General Psychiatry PDF

General Psychiatry a. Delusions: Fixed false beliefs involving misinterpretations of reality that are resistant to evidence refuting them. Trying to dispel a delusion can undermine therapeutic alliance. Examples include persecutory (e.g., someone is going to get me), paranoid (e.g., someone i...

General Psychiatry a. Delusions: Fixed false beliefs involving misinterpretations of reality that are resistant to evidence refuting them. Trying to dispel a delusion can undermine therapeutic alliance. Examples include persecutory (e.g., someone is going to get me), paranoid (e.g., someone is watching), and command (e.g., someone told me to do it). b. Hallucinations: Perceptual abnormalities that can involve any sensory system. Auditory hallucinations are the most common. c. Disorganized speech: This manifests as frequent “derailment” of speech or incoherence. i. “Loose associations”: Going from one unrelated topic to another as though the topics were connected ii. “Tangential” speech refers to answers to questions that are only slightly related or that are totally unrelated to the question. iii. “Word salad” refers to speech that is almost incomprehensible and is very much like receptive aphasia. d. Grossly disorganized or catatonic behavior e. Negative symptoms (Table 1) 2. Schizophrenia can be divided into positive, negative, and cognitive symptoms (see Table 1). 3. Anosognosia: Many patients (57%–98%) with schizophrenia may lack awareness of or insight into their illness, particularly during an acute episode. Anosognosia may or may not improve with treatment. It is the most common predictor of nonadherence and predicts higher relapse rates, more involuntary treatments, poorer psychosocial functioning, aggression, and a poorer course of illness. Table 1. Categories of Schizophrenia-Associated Signs and Symptoms Positive (presence of something that should not be there) Antipsychotics are most effective Hallucinationsa Delusionsa Paranoia or suspiciousnessa Negative (absence of something that should be present) Antipsychotics may not be completely effective Blunted or flat affecta Social withdrawal (passive-apathetic)a Lack of personal hygiene Conceptual disorganizationa,b Hostilitya Grandiositya Excitementa Prolonged time to responda Poor rapporta Poor abstract thinkinga Poverty of speech (lack of spontaneity and flow of conversation)a Emotional withdrawala Alogia (poverty of speech) Ambivalence (simultaneous, contradictory thinking); prevents decision-making Asociality; internally directed Amotivation (avolition) Anhedonia Loose associations Thought broadcasting Thought insertion Cognitive No current medications effectively treat Poor executive function Impaired attention Impaired working memory (does not learn from mistakes) These symptoms are used to score the positive and negative portions of the Positive and Negative Syndrome Scale (PANSS). Conceptual disorganization, according to the Brief Psychiatric Rating Scale (BPRS), is the “degree to which speech is confused, disconnected, vague or disorganized.” This includes tangential thinking, circumstantiality, sudden topic shifts, incoherence, derailment, blocking, neologisms, clanging, word salad, and other speech disorders. a b ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-416 General Psychiatry B. Course of Illness 1. Onset is usually between adolescence and early adulthood. Schizophrenia occurs earlier in men (i.e., early 20s) than in women (i.e., late 20s to early 30s). The prevalence is around 1.1% and is equal between the sexes. 2. Some patients fluctuate between acute episodes and decreased or absence of positive symptoms. Residual symptoms are often present between episodes. 3. The lifetime course of schizophrenia has four phases: prodromal, acute, stabilization, and stable. a. Prodromal: Characterized by the gradual development of symptoms that may go unnoticed until a major positive symptom occurs. This phase may include isolation, deterioration of hygiene, loss of interest in work or school, and dysphoria. b. Acute: Clinically significant positive symptoms are present, often requiring hospitalization. Patients may be unable to care for themselves during this phase. c. Stabilization: The acute symptoms begin to decrease, and this phase may last for several months. d. Stable: During this phase, positive symptoms have markedly declined and may not be present. Negative symptoms may resolve. Cognitive symptoms may be present. Nonpsychotic symptoms such as anxiety and depression may be present. 4. Complete remission without symptoms is uncommon. C. Causes 1. The causes of schizophrenia are unknown. Schizophrenia appears to involve neurophysiologic and psychological abnormalities. 2. The primary neurotransmitters believed to be involved in the cause are dopamine and serotonin. The exact relationship between these neurotransmitters remains unknown. In some areas of the brain, dopamine overactivity appears to result in some symptoms, whereas in others, underactivity may occur. Glutamatergic receptor dysfunction may also play a role in causing schizophrenia. Glutamate is associated with several processes that involve cognition, memory, and perception. 3. Schizophrenia is likely a constellation of disorders rather than one distinct disorder. It likely results from a combination of genetics and environment. Many potential risk factors for schizophrenia have been identified, including a family history of schizophrenia, perinatal trauma (e.g., hypoxia, fetal distress, influenza, and nutritional deficiencies), obstetric complications, living in an urban area, having stress, and being born during the winter. D. Rating Scales 1. The Brief Psychiatric Rating Scale (BPRS), developed in 1962, is a general psychiatric rating scale that has been used to measure outcomes in clinical trials, including those involving schizophrenia. 2. The Positive and Negative Syndrome Scale (PANSS) is a 30-item, 7-point scale that was partly adapted from the BPRS. Lower scores mean fewer symptoms. The PANSS is considered the gold standard and is widely used to evaluate antipsychotic therapy in clinical trials but not in daily clinical practice. This scale requires a 45-minute interview with the patient. The interviewer must be specially trained to administer it. 3. The PANSS-6 is a scalable abbreviated version of the PANSS that can be used clinically. It consists of the following components: delusions, conceptual disorganization, hallucinations, blunted affect, social withdrawal, and lack of spontaneity and flow of conversation. It is sensitive to changes in treatment. A score of less than 14 signifies remission. E. Antipsychotics 1. First-line agents for treating schizophrenia 2. Two classes ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-417 General Psychiatry a. First-generation antipsychotics (FGAs; also called typical or conventional antipsychotics; Table 2). These include all the older antipsychotics. Chlorpromazine, a phenothiazine, was the first to be used clinically. Table 2. First-Generation Antipsychotics for Schizophrenia Agent Dose Potencya Anticholinergic Sedation Orthostatic Extrapyramidal Equivalent Hypertension Symptoms (mg) Chlorpromazine (Thorazine)b 100 Low 2 High Haloperidol (Haldol) 2 High Loxapine (Adasuve, Loxitane) 10 Int. Molindone (Moban) — — 10 Int. Fluphenazine (Prolixin) Perphenazine (Trilafon) b b Pimozide (Orap) Thioridazine (Mellaril)b Thiothixene (Navane) Trifluoperazine (Stelazine) b 2 High 100 Low 4 High 5 Int +++ + + ++ + ++ + +++ + ++ ++++ + + ++ ++ ++ + +++ + + +++ + + ++ + ++ + +++ + + ++ +++ +++ ++ ++ ++ +++ + +++ ++ Potency = D2 receptor affinity. b Phenothiazine. Int. = intermediate. a i. These agents can be categorized according to potency as antagonists at the dopamine D2 receptors, which are thought to be the mechanism of pharmacologic activity, particularly in the mesolimbic areas of the brain for treating psychotic symptoms. Blockade in the mesocortical areas may worsen negative and cognitive symptoms. Potency at the D2 receptors can be split into low, intermediate, and high. FGAs can be interconverted using chlorpromazine dose equivalents. ii. Adverse effect profiles also differ by potency and are relatively uniform for agents with similar dopamine potency. (a) Low potency: Concomitant anticholinergic, antihistaminic, and α-adrenergic blocking properties are also present. (b) High potency: Less potency at the other receptors; dopamine-related adverse effects, including extrapyramidal symptoms (EPS) and hyperprolactinemia, tend to be the main adverse effects and are more prevalent than with low-potency agents. (c) Sedation: More common with low-potency agents. Sedation is usually worse initially and then better tolerated with time. Sedation tends to be dose related. (d) Anticholinergic effects: More common with low-potency agents. Dry mouth, constipation, blurred vision, and urinary hesitancy can occur. Dose-dependent. (e) Orthostatic hypotension (OH): More common with low-potency agents because of blockade of the α-adrenergic receptor. b. Second-generation antipsychotics (SGAs; also called atypical antipsychotics; see Table 3): These include the newer agents, beginning with clozapine. The adverse effect profile of SGAs is more heterogeneous and differs from that of FGAs. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-418 General Psychiatry Table 3. Second-Generation Antipsychotics for Schizophrenia Drug (generic/ brand) Metabolic Syndrome Anticholinergic Sedation Orthostasis Weight Glucose Dyslipidemia Gain Abnormality Extrapyramidal Symptoms Akathisia Parkinsonism + + + + + + ++ + ++ ++ ++ + ++ ++ ++ + + + ++ + ++ + ++ + ++ + + ++ ++ ++ ++ + +++ +++ +++ +++ +++ +++ + + ++ ++ + + + +++ + + Lumateperone (Caplyta) + - - + + + - - Lurasidone (Latuda) + ++ ++ + + + ++ ++ Olanzapine (Zyprexa) +++ +++ +++ ++ ++ ++ ++ ++ Paliperidone (Invega) ++ + ++ + + ++ ++ ++ Quetiapine (Seroquel) ++ ++ +++ ++ +++ ++ + + Risperidone (Risperdal) ++ ++ + + ++ ++ ++ ++ Ziprasidone (Geodon) + + + + ++ ++ ++ + Aripiprazole (Abilify) Asenapine (Saphris) Brexpiprazole (Rexulti) Cariprazine (Vraylar) Clozapine (Clozaril) Iloperidone (Fanapt) i. SGAs were developed to reduce EPS adverse effects, including tardive dyskinesia, and to improve efficacy. The characteristics that define “atypicality” are not all agreed on, but in general, they all share at least three characteristics: (a) The risk of EPS is lower than with typical antipsychotics at usual clinical doses, (b) The risk of tardive dyskinesia is reduced, and (c) The ability to block serotonin-2A receptors is present. This third property may improve the negative symptoms of schizophrenia and reduce the risk of EPS. This may also be related to SGA efficacy in mood disorders. ii. Some unique mechanisms exist among individual SGAs that may influence the effects on symptoms of schizophrenia: (a) Some low-potency SGAs, including quetiapine and clozapine, have faster dissociation/ weaker affinity binding at D2 receptors. (b) Some SGAs have partial agonism at D2 receptors (aripiprazole, brexpiprazole, cariprazine). This may stabilize dopamine transmission by reducing D2 hyperactivity in the mesolimbic neurons. (c) Cariprazine has high potency at D3 receptors, with may confer some benefit against negative and cognitive symptoms. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-419 General Psychiatry (d) Many SGAs have partial activity at serotonin-1A receptors. This may increase the release of dopamine in the prefrontal cortex, which may benefit cognition. It may also decrease EPS and improve mood. Clozapine, quetiapine, and ziprasidone have some serotonin-1A activity, but aripiprazole, brexpiprazole, and cariprazine appear to have more potent activity. iii. Many clinicians see SGAs as first-line agents, likely because of the decreased risk of EPS. SGAs (particularly clozapine and olanzapine) have been associated with new-onset diabetes and metabolic syndrome. All patients prescribed SGAs should be monitored for BMI, blood pressure, fasting glucose, lipids, and waist circumference at baseline and periodically thereafter according to the American Psychiatric Association (APA)/American Diabetes Association (ADA) consensus recommendations. F. Adverse Effects of Antipsychotics 1. All antipsychotics carry a black boxed warning against use in older adults with dementia. FGAs may have a higher mortality rate than SGAs when used in older adults with dementia. 2. Some antipsychotics indicated for the treatment of mood disorders (particularly depression) carry a black boxed warning for an increased risk of suicidal thoughts and behavior in children, adolescents, and young adults (24 years and younger) similar to antidepressants (see the Major Depressive Disorder [MDD] section in the text that follows for more details). The antipsychotics included in this warning are aripiprazole, brexpiprazole, cariprazine, lumateperone, lurasidone, and quetiapine. 3. EPS: Can occur with all antipsychotics, but are most common among the FGAs, particularly the high-potency agents. EPS are thought to result from blockade of D2 receptors in the nigrostriatal pathway. There are four main manifestations: a. Pseudoparkinsonism: This is manifested by symptoms such as bradykinesia, rigidity, tremor, or akinesia. If possible, the dose of the antipsychotic should be lowered or the patient changed to another antipsychotic with less possibility of causing parkinsonism. If neither is possible, parkinsonism is usually responsive to oral anticholinergic agents such as diphenhydramine, trihexyphenidyl, and benztropine. b. Dystonia: These episodes are often acute. The risk is greatest in young men and with high doses of parenteral antipsychotics. Examples include torticollis, laryngospasm, and oculogyric crisis. Acute dystonia is treated with intramuscular anticholinergics. Oral anticholinergics are often used to prevent dystonias in high-risk patients. c. Akathisia: This is a somatic restlessness and inability to stay still or calm. Reducing the antipsychotic dose and changing to an agent with a lower incidence of akathisia are the best options, but these are not always feasible. Akathisia responds poorly to anticholinergics. Lipophilic (fat soluble) β-blockers such as propranolol are typically used. Data analyses for efficacy are inconclusive, but β-blockers are commonly used in practice. Benzodiazepines can also be used to treat akathisia but are considered second line behind β-blockers. Agents with serotonin-2 activity, including mirtazapine (which has the most evidence), trazodone, and cyproheptadine, may also be helpful. d. Tardive dyskinesia: Characterized by abnormal involuntary movements that occur with long-term antipsychotic therapy. Tardive dyskinesia usually involves the orofacial muscles and is often insidious. With continued drug exposure, particularly at high doses, tardive dyskinesia is often irreversible. Risks are likely related to the total cumulative dose. Those taking high antipsychotic doses, those older than 54 years, women, and those with mood disorders are also at an increased risk. Symptoms may decrease over time with lowering the antipsychotic dose (after an initial symptom increase). However, this dose reduction must be weighed against worsening symptoms of schizophrenia. Changing to an agent that is associated with less tardive dyskinesia is also an option. The risk is higher with FGAs than with SGAs. Clozapine has not been associated with tardive dyskinesia, and changing to this drug may be appropriate for patients with moderate to severe symptoms. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-420 General Psychiatry The other SGAs also appear to have a low potential to cause tardive dyskinesia. Patients taking antipsychotics should be monitored at least annually using a rating scale, such as AIMS (Abnormal Involuntary Movement Scale) or DISCUS (Dyskinesia Identification System Condensed User Scale). i.  Valbenazine (Ingrezza) and deutetrabenazine (Austedo) are both U.S. Food and Drug Administration (FDA) approved as the first drugs to carry an indication for tardive dyskinesia. The exact mechanism of action is unknown, but both agents reversibly and selectively inhibit the vesicular monoamine transporter 2 (VMAT2). This transporter regulates the packaging of dopamine and other monoamines in the neuronal cytoplasm into vesicles for storage and release into synapses. Valbenazine is dosed once daily and must be adjusted for strong 3A4 and 2D6 inhibitors. Deutetrabenazine is dosed twice daily and must be adjusted for strong 2D6 inhibitors. Adverse effects of both include sleepiness, depression, and QTc prolongation. Deutetrabenazine carries a black boxed warning regarding increased risk of suicidality. Tetrabenazine, a VMAT2 inhibitor indicated for the treatment of chorea associated with Huntington disease, is also used off-label for tardive dyskinesia. ii. Anticholinergic agents should not be given to treat tardive dyskinesia and may in fact worsen the symptoms. 4. Neuroleptic malignant syndrome (NMS): Occurs with all agents but is more common with highpotency FGAs. This syndrome is manifested by agitation, confusion, changing levels of consciousness, muscle rigidity, fever, tachycardia, autonomic instability, and diaphoresis. The mortality rate is high and should be treated as a medical emergency. Discontinue the offending agent and give supportive therapy, including fluids and cooling. Bromocriptine and dantrolene have been used with varying success. Do not reinitiate antipsychotics until at least 14 days after resolution of NMS symptoms. 5. Hyperprolactinemia: Antipsychotics, particularly FGAs, can block the effects of dopamine in the tuberoinfundibular pathway. This increases prolactin excretion, which can lead to breast enlargement, galactorrhea, sexual dysfunction, infertility, and menstrual changes. Among the SGAs, risperidone and paliperidone carry the highest risk of hyperprolactinemia. Aripiprazole, with its partial dopaminergic agonist activity, has been shown to lower prolactin concentrations. 6. Sexual dysfunction: Erectile dysfunction occurs in 23%–54% of men. Loss of libido and anorgasmia may occur in men and women. 7. Weight gain and diabetes: Weight gain occurs in up to 40% of patients. Diabetes can also develop, with 60% of cases occurring within the first 6 months. Among the SGAs, the risk is highest with clozapine and olanzapine, followed by quetiapine and risperidone. Among the FGAs, low-potency agents have a higher risk than high-potency agents. Important interventions include keeping the dose as low as possible and implementing dietary management to minimize weight gain. Weight gain may occur because of actions at histamine or serotonin receptors. 8. QTc prolongation: Electrocardiographic (ECG) changes occur with antipsychotics. QTc prolongation can predispose the patient to ventricular arrhythmias, including torsades de pointes. The risk of QTc prolongation appears highest with chlorpromazine, intravenous haloperidol, and thioridazine. Among the SGAs, clozapine, ziprasidone, and iloperidone appear to have the highest risk, though the other agents may cause ECG changes to a lesser extent or when combined with other agents that prolong the QTc interval. Patients must be assessed for predisposing factors such as preexisting ECG abnormalities, electrolyte disturbances, and concurrent therapy with other drugs that prolong the QTc interval. A list of medications that can prolong the QTc is available at https://www.crediblemeds.org/. 9. Seizures: Antipsychotic medications lower the seizure threshold. The risk is highest with predisposing factors such as pre-existing seizure disorder or concomitant treatment with other medications that lower the seizure threshold. Chlorpromazine, cariprazine, and clozapine carry the highest risk. Aripiprazole, fluphenazine, haloperidol, pimozide, risperidone, thioridazine, and trifluoperazine carry the lowest risk. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-421 General Psychiatry 10. Thermoregulation: Antipsychotics are associated with poikilothermia, or difficulty regulating the body temperature. Patients should use caution when exercising or during exposure to high temperatures because hyperthermia can occur. In addition, the anticholinergic effects of antipsychotics can interfere with sweating, further compounding the problem. Patients should be educated to avoid the heat and, if they cannot, to hydrate well. Hypothermia is a risk with low temperatures. Thermoregulatory problems are more common with low-potency FGAs, but they are also possible with SGAs that have more anticholinergic properties, such as clozapine, olanzapine, and quetiapine. G. Drug-Drug Interactions: Many antipsychotics are metabolized by the cytochrome P450 (CYP) system (Table 4). The presence of a CYP inducer or inhibitor may require antipsychotic dose adjustment. For example, tobacco dependence, particularly smoking, is common in patients with schizophrenia. A patient taking a CYP1A2 substrate antipsychotic who undergoes smoking cessation may require a reduced antipsychotic dose. This is particularly true of clozapine, olanzapine, and asenapine. Many SGAs metabolized by 2D6 and/or 3A4 carry dose adjustment recommendations. Table 4. Selected Antipsychotics and the CYP System a 1A2 2D6 3A4 Substrate Asenapine Clozapinea Olanzapine Ziprasidone Aripiprazole Brexpiprazolea Iloperidonea Perphenazine Risperidone Aripiprazole Brexpiprazolea Cariprazinea Haloperidol Iloperidonea Lumateperoneb Lurasidonea Pimavanserina Quetiapinea Ziprasidone Inducer Cannabis (smoking) Tobacco (smoking) Inhibitor Caffeine (high dose) Cannabis Chlorpromazine Fluphenazine Dose adjustment required when used concomitantly with an inhibitor or inducer of that specific CYP enzyme. Avoid use with concomitant inducers or inhibitors. b H. FGAs for Schizophrenia: Administration Tips and Specific Agents 1. Oral tablet therapy is the most common. 2. Parenteral antipsychotics can be used acutely if patients do not adhere to therapy, are agitated and will not take oral medications, or are a danger to themselves and/or others. Several FGAs are available as parenteral injections that are given intramuscularly, including fluphenazine and chlorpromazine, but haloperidol is most commonly used. Intravenous haloperidol has been linked to cardiac toxicity, including torsades de pointes, and is not recommended. 3. Loxapine is available in an inhalable formulation for the treatment of agitation associated with schizophrenia or type I bipolar disorder. Patients should be screened for pulmonary disease. Inhalable loxapine should not be administered to patients with a history of asthma, chronic obstructive pulmonary disease, or other forms of bronchospasm. Loxapine has a Risk Evaluation and Mitigation Strategies (REMS) program associated with the bronchospasm. Health professionals must be specially trained on the Adasuve system and have supplies on hand to treat bronchospasm, including a shortacting bronchodilator such as albuterol, a nebulizer, and nebulizer solution. The most common adverse effects include dysgeusia, sedation, and throat irritation. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-422 General Psychiatry 4. Depot forms (or long-acting injectables [LAIs]) of haloperidol and fluphenazine are available, providing sustained concentrations for about 1 month for haloperidol and 2–3 weeks for fluphenazine. LAIs are indicated as chronic therapy in patients who have benefitted from and have tolerability to oral therapy, but may have difficulty adhering to taking a daily medication, or patient preference. Both haloperidol and fluphenazine decanoate may require “bridging” (oral overlap) with oral therapy when treatment is initiated. Haloperidol decanoate can alternatively be loaded without the need for overlap with oral medication. Both haloperidol decanoate and fluphenazine decanoate contain sesame oil and thus should be avoided in patients with relevant allergies. I. SGAs for Schizophrenia: Specific Agents 1. Clozapine: The first “atypical” antipsychotic. Clozapine is indicated only for treatmentresistant schizophrenia (defined as lack of response to two or more adequate trials of antipsychotics, usually of different classes). Lack of response usually refers to positive symptoms, though it may also include negative symptoms. Clozapine is also indicated in patients with schizophrenia or schizoaffective disorder who have suicidal ideation. The American Psychological Association (APA) endorses this indication, as well as clozapine for patients with schizophrenia with substantial aggressive behavior despite other treatments. Clozapine is not associated with EPS or tardive dyskinesia, and it better reduces negative symptoms than FGAs. a. Several black boxed warnings limit its use. i. Severe neutropenia (agranulocytosis): This is the most limiting adverse effect. Severe neutropenia can lead to a dramatic decrease in neutrophils, which increases the risk of serious or fatal infections. Severe neutropenia is defined as an absolute neutrophil count (ANC) less than 500 cells/mm3. The incidence is about 0.9% and is highest during the first 4–6 months of therapy. Previously, both the white blood cell count and the ANC were used to monitor safety. As of 2015, only the ANC is used, and lower values are allowed for therapy. Allowances are also made for patients who have benign ethnic neutropenia (BEN; included in Table 5). Because of the severity of the neutropenia, all patients must be registered under a centrally managed REMS program (www.newclozapinerems.com), which consolidates the six previous individual programs. Prescribers and pharmacies must also be registered. Laboratory work must be submitted to the national registry before clozapine can be dispensed. Table 5 presents details of hematologic monitoring. Table 5. Hematologic Monitoring for Clozapine ANC Concentration Clozapine Treatment Recommendations ANC Monitoring Normal range for a new patient: Initiate treatment Weekly from initiation to 6 mo General population (> 1500 cells/mm3) If treatment interrupted: Every 2 wk from 6 to 12 mo < 30 days, continue monitoring as before Monthly after 12 mo BEN population ≥ 30 days, monitor as if new patient (≥ 1000 cells/mm3) Obtain at least two baseline ANC concentrations before initiating treatment ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-423 General Psychiatry Table 5. Hematologic Monitoring for Clozapine (Cont’d) ANC Concentration Clozapine Treatment Recommendations ANC Monitoring Mild neutropenia (1000–1499 cells/mm3)a GENERAL POPULATION GENERAL POPULATION Continue treatment Three times weekly until ANC ≥ 1500 cells/mm3 Once ANC ≥ 1500 cells/mm3, return to patient’s last “normal-range” ANC monitoring interval BEN POPULATION BEN POPULATION Mild neutropenia is normal range for BEN population, continue treatment Weekly from initiation to 6 mo Every 2 wk from 6 to 12 mo Obtain at least two baseline ANC concentrations Monthly after 12 mo before initiating treatment If treatment interrupted: < 30 days, continue monitoring as before ≥ 30 days, monitor as if new patient Discontinuation for reasons other than neutropenia Severe neutropenia (< 500 cells/mm3)a GENERAL POPULATION GENERAL POPULATION Recommend hematology consult Daily until ANC ≥ 1000 cells/mm3 Interrupt treatment for suspected clozapine-induced neutropenia Three times weekly until ANC ≥ 1500 cells/mm3 Do not rechallenge unless prescriber determines that benefits outweigh risks If patient rechallenged, resume treatment as a new patient under “normal-range” monitoring once ANC ≥ 1500 cells/mm3 BEN POPULATION BEN POPULATION Recommend hematology consult Daily until ANC ≥ 500 cells/mm3 Interrupt treatment for suspected clozapine-induced neutropenia Three times weekly until ANC ≥ a patient’s established baseline Do not rechallenge unless prescriber determines that benefits outweigh risks If patient rechallenged, resume treatment as a new patient under “normal-range” monitoring once ANC ≥ 1000/mm3 or at patient’s baseline Confirm all initial reports of ANC > 1500 cells/mm3 with a repeat ANC measurement within 24 hr. If clinically appropriate. ANC = absolute neutrophil count; BEN = benign ethnic neutropenia. Information from: Clozapine and the Risk of Neutropenia: A Guide for Healthcare Providers. (package inserts) a b (a) OH, bradycardia, syncope, and cardiac arrest: Are dose related and patients are at highest risk at initiation of therapy or with rapid dose titration. Must be initiated at 12.5 mg once or twice daily, titrated slowly, and given in divided doses (b) Seizures: Risk is dose related and can be minimized by starting low and titrating slowly. (c) Myocarditis and cardiomyopathy: These are rare. They can occur at any point in treatment; however, myocarditis is more common in the first 2 months of treatment, and cardiomyopathy is more common after 8 weeks of treatment. Cardiomyopathy is usually delayed in onset. Risk factors for myocarditis include rapid dose titration and initiation of clozapine at high doses. If patients develop either of these, they should not be rechallenged with clozapine unless benefits are judged to outweigh risks. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-424 General Psychiatry ii. Additional adverse effects include weight gain, sedation, hypersalivation, rapid heart rate, anticholinergic adverse effects, and fever. The presence of fever should alert the clinician to the possibility of infection and agranulocytosis. If the drug is discontinued for 48 hours or more, retitration is required to avoid seizures or cardiac adverse effects. iii. In January 2020, the FDA strengthened an existing warning regarding clozapine-associated constipation. It can progress to serious complications, including necrotizing colitis and intestinal ischemia, hospitalization, and death. Risk increases with clozapine dose and when clozapine is combined with other medications that can slow GI motility. Prophylactic laxatives should be used in high-risk patients. b. Aripiprazole i. Aripiprazole is a partial agonist at D2 with high affinity for the D3 receptor. As a result, it is not associated with hyperprolactinemia. ii. Has a low risk of most forms of EPS, including tardive dyskinesia. Is associated with a high incidence of akathisia iii. Aripiprazole has been associated with pathological gambling and other compulsive behaviors, which may be related to its affinity for D3 and partial agonism at D2. iv. Available in two LAIs: Abilify Maintena and Aristada (aripiprazole lauroxil). As with any other LAIs, patients should demonstrate tolerability with the oral formulation before receiving the injection. Abilify Maintena requires 14 days of overlap with oral aripiprazole. Aristada Initio is a special formulation of aripiprazole lauroxil that is intended to be given as a single 675-mg dose with 30 mg of oral aripiprazole to initiate long-acting aripiprazole lauroxil or reinitiate therapy after a missed dose of aripiprazole lauroxil. This formulation is not intended to be used as a repeat injection. If Aristada is initiated without the Initio formulation, a 21-day overlap with oral aripiprazole is required. v. Aripiprazole is also available as a tablet that contains an ingestible event marker that detects when the medication has been taken and is tracked through a smartphone app and web portal (Abilify MyCite). c. Asenapine i. Available only as a sublingual formulation and as a patch. ii. It is important to avoid eating or drinking for 10 minutes after administration of the sublingual tablet. iii. The patch is changed daily. It can be worn while showering but has not been evaluated for bathing or swimming. iv. Asenapine has been associated with a high risk of orthostasis and sedation. v. There has also been a warning about the risk of hypersensitivity reactions with asenapine. vi. Asenapine use is contraindicated in severe hepatic impairment (Child-Pugh class C). d. Brexpiprazole i.  Chemically related to aripiprazole ii. The most common dose-dependent adverse effects are akathisia, weight gain, and somnolence. Clinically significant weight gain (greater than 7%) occurs in 8%–12% of patients. Brexpiprazole can also cause hyperglycemia and dyslipidemia. iii. Must be adjusted for renal function (CrCl less than 60 mL/minute/1.73 m2) and moderate to severe hepatic impairment (Child-Pugh class B or C) iv. Like aripiprazole, brexpiprazole may increase the risk of pathological gambling and other compulsive behaviors. e. Cariprazine i. Cariprazine has a half-life of 2–4 days. It also has active metabolites that have long half-lives (DCAR 1–2 days, DDCAR 1–3 weeks). Hence, changes in dose may not be reflected clinically for long periods. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-425 General Psychiatry ii. Cariprazine is not recommended for patients with a CrCl of less than 30 mL/minute/1.73 m2 or severe hepatic impairment (Child-Pugh class C). iii.  Cariprazine is associated with dose-related OH, particularly at initiation and with dose increases. iv. Limited studies suggest a low rate of weight gain over 6 weeks (1%–8% incidence, with 8% of those gaining more than 7%). Other adverse drug reactions include gastrointestinal (GI) symptoms, somnolence, dizziness, parkinsonism (13%–21%), and seizures. v. Leukopenia and neutropenia have occurred, but there are no current recommendations for monitoring. f. Iloperidone i. Iloperidone has a high risk of orthostasis but a lower risk of EPS, anticholinergic symptoms, and sedation. Iloperidone has a strict titration schedule to minimize OH. Retitration should occur if more than 3 days of medication have been missed. ii. Short- and long-term studies have also shown an association with QTc prolongation similar to that of haloperidol and ziprasidone. iii. Dosage should be adjusted for moderate intensity, and use should be avoided in severe hepatic impairment. g. Lumateperone i. Approved in December 2019 for the treatment of schizophrenia ii. Has presynaptic partial agonism and postsynaptic antagonism for D2 receptors and at least 60 times more affinity for the serotonin-2A receptor than the D2 receptor. This is theorized to be associated with the low incidence of EPS in clinical trials. It also indirectly modulates glutamatergic activity. iii. The recommended starting and target doses are both 42 mg daily. It should be administered with food. iv. The most common adverse effects are sedation/somnolence, dry mouth, fatigue, nausea, constipation, and dizziness. v.  Avoid use with CYP3A4 inducers or inhibitors. It is also a substrate for UGT (UDP glucuronosyltransferase). vi. Avoid use in moderate and severe hepatic impairment (Child-Pugh class B or C). h. Lurasidone i. Has a low risk of metabolic and cardiac effects ii. Dose-related EPS may occur. iii. Lurasidone should be taken with at least 350 kcal of food. iv. The dose must be tapered for moderate and severe renal impairment, when used with a moderate CYP3A4 inhibitor (e.g., diltiazem), and for moderate and severe hepatic impairment. i. Olanzapine i. This drug is structurally similar to clozapine and has a similar pharmacologic profile. ii. Unlike clozapine, it does not require strict monitoring for agranulocytosis. iii. In one study, negative symptoms responded better to olanzapine than to haloperidol. iv. Together with clozapine, olanzapine carries the highest risk of diabetes. For this reason, many schizophrenia treatment guidelines do not consider it first-line therapy. v. Olanzapine is available in a short-acting parenteral formulation for the treatment of acute agitation or aggression associated with psychiatric disorders. vi. Olanzapine is also available as a depot injection olanzapine pamoate (Zyprexa Relprevv). Because administration of olanzapine pamoate has been associated with extreme sedation and delirium, it is part of a REMS program (called the Zyprexa Relprevv Patient Care Program). Prescribers must undergo training, and it can only be administered within an approved institution where the patient has postdose supervision for 3 hours. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-426