aimed at developing self-management skills and enhancing person-oriented recovery. 5. When assessing adherence, a patient-centered approach is crucial, particularly if anosognosia exists. Methods that enhance the therapeutic alliance, such as motivational interviewing, and that are objective and nonjudgmental have the greatest chance of success. L. Treatment with Antipsychotics 1. Choosing an antipsychotic: In practice, SGAs are preferred as first-line treatment. However, most guidelines recommend either an FGA or an SGA. The 2020 APA guidelines recommend individualizing treatment to the specific patient. This includes gathering information on previous treatment experiences and responses and the patient’s treatment preferences and discussing the potential risk-benefit of potential medications, as well as other treatment options. 2. Therapy initiation a. First episode: Younger patients (children, adolescents, and young adults) or treatment-naive patients may be more sensitive to adverse effects and may respond more quickly to treatment. Hence, it is recommended to start with a lower dose. This may also improve chances of adherence by avoiding adverse effects. Early LAI use has shown benefit in first episodes. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-428 General Psychiatry b. In patients with a history of treatment with antipsychotics, higher doses and more aggressive titrations may be appropriate. c. Older individuals with concomitant physical health issues and medications may need starting doses that are as small as one-fourth to one-half the usual adult starting dose. d. Once medication is initiated, escalation to a therapeutic dose can be achieved relatively rapidly, though this will vary depending on the individual drug. 3. Dose optimization: a. Can be difficult to determine during the acute phase because it may take patients 2–4 weeks to show an initial response with conservative titration; often, more aggressive titration is used for inpatients to hasten response. This must be weighed against the increased risk of adverse effects. It may take longer to show optimal response. b. Data suggest that patients who have experienced less than a 20% response after 2 weeks on a therapeutic dose are unlikely to be much improved at 4–6 weeks (as reflected by a 50% or greater reduction in symptoms). Thus, response should be assessed at 2–4 weeks after achieving a therapeutic dose. c. Patients should continue to be treated with the same medication that improved their symptoms while carefully monitoring for adverse effects, particularly development of metabolic syndrome. Development of metabolic syndrome or problematic adverse effects requires a change in medication to decrease patient-driven cessation of therapy. 4. Therapy duration: The chronicity of schizophrenia usually results in lifelong antipsychotic treatment. Benefits of a particular medication must be weighed against long-term adverse effects (e.g., tardive dyskinesia) when selecting a specific antipsychotic. Relapse rates within the first year of medication discontinuation are greater than 50%; thus, maintaining the antipsychotic at the minimal effective dose continuously may be the best approach for most patients. Long-term therapy should include monitoring for metabolic complications such as diabetes, weight gain, and lipid abnormalities, as well as abnormal movements. 5. Any changes in antipsychotics (other than between FGAs) or discontinuations should be performed gradually to avoid withdrawal symptoms. 6. Treatment-resistant schizophrenia: Clozapine is the agent of choice. See the Clozapine section earlier for more details. 7. Use of several antipsychotics: Current data do not support routine combination of antipsychotics. Some data suggest benefit for augmenting clozapine, but more information is needed. M. Adjunctive Medications 1. Lamotrigine may be beneficial when added to clozapine in patients with partial response. Data do not support the use of other antiseizure medications, including valproate, carbamazepine, and topiramate. 2. Benzodiazepines: May be useful during the acute phase for agitation or anxiety but are less effective for psychotic symptoms. These drugs must also be used with caution in patients with schizophrenia because this population is at high risk of substance use disorder (SUD). 3. Antidepressants are indicated when patients with schizophrenia develop depression. 4. Dexmetomidine, an alpha2-adrenergic agonist with anesthetic and sedative properties, can be used to treat agitation associated with schizophrenia in the acute setting. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-429 AL GRAWANY General Psychiatry II. MAJOR DEPRESSIVE DISORDER (MDD) A. Identification of Depressive Disorders. This overview is based on the DSM-5-TR; please consult for complete diagnostic criteria. 1. MDD is also called unipolar depression, or just depression. MDD is diagnosed when a patient has at least five of the following symptoms almost every day for at least 2 weeks: a. Must have a depressed mood or anhedonia (loss of interest in pleasurable activities) b. Additional symptoms include sleep disturbances, changes in weight or appetite, decreased energy, feelings of guilt or worthlessness, psychomotor retardation or agitation, decreased concentration, and suicidal ideation. c. The symptoms must interfere with the patient’s everyday ability to function. 2. Persistent depressive disorder (dysthymia): Chronic depressed mood occurring more days than not for at least 2 years but that does not meet the criteria for MDD. B. Assessment of Patients with MDD 1. Psychiatric history: A thorough history of symptoms is compared with the diagnostic criteria, and the diagnosis is made from the collected data. 2. Clinician rating scales: Psychometric instruments used to identify depression and assess its severity. Common examples include: a. Hamilton Rating Scale for Depression (HAM-D/HDRS): Often used to show efficacy in clinical trials for FDA approval of antidepressants. A common clinical trial enrollment score is greater than 18 (moderate-severe depression). A response is usually defined as at least a 50% reduction in the HAM-D score. “Remission” is a return to a normal state or a HAM-D of 7 or less. b. CGI (Clinical Global Impressions) scale is a clinician-rated scale that evaluates the severity and improvement of patients overall. c. MADRS (Montgomery-Åsberg Depression Rating Scale) also evaluates symptoms of depression. It is commonly used in clinical trials. 3. Patient rating scales: Patient-completed rating instruments. Answers to the questions are used to identify and assess the level of depression. a. Patient Health Questionnaire-9 (PHQ-9) is based on the DSM-5-TR diagnostic criteria for major depression. The PHQ-9 is easily administered and assessed. For this reason, it is often used in the primary care setting. Patients can be screened with an abbreviated version (the PHQ-2). If patients test positive, the PHQ-9 is administered. The PHQ-9 can also be used to monitor treatment response. b. Beck Depression Inventory (BDI) c. Quick Inventory of Depressive Symptoms (QIDS): Self-Rated d. Geriatric Depression Scale (GDS) 4. Physical examination and laboratory tests: Necessary to rule out physical causes (e.g., thyroid disorders, vitamin deficiencies) that may mimic symptoms of depression 5. Biologic testing: Depression is commonly associated with abnormalities in the dexamethasone suppression test and tests of the thyroid axis. However, these tests are not routinely used in clinical practice. 6. Medications and substances (e.g., interferons, benzodiazepines, barbiturates, alcohol, central nervous system [CNS] depressants, withdrawal from stimulants [cocaine, amphetamines]) can have depression as an adverse effect. Pharmacists should perform a medication and substance use review to identify possible causes. 7. All patients should be screened for suicidal ideation. a. The National Suicide Hotline is 988. b. The website is https://988lifeline.org/. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-431 General Psychiatry C. Therapeutic Options 1. Nonpharmacologic treatment options: Examples include interpersonal psychotherapy and CBT. It takes longer to achieve effective results with psychotherapy than with pharmacotherapy. Psychotherapy may have broader and longer-lasting effects than pharmacotherapy monotherapy. Psychotherapy is recommended as monotherapy for initial treatment in patients with mild to moderate MDD (CBT and interpersonal therapy have the best evidence). Psychotherapy combined with pharmacotherapy is recommended for moderate to severe depression. Combination is more effective than either intervention alone. 2. Pharmacotherapy: Antidepressant therapy may lead to a more rapid response than psychotherapy, but when discontinued, there is a risk of relapse and adverse effects. 3. Electroconvulsive therapy (ECT): Option for refractory depression, depression in pregnancy, psychotic depression, and other conditions for which medications may not be optimal or effective. The usual induction cycle is two or three treatments per week for 6–12 treatments. Maintenance dosing is individualized to the patient, and frequency can vary from weekly to monthly. Temporary memory loss is common, and medications that affect seizure threshold must be tapered or held before treatment. ECT is also suggested as initial treatment if symptoms are severe or life threatening. D. Pharmacotherapeutic Options: Considerations and Keys to Use 1. Selection: All antidepressants are considered equally efficacious. First-line medications include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, and vortioxetine. Consider possible drug-drug and drug-disease interactions, concurrent illnesses, prior responses, family members’ prior responses, patient preference, and cost. 2. Adequate trial: An adequate trial includes the correct drug for the patient and a therapeutic dose for an appropriate duration. A therapeutic trial lasts 4–8 weeks. 3. Response and remission: A response is usually defined as a 50% reduction in symptoms. Remission is a return to normal mood (e.g., HAM-D of 7 or less; PHQ-9 less than 5). Remission is also defined as at least 3 weeks with no symptoms of depressed mood and anhedonia and no more than three remaining symptoms of depression. Remission is the goal of therapy. Optimizing the dose or duration is important for achieving remission. 4. Treatment phases a. Acute i. The goal of this phase is remission. ii. Onset of antidepressant effect: Physical symptoms (energy levels, sleep disturbances) improve before affective symptoms. For this reason, patients with suicidal ideation may be at an increased risk of carrying out plans during this phase and should be closely monitored. Early response (20%–30% reduction in symptoms) in the first 2–4 weeks is a strong predictor of remission at 12 weeks. A patient who has a partial response in the first 4 weeks should be allowed a longer trial (and at the full therapeutic dose) before moving on to other therapy. In general, it takes 4–6 weeks to see the full effect of antidepressants, given the correct drug, dose, and adherence, but it may take as long as 8 weeks to see a response. Remission may take up to 12 weeks. iii. Monitoring therapy: Patients should be monitored for response through interviews or by repeating rating scales. In addition, patients (and their support systems, if available) should be educated about therapy and closely monitored for adverse effects. Although most of the adverse effects are not life threatening, they do affect adherence. iv. Nonresponders: A nonresponder can be changed to another antidepressant within either the same class or a different class. A patient who does not respond to one SSRI may respond to another in the same class, as shown in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-432 General Psychiatry b. Maintenance i. Once a patient has achieved remission, treatment should continue for at least another 6–9 months. ii. Those with risk factors for recurrent depression should receive treatment for 2 years or longer. Risk factors include frequent, recurrent episodes; severe episodes (including psychosis, severe impairment, or suicidality); chronic episodes; presence of comorbid psychiatric or medical conditions; and presence of residual symptoms or difficult-to-treat episodes. 5. Efficacy of antidepressants according to rigorous clinical trials occurs in 60%–70% of patients, regardless of drug. Effectiveness, which is more reflective of clinical practice, is lower, about 50%–60%. The remission rate with one antidepressant trial is about 30%, as seen in the STAR*D trial. 6. Drug interactions (Table 6): Many antidepressants are metabolized or inhibited by CYP enzymes. Table 6. Antidepressants and the CYP Systema 1A2 2C19 2D6 3A4 Substrate Duloxetine Citalopram Escitalopram Fluoxetine Imipramine Vilazodone Amitriptyline Desipramine Duloxetine Fluoxetine Imipramine Nefazodone Nortriptyline Trazodone Venlafaxine Vortioxetine Citalopram Escitalopram Levomilnacipran Nefazodone Trazodone Venlafaxine Vilazodone Inducer Cannabis (smoking) St. John’s wort Tobacco (smoking) Caffeine (high dose) Amitriptyline Fluvoxamine Cannabis Fluoxetine Fluvoxamine Imipramine Inhibitor a St. John’s wort Bupropionb Cannabis Duloxetine Fluoxetine Paroxetine Sertraline Fluvoxamine Nefazodone Boldface type in table body indicates strong inhibitor. Metabolized by CYP2B6. b E. Selective Serotonin Reuptake Inhibitors (Table 7) 1. SSRIs selectively inhibit the reuptake of serotonin into the presynaptic neuron and desensitize the presynaptic serotonin autoreceptor, resulting in increased serotonin concentrations. Two additional SSRIs, vortioxetine and vilazodone, have additional activity and are covered separately in the text that follows. Table 7. SSRI Characteristics Characteristic a Citalopram (Celexa) Escitalopram (Lexapro) Fluoxetine (Prozac) Fluvoxaminea (Luvox) Paroxetine (Paxil) Sertraline (Zoloft) Half-life 32 hr 27–32 hr 1–4 days 15 hr 21 hr 26 hr Active metabolite No No Yesb No No No Usual dose (mg/day) 20–40 10–20 20–60 50–300 10–60 50–200 Maximum daily dose (mg) 40 20 (age > 60) 20 80 300 50 (depression) 60 (anxiety) 200 Indicated only for obsessive-compulsive disorder; seldom used for depression. Norfluoxetine. b ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-433 General Psychiatry 2. The efficacy of SSRIs is equal for the treatment of depression. Adverse effect profiles differ slightly, and patients may tolerate one SSRI better than another. 3. Blockade of serotonin reuptake leads to an increase in serotonin overall and may influence all subtypes of serotonin receptors. Some (serotonin-2A, -2C, -3, and -4) may be responsible for some of the unwanted adverse effects (e.g., insomnia, restlessness, GI concerns). Activation, agitation, anxiety, or panic may occur in some patients, especially during the early phase of therapy. The most common adverse effects associated with this class of agents include GI concerns, insomnia, restlessness, headache, and sexual dysfunction. In general, the most activating SSRIs are fluoxetine and sertraline, whereas paroxetine and fluvoxamine are the most sedating. Citalopram and escitalopram have no appreciable sedating or activating effects. Sexual dysfunction is more common than reported in the prescribing information and may occur in 50% or more of patients receiving these agents. Interventions to consider for SSRIinduced sexual dysfunction include using the wait-and-see method, adding bupropion, and lowering the SSRI dose. PDE-5 (phosphodiesterase type 5) inhibitors may be beneficial for men with erectile dysfunction. Data are less robust for women. Other interventions with weaker data include adding buspirone and mirtazapine. 4. Because these drugs have such potent serotonergic activity, combinations with other drugs affecting serotonin can lead to serotonin syndrome. Examples include the monoamine oxidase inhibitors (MAOIs), dextromethorphan, meperidine, tramadol, sympathomimetics, linezolid, lithium, TCAs, and SNRIs. Although triptans have traditionally been listed among the agents to watch, a 2010 statement released by the American Headache Society reports poor evidence for the interaction. The finding was supported by a 2018 article (JAMA Neurol 2018;75:566-72) suggesting that the FDA reconsider the advisory. Triptans bind to different serotonin receptors than SSRIs or SNRIs and thus pose a low risk. Serotonin syndrome includes symptoms from three clusters: neuromuscular hyperactivity (e.g., myoclonus, rigidity, tremors, incoordination), altered mental status (agitation, confusion, hypomania), and autonomic instability (hyperthermia, diaphoresis). Serotonin syndrome can be subtle in onset or confused with NMS. Several criteria exist to identify serotonin syndrome, with the Hunter criteria considered the most accurate. These rely heavily on neurologic findings, with the presence of clonus being the most prominent, though tremor plus hyperreflexia are also considered adequate for diagnosis. Treatment includes discontinuing the offending agent, providing supportive measures such as cooling blankets and respiratory assistance, and providing cyproheptadine; a benzodiazepine for myoclonus; antiseizure medications; and nifedipine for hypertension. 5. SSRIs have been associated with EPS, including akathisia, dystonia, and bradykinesia, but these are uncommon. EPS appears to result from an effect of serotonin on dopaminergic neurotransmission in the basal ganglia. 6. SSRIs can cause hyponatremia of the SIADH (syndrome of inappropriate antidiuretic hormone secretion) type, particularly in older adult patients. Individuals should be monitored for symptoms suggestive of hyponatremia. 7. A withdrawal syndrome has been observed, especially for the drugs with shorter half-lives, so a gradual dose reduction (e.g., over 2–4 weeks) may be indicated. Symptoms include flu-like symptoms, such as nausea and chills, and neurologic symptoms, such as paresthesias, insomnia, anxiety, and “electric shock”–type sensations. If the problem is severe or persists, the SSRI can be reinitiated and the dose gradually reduced again. The timing of withdrawal syndrome symptoms correlates with SSRI half-life, so withdrawal symptoms occur the earliest with paroxetine. Even though fluoxetine has a significantly longer half-life, withdrawal symptoms may still occur and be delayed in onset. 8. The FDA ordered changes to citalopram package labeling, limiting the daily dose to no more than 40 mg because of an increased risk of QTc prolongation at daily doses greater than 40 mg. Patients who have risk factors for QTc prolongation (congenital long QTc syndrome, bradycardia, hypokalemia, hypomagnesemia, recent acute myocardial infarction, and uncompensated heart failure) or who are taking concomitant medications that may increase the QTc interval should not be treated with citalopram. The ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-434 General Psychiatry maximum recommended citalopram dose is 20 mg/day for patients with hepatic impairment, patients who are older than 60, patients who are 2C19 poor metabolizers, or patients who are taking concomitant 2C19 inhibitors. Studies in these populations taking 40 mg daily have failed to find an increase in mortality despite the warning. 9. These drugs are not as lethal in overdose cases as TCAs. 10. All SSRIs listed in Table 7 are available in generic form. The low cost and better tolerability and safety of SSRIs warrant their use as first-line treatment of MDD in most patients. 11. Extended-dosing formulations: Fluoxetine 90 mg can be taken once weekly. Fluoxetine 90 mg is taken only during continuation therapy rather than as initial treatment. It is not commonly used in clinical practice. Paroxetine controlled release (CR) may have lower rates of nausea in the first week of treatment; efficacy is comparable, and both formulations are administered once daily. The weekly and CR products are available in generic form but are higher in cost. 12. Escitalopram is the S-isomer of citalopram and is the active component of the racemic mixture. At a 10-mg dose, escitalopram is at least as effective as citalopram 20 mg, but at this dose, there are fewer adverse effects. At higher doses, this advantage is not as pronounced. 13. SSRIs appear to modestly increase the risk of bleeding by inhibiting the serotonin reuptake into platelets. 14. This leads to a decrease in serotonin-mediated platelet activation. Case-control and cohort studies also suggest an increased incidence of both vertebral and non-vertebral bone fractures. F. Serotonin-Norepinephrine Reuptake Inhibitors (Table 8) Table 8. SNRI Characteristics Characteristic Desvenlafaxine (Pristiq) Half-life 10–11 hr Active metabolite No Usual dose (mg/day) 50 Maximum daily dose (mg) 100a a Duloxetine (Cymbalta) 8–17 hr No 60 120b Levomilnacipran (Fetzima) 21–29 hr No 40–120 120 Venlafaxine (Effexor) 5–11 hr Yes 75–225 225 Doses > 50 mg do not necessarily confer further benefit. Doses of ~60 mg do not necessarily confer further benefit for depression. Higher doses are beneficial for anxiety and pain. b 1. Venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran block the reuptake of norepinephrine and serotonin. Although milnacipran is considered an SNRI, it is only FDA approved for fibromyalgia. Unlike TCAs, SNRIs have negligible effects at other receptors that cause anticholinergic or antihistaminic adverse effects, with the possible exception of duloxetine, which appears to have a slightly higher incidence of anticholinergic symptoms. Venlafaxine has a dose-related effect on norepinephrine compared with desvenlafaxine and duloxetine. At doses of less than 150 mg/day, venlafaxine is a serotonin reuptake inhibitor. a. Whether the dual action of venlafaxine makes it more effective than SSRIs is an area of continued research. Some patients (e.g., treatment nonresponders or those with significant anhedonia) appear to benefit either from agents that affect norepinephrine and serotonin or from combinations of drugs with that effect. b. The adverse effect profile of venlafaxine is similar to that of the SSRIs, with GI concerns being common. Of note, SNRIs can cause increases in blood pressure, which are usually mild and not clinically significant unless the patient has uncontrolled hypertension. This is a dose-related phenomenon, as described earlier, particularly for venlafaxine and desvenlafaxine. Levomilnacipran and desvenlafaxine are also associated with OH. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-435 General Psychiatry 2. Levomilnacipran is the more potent enantiomer of milnacipran. Levomilnacipran is only approved for depression, not fibromyalgia. The dose must be adjusted in renal insufficiency, and the drug is not recommended in end-stage renal disease. Levomilnacipran can cause hyponatremia and increase bleeding risk. The capsule should not be crushed or opened. Levomilnacipran is metabolized through 3A4 (major pathway) and 2C19 and 2D6, among others (minor pathways). Monitor signs and symptoms of potential toxicities if 3A4 inhibitors are used concomitantly. Both blood pressure elevations and OH can occur. Levomilnacipran can cause an elevated heart rate and palpitations, which are common reasons for discontinuation. Levomilnacipran is a more potent inhibitor of norepinephrine than venlafaxine or duloxetine (norepinephrine is slightly preferred to serotonin). 3. All SNRIs can produce serotonin syndrome. In overdose situations, both duloxetine and venlafaxine have been associated with higher rates of death than SSRIs. The risk of death because of overdose of SNRIs is still lower than with TCAs. 4. Duloxetine has also been approved for the treatment of diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain caused by chronic lower back pain or osteoarthritis pain. Be careful when using this drug with 2D6 inhibitors. Monitor blood pressure because increases have been observed. Duloxetine can cause liver toxicity and should not be used in patients with hepatic insufficiency, end-stage renal disease requiring dialysis, or severe renal impairment. 5. SNRIs can cause a withdrawal syndrome similar to the SSRIs and thus should be tapered slowly when discontinued. 6. Desvenlafaxine is an active metabolite of venlafaxine. Benefits over the parent drug are limited. Because it bypasses CYP metabolism, it may be advantageous in patients with hepatic insufficiency or those taking major 2D6 inducers or inhibitors. 7. Renal dosing is required for both desvenlafaxine and levomilnacipran. G. Mixed Serotonergic Medications 1. Vilazodone (Viibryd) is an SSRI with partial agonist activity at the serotonin-1A receptor. The clinical significance of this effect is unknown. Vilazodone has a half-life of 25 hours but does not have active metabolites. Both the usual and maximum doses are 40 mg daily. Vilazodone should be taken with food. The most common adverse effects are nausea and diarrhea. Vilazodone may cause a lower incidence of sexual dysfunction. Vilazodone should not be used in patients with a history of seizure disorder. The dose must be decreased when given with strong 3A4 inhibitors. Postmarketing reports include acute pancreatitis and sleep paralysis, but the true frequency is unknown, and the FDA labeling has not been changed. 2. Vortioxetine (Trintellix) is an SSRI, but its pharmacologic profile differs from other SSRIs. Vortioxetine has additional agonist activity at the serotonin-1A receptor, partial agonist activity at the serotonin-1B receptor, and antagonistic activity at the serotonin-3, serotonin-1D, and serotonin-7 receptors. The clinical significance of vortioxetine’s effect on the serotonin receptors is currently unknown, but in patients with depression, it also appears to improve measures of cognitive function that appear independent of its antidepressant effects. Vortioxetine has a half-life of 66 hours and no active metabolites. The starting and usual dose is 10 mg daily, with a maximum daily dose of 20 mg. Vortioxetine is metabolized by 2D6, and the maximum dose for poor metabolizers or patients taking a strong 2D6 inhibitor is 10 mg daily. Vortioxetine also appears to be associated with a lower incidence of sexual dysfunction. Common adverse effects include nausea, dizziness, vomiting, xerostomia, and diarrhea or constipation. 3. Trazodone (Desyrel): A serotonin reuptake inhibitor that also blocks serotonin-2A receptors. Trazodone does not cause anticholinergic or cardiotoxic effects, as do the TCAs, but it still causes OH and sedation. Because of its sedative properties (mediated by histamine-1 antagonism), trazodone is often used for insomnia but at lower doses than for depression. It is important to be aware of the potential for priapism, even though it is rare (0.1% or less). Patients should be educated about this risk, and it should be treated as a medical emergency. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-436 General Psychiatry 4. Nefazodone (Serzone): Nefazodone is a serotonin-2A antagonist like trazodone, but it also blocks the reuptake of serotonin and norepinephrine. Some have called this class “serotonin antagonist reuptake inhibitors” (serotonin-2A antagonist/reuptake inhibitors). Unlike trazodone, nefazodone has minimal effects on sexual function and is less likely to cause OH. Data suggest that the serotonin-2A–blocking activity makes nefazodone more effective for anxiety associated with depression. Nefazodone’s short half-life makes it necessary to administer doses twice daily. The most common adverse effects include sedation, GI concerns, dry mouth, constipation, confusion, and light-headedness. Because nefazodone is a potent inhibitor of 3A4, caution is necessary when using it concomitantly with drugs metabolized by this system. Given the potential for liver toxicity and its black boxed warning, nefazodone is now considered a second- or third-line agent. Liver function tests must be monitored if nefazodone is used. H. Mirtazapine (Remeron) 1. Mirtazapine is an antagonist of presynaptic α2-autoreceptors and heteroreceptors, which results in an increase in norepinephrine and serotonin release in the synapse. In addition, the drug blocks serotonin-2A (resulting in minimal to no sexual dysfunction, anxiety, or sedation), serotonin-3 (no nausea or GI disturbances), and serotonin-2C (weight gain) receptors. 2. Although mirtazapine is better tolerated than the TCAs, it still has a pronounced sedative effect, together with increased appetite, weight gain, constipation, and asthenia. 3. Abnormal liver function tests may occur, and there appears to be a very small risk of neutropenia or agranulocytosis. 4. Lower doses may be sedating, whereas higher doses may cause insomnia. I. Bupropion (Aplenzin, Forfivo, Wellbutrin) 1. Bupropion is primarily an inhibitor of dopamine and norepinephrine reuptake with minimal effects on serotonin. Bupropion’s exact mechanism of action remains to be defined. The parent drug blocks dopamine reuptake, whereas the metabolite blocks norepinephrine reuptake. 2. The most important adverse effect is increased risk of seizures. This risk can be minimized by the following: a. Avoid use in susceptible patients (e.g., history of seizure disorder, eating disorders). b. Do not give more than 150 mg/dose or 450 mg/day (immediate release [IR] or ER) or 400 mg/day (sustained release [SR]). c. Avoid dosage titration more often than every 4 days for SR or ER and every 3 days for IR. d. The SR and ER products may also cause fewer adverse effects; they have largely replaced the IR tablets. 3. The most common adverse effects include insomnia, anxiety, irritability, headache, and decreased appetite. Bupropion may also increase energy and cause psychosis in susceptible individuals. As noted previously, bupropion may actually improve sexual function; thus, it may be useful in patients not tolerating other agents for this reason. Bupropion has also been used off-label for attention-deficit/ hyperactivity disorder and may help with concentration. J. Tricyclic Antidepressants 1. TCAs are effective, but adverse effects have limited their use. Now that newer agents with more tolerable adverse effect profiles are available, TCAs are used less often. TCAs have several off-label uses such as treatment for pain syndromes, migraine prophylaxis, and anxiety disorders. 2. TCAs block serotonin and norepinephrine uptake. Tertiary amines such as amitriptyline and imipramine are more potent for serotonin uptake and are metabolized to active secondary amines. The corresponding secondary amines (nortriptyline and desipramine, respectively) are more selective for norepinephrine and have less anticholinergic activity. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-437 General Psychiatry 3. TCAs have α-adrenergic blockade, antihistaminic effects, and anticholinergic effects, leading to orthostasis, sedation, and anticholinergic symptoms, respectively. TCAs can cause sexual dysfunction. 4. TCAs can be cardiotoxic in overdose, causing prolonged QTc intervals and torsades de pointes as well as seizures (Table 9). An ECG should be monitored in patients older than 40 years who are initiated on TCAs. An actively suicidal patient should not receive a TCA. Table 9. Adverse Effect Profile of Commonly Used TCAs Drug Tertiary amines Amitriptyline Imipramine Secondary amines Desipramine Nortriptyline Anticholinergic Sedation Orthostatic Hypotension Cardiotoxicity High Moderate High Moderate Moderate High High High Low Moderate Low Moderate Moderate Low Moderate Moderate 5. TCAs are not recommended in patients with cardiac disease or seizure disorders. Patients at risk of OH are at increased risk of falls if they take these agents, and appropriate caution should be taken. 6. TCA serum concentrations can confirm adherence or toxicity. However, this is an infrequent clinical practice. 7. A withdrawal syndrome occurs if these drugs are discontinued too quickly. Symptoms reflect the reversal of anticholinergic effects and include lacrimation, nausea, and diarrhea, with insomnia, restlessness, and possible balance problems. Gradual dose reductions help reduce these symptoms. K. Monoamine Oxidase Inhibitors 1. MAOIs irreversibly block the enzyme responsible for the breakdown of certain neurotransmitters, such as norepinephrine. There are two forms of this enzyme (MAO-A and MAO-B), and drugs can block one or both of them. 2. Nonselective MAOIs (isocarboxazid, phenelzine, and tranylcypromine) are available in the United States. 3. Patients taking MAOIs must be educated and monitored to avoid foods high in tyramine (e.g., aged cheese, preserved meats, wine, beer) because of the potential for precipitating a hypertensive crisis. A dietary consultation can be helpful in this respect. 4. Drug interactions with MAOIs are considerable and include over-the-counter decongestants, antidepressants, stimulants, and antihypertensives. When changing a patient from another antidepressant to an MAOI, it is prudent to wait 2 weeks after the antidepressant is discontinued before initiating the MAOI (except for fluoxetine, in which case the waiting period should be 5–6 weeks, and vortioxetine is 3 weeks) to avoid serotonin toxicity. When a patient is changed from an MAOI to another antidepressant, a 2-week washout period is usually adequate. 5. Selegiline (MAO-B inhibitor) is available in a patch formulation for depression. Selegiline is available in doses of 6 mg/24 hours, 9 mg/24 hours, and 12 mg/24 hours. Once the dose reaches 9 mg/24 hours, an MAOI diet is required. How this drug compares with other antidepressants remains unknown. L. Antidepressants and Suicidality: All antidepressants have an FDA black boxed warning for an increased risk of suicidal thinking and behaviors in children, adolescents, and young adults (up to 24 years of age). Risk is highest at treatment initiation or dose adjustment. Other signs to watch for include agitation and anxiety (activation syndrome) and other symptoms that are unlike the patient’s presenting symptoms of depression. A medication guide must be distributed before antidepressants are dispensed. The warning ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-438