Chapter 4: Psychopharmacology - Medications & Nursing

Chapter 4 PsychPharm \*\*\*\*\*\*\*\*\*Historical Perspectives Historically, reaction to and treatment of individuals with mental illness have ranged from benign involvement to interventions that some would consider inhumane. Individuals with mental illness were feared because of common beliefs a...

Chapter 4 PsychPharm \*\*\*\*\*\*\*\*\*Historical Perspectives Historically, reaction to and treatment of individuals with mental illness have ranged from benign involvement to interventions that some would consider inhumane. Individuals with mental illness were feared because of common beliefs associating them with demons or the supernatural. They were looked upon as loathsome and often were mistreated. Beginning in the late 18th century, a type of "moral reform" in the treatment of people with mental illness began to occur. Community and state hospitals concerned with the needs of individuals with mental illness were established. Considered a breakthrough in the humanization of care, these institutions, however well intentioned, fostered the concept of custodial care. Patients were ensured food and shelter but received little or no hope of change for the future. As they became increasingly dependent on the institution to fulfill their needs, the likelihood of their return to the family or community diminished. \*\*\*\*\*\*\*\*\*\*\*The early part of the 20th century saw the advent of somatic therapies in psychiatry. Individuals with mental illness were treated with insulin-shock therapy, wet sheet packs, ice baths, electroconvulsive therapy, and psychosurgery. \*\*\*\*\*\*\*\*Before 1950, sedatives and amphetamines were the only significant psychotropic medications available. Even these drugs had limited use because of their potential for toxicity and physical dependence. Since the 1950s, the development of psychopharmacology has expanded to include widespread use of antipsychotic, antidepressant, antianxiety, and mood-stabilizer medications. Research into how these drugs work has provided an understanding of the biochemical influences in many psychiatric disorders. Psychotropic medications are not a "cure" for mental illness. Most mental health practitioners who prescribe these medications for their clients use them as an adjunct to individual or group psychotherapy. Although their contribution to psychiatric care cannot be minimized, it must be emphasized that psychotropic medications relieve some physical and behavioral symptoms. They do not eliminate mental disorders. \*\*\*\*\*\*\*\*\*The Role of the Nurse in Psychopharmacology Ethical and Legal Implications Nurses must understand the ethical and legal implications associated with the administration of psychotropic medications. Laws differ from state to state, but most adhere to the patient's right to refuse treatment. Exceptions exist in emergency situations when it has been determined that patients are likely to harm themselves or others. Many states have adopted laws that allow courts to order outpatient treatment, which may include medication, in circumstances where an individual is not seeking treatment and has a history of violent, aggressive behavior. The original law, called Kendra's law, was enacted after a young woman named Kendra Webdale was pushed in front of a New York City subway train by a man who lived in the community but was not seeking treatment for his mental illness (New York State Office of Mental Health, 2012). This law is perhaps more developed than those in other states. It includes a medication grant clause that provides uninterrupted medication for those transitioning from hospitals or correctional facilities. Some states do not have similar laws; it is important, then, for nurses to be informed about local, state, and federal laws when working in any health-care setting or correctional facility and providing care to patients with psychiatric disorders. \*\*\*\*\*\*\*\*\*\*\*Assessment A thorough baseline assessment must be conducted before a patient is placed on a regimen of psychopharmacological therapy. A nursing history and assessment, an ethnocultural assessment, and a comprehensive medication assessment are all essential components of this database. The ethnocultural assessment is necessary because genetic variations in selected populations and cultural factors, including dietary preferences, may influence response to some medications; CYP450 isoenzyme variations, for example, influence metabolism of some medications and pharmacogenetic testing may be ordered to identify individuals at risk for being poor metabolizers Individuals who metabolize drugs poorly are more vulnerable to adverse drug reactions including toxicity. \*\*\*\*\*\*\*\*\*Medication Administration and Evaluation The nurse is the key health-care professional in direct contact with individuals receiving psychotropic medication in inpatient settings, in partial hospitalization programs, day treatment centers, home health care, and other settings. Medication administration is followed by ongoing monitoring for side effects and adverse reactions. The nurse also evaluates the therapeutic effectiveness of the medication. It is essential for the nurse to have a thorough knowledge of psychotropic medications to be able to anticipate potential problems and outcomes associated with their administration. \*\*\*\*\*\*\*\*\*\*\*Patient Education The information associated with psychotropic medications is copious and complex. An important role of the nurse is to translate this complex information into terms that can be easily understood by the patient. Patients must understand why the medication has been prescribed, when it should be taken, and what they may expect in terms of side effects and adverse reactions. They must know whom to contact when they have a question and when it is important to report to their physician. Medication education encourages patient collaboration and promotes accurate and effective management of the treatment regimen. For women of childbearing age, pregnancy risk information is an essential aspect of patient education. In 2015, a new U.S. Food and Drug Administration (FDA) rule went into effect that requires drug labeling to include specific narrative information on pregnancy-associated risks, lactation considerations, and reproductive potential (Drugs.com, 2022). This new system replaces the lettered risk categories that were criticized for being overly simplistic. Nurses should use the latest informatics resources to provide current and relevant education on this and other medication-related topics. \*\*\*\*\*\*\*\*\*\*\*CORE CONCEPT Neurotransmitters and Receptors A neurotransmitter is a chemical that is stored in the axon terminals of the presynaptic neuron. An electrical impulse through the neuron stimulates the release of the neurotransmitter into the synaptic cleft, which in turn determines whether another electrical impulse is generated. Receptors are molecules situated on the cell membrane that are binding sites for neurotransmitters. \*\*\*\*\*\*\*\*\*\*How Do Psychotropic Medications Work? Most psychotropic medications affect the neuronal synapse, producing changes in neurotransmitter release and the receptors to which they bind (Fig. 4--1). Antagonist drugs exert their effect by blocking a receptor and dampening the biological reaction. Conversely, agonist drugs activate receptors. Researchers hypothesize that most antidepressants work by blocking the reuptake of neurotransmitters, specifically, serotonin and norepinephrine. Reuptake is the process of neurotransmitter inactivation by which the neurotransmitter is reabsorbed into the presynaptic neuron from which it was released. Blocking the reuptake process allows more of the neurotransmitter to be available for neuronal transmission. This mechanism of action may also result in undesirable side effects (Table 4--2). Some antidepressants, for example, also block receptor sites that are unrelated to their mechanisms of action on mood and emotions. These include alpha-adrenergic, histaminergic, and muscarinic cholinergic receptors. Blocking these receptors is associated with certain side effects; for example, individuals treated with tricyclic antidepressants are at risk for developing postural hypotension. The specific type of receptor that a medication binds to is also relevant to the drug's level of antianxiety, antidepressant, and sedative properties (see Table 4--2). FIGURE 4-1 Area of synaptic transmission that is altered by drugs. TABLE 4--2    Effects of Psychotropic Medications on Neurotransmitters EXAMPLE OF MEDICATION ACTION ON NEUROTRANSMITTER OR RECEPTOR DESIRED EFFECTS SIDE EFFECTS Selective serotonin reuptake inhibitors (SSRIs) Inhibit reuptake of serotonin (5-HT) Reduce depression Control anxiety Control obsessions Nausea, agitation, headache, sexual dysfunction Tricyclic antidepressants Inhibit reuptake of serotonin (5-HT) Inhibit reuptake of NE Block NE (α1) receptor Block ACh receptor Block histamine (H1) receptor Reduce depression Relieve severe pain Prevent panic attacks Sexual dysfunction (NE and 5-HT) Sedation, weight gain (H1) Dry mouth, constipation, blurred vision, urinary retention (ACh) Postural hypotension and tachycardia (α1) Monoamine oxidase inhibitors (MAOIs) Increase NE and 5-HT by inhibiting the enzyme that degrades them (MAO-A) Reduce depression Control anxiety Sedation, dizziness Sexual dysfunction Hypertensive crisis (interaction with tyramine and foods or beverages with high caffeine content) Trazodone and nefazodone 5-HT reuptake block 5-HT2 receptor antagonism Adrenergic receptor blockade Reduce depression Reduce anxiety Nausea (5-HT) Sedation (5-HT2) Orthostasis (α1) Priapism (α2) Selective norepinephrine reuptake inhibitors (SNRIs): venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran Potent inhibitors of serotonin and norepinephrine reuptake Weak inhibitors of dopamine reuptake Reduce depression Relieve pain of neuropathy (duloxetine) Relieve anxiety (venlafaxine) Nausea (5-HT) ↑ Sweating (NE) Insomnia (NE) Tremors (NE) Sexual dysfunction (5-HT) Bupropion Inhibits reuptake of NE and D Reduces depression Aids in smoking cessation Reduces symptoms of ADHD Insomnia, dry mouth, tremor, seizures Esketamine (nasal spray) Nonselective, noncompetitive antagonist of the NMDA receptor (an ionotropic glutamate receptor) Reduce depression in treatment-resistant depression (in conjunction with an oral antidepressant) Dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, and vomiting Antipsychotics: phenothiazines and haloperidol Strong D2 receptor blockades Weaker blockades of ACh, H1, α1-adrenergic, and 5-HT2 receptors Relieve psychosis Relieve anxiety (Some) provide relief from nausea and vomiting and intractable hiccoughs Blurred vision, dry mouth, ↓ sweating, constipation, urinary retention, tachycardia (ACh) EPS (D2) ↑ Plasma prolactin (D2) Sedation; weight gain (H1) Ejaculatory difficulty (5-HT2) Postural hypotension (α; H1) Antipsychotics (second generation, atypical): aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone Receptor antagonism of 5-HT1A and 5-HT2A D1--D5 (varies with drug) H1, α1-adrenergic muscarinic (ACh) Relieve psychosis (with minimal or no EPS) Relieve anxiety Relieve acute mania Potential with some of the drugs for mild EPS (D2) Sedation, weight gain (H1) Orthostasis and dizziness (alpha-adrenergic) Blurred vision, dry mouth, ↓ sweating, constipation, urinary retention, tachycardia (ACh) Antianxiety: benzodiazepines Bind to BZ receptor sites on the GABAA receptor complex; increase receptor affinity for GABA Relieve anxiety Produce sedation Dependence (with long-term use) Confusion, memory impairment, motor incoordination Antianxiety: buspirone 5-HT1A agonist D2 agonist D2 antagonist Relieves anxiety Nausea, headache, dizziness Restlessness 5-HT, 5-hydroxytryptamine (serotonin); ACh, acetylcholine; ADHD, attention deficit-hyperactivity disorder; BZ, benzodiazepine; D, dopamine; EPS, extrapyramidal symptoms; GABA, gamma-aminobutyric acid; H, histamine; MAO, monoamine oxidase; MAO-A, monoamine oxidase A; NE, norepinephrine; NMDA, N-methyl-D-aspartate receptor. \*\*\*\*\*\*\*\*\*\*\*\*\*Antipsychotic medications block dopamine receptors, and some affect muscarinic, cholinergic, histaminergic, and alpha-adrenergic receptors. Atypical (or second generation) antipsychotics focus primarily on blocking specific serotonin receptors. Benzodiazepines facilitate the transmission of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Psychostimulants work by increasing norepinephrine, serotonin, and dopamine release. Although each psychotropic medication affects neurotransmission, the specific drugs within each class have varying neuronal effects. Their exact mechanisms of action are unknown. Many neuronal effects occur rapidly; however, therapeutic effects of some medications, such as antidepressants and atypical antipsychotics, may take weeks to manifest full therapeutic benefits. Acute alterations in neuronal function do not fully explain how these medications work. Boland and Verduin (2022, p. 592) note that if merely raising or lowering levels of neurotransmitter activity is associated with the clinical effects of a drug, then all drugs that cause these changes should produce equivalent benefits \[and\] this predictability is not the case. Long-term neuropharmacological reactions to increased norepinephrine and serotonin levels may better explain their mechanisms of action. Other researchers (Chaves et al., 2021; Yin & Yuan, 2015) suggest that the therapeutic effects are related to the nervous system's adaptation to increased levels of neurotransmitters. These adaptive changes result from a homeostatic mechanism, much like a thermostat, that regulates the cell and maintains equilibrium. \*\*\*\*\*\*\*\*\*\*\*Applying the Nursing Process in Psychopharmacological Therapy The Medication Assessment Tool, an assessment tool for obtaining a drug history (see Box 4--1), may be adapted for use by staff nurses admitting patients to the hospital or by nurse practitioners with prescriptive privileges. Some psychotropic medications (such as benzodiazepines, ketamine, and many sedative-hypnotic medications) are controlled substances because of their potential for misuse. Box 4--2 describes the different levels of controlled substance schedules. One of the Quality and Safety Education for Nurses (QSEN) criteria culminating from the Institute of Medicine (IOM) (2003) report on essential competencies for health-care professionals stresses that the patient must be at the center of decisions about treatment (patient-centered care), and a type of assessment tool such as the Medication Assessment Tool provides an opportunity to actively engage the patient in describing what medications have been effective or ineffective and identifying side effects that may affect willingness to adhere to a medication regimen. BOX 4--2 Controlled Substance Schedules Schedule I: Substances in this schedule have no currently accepted medical use in the United States, a lack of accepted safety for use under medical supervision, and a high potential for abuse. Schedule II: Substances in this schedule have a high potential for abuse which may lead to severe psychological or physical dependence. Schedule III: Substances in this schedule have a potential for abuse less than substances in schedules I or II and abuse may lead to moderate or low physical dependence or high psychological dependence. Schedule IV: Substances in this schedule have a low potential for abuse relative to substances in schedule III. Schedule V: Substances in this schedule have a low potential for abuse relative to substances listed in schedule IV and consist primarily of preparations containing limited quantities of certain narcotics. Source: U.S. Department of Justice. (n.d.). Controlled substance schedules. https://www.deadiversion.usdoj.gov/schedules/\#:\~:text=Definition% \*\*\*\*\*\*\*\*\*\*Antianxiety Agents Antianxiety agents are also called anxiolytics and historically were referred to as minor tranquilizers. Typically, this has included benzodiazepines, buspirone, and some selective serotonin reuptake inhibitors (SSRIs). Other medications that have been used off-label to treat anxiety disorders include anticonvulsants (such as divalproex, gabapentin, and pregabalin), beta blockers (such as atenolol, propranolol, and nadolol), antihistamines (hydroxyzine), and the antipsychotic medication quetiapine. \*\*\*\*\*\*\*\*\*\*Background Assessment Data Indications Antianxiety agents are used in the treatment of anxiety disorders, anxiety symptoms, acute alcohol withdrawal, skeletal muscle spasms, convulsive disorders, status epilepticus, and preoperative sedation. They are most appropriate for the treatment of acute anxiety states rather than long-term treatment. Their use and efficacy for longer than 4 months have not been evaluated. For long-term management of anxiety disorders, antidepressants (such as SSRIs and selective norepinephrine reuptake inhibitors \[SNRIs\]) are often used as the first line of treatment because they are not addictive. \*\*\*\*\*\*\*\*\*Action Antianxiety drugs depress subcortical levels of the central nervous system (CNS), particularly the limbic system and reticular formation. They may potentiate the effects of the powerful inhibitory neurotransmitter GABA in the brain (inhibiting excitation), thereby producing a calmative effect. All levels of CNS depression can be affected from mild sedation to hypnosis to coma. The most commonly prescribed antianxiety agents are benzodiazepines (which are schedule IV controlled substances), including clonazepam (Klonopin), lorazepam (Ativan), diazepam (Valium), and alprazolam (Xanax). Benzodiazepines are similar to alcohol in their effects on GABA receptors, which explains why benzodiazepines may be used for the management of alcohol withdrawal. The antianxiety agent buspirone (BuSpar) is not a benzodiazepine and does not depress the CNS. Although its action is unknown, the drug is believed to produce its effects through interactions with serotonin, dopamine, and other neurotransmitter receptors. Patients should be instructed that buspirone has a lag period of 7 to 10 days before full therapeutic benefits are achieved. It does not have the physical dependence potential of the other antianxiety agents; therefore it may be a better option for patients with anxiety disorders who also have substance use disorders. One area of concern is the increased use of benzodiazepines in the older adult population despite known safety concerns, including psychomotor impairment, impaired cognitive function, and paradoxical increase in anxiety. Gerlach and associates (2018), in a systematic review, concluded that benzodiazepine prescribing to older adults "is significantly in excess of what the available evidence would suggest is appropriate" (p. 264). Other researchers (Gress et al., 2020) found that benzodiazepines are often prescribed for long-term use in older adults, a practice that has not been supported by scientific evidence and one that increases risks for side effects and dependence. Further, Maust and associates (2016) found that most older adults who were prescribed benzodiazepines did not receive a clinical mental health diagnosis and almost none were referred for psychotherapy. Nurses are in a position to assess safety risks and, in collaboration with the patient, physician, and other health-care team members, explore other options for treatment of anxiety and insomnia. Despite the concerns about long-term use, side effects, and potential for dependence, benzodiazepines remain a mainstream treatment choice. In 2020 a new vehicle for diazepam administration came with the approval of diazepam nasal spray, but it should be noted that this is approved only for the rescue treatment of seizure clusters in patients with epilepsy age 6 years and older (Remaly, 2020). \*\*\*\*\*\*\*\*\*\*Interactions   Increased effects of antianxiety agents can occur when they are taken concomitantly with alcohol, barbiturates, narcotics, antipsychotics, antidepressants, antihistamines, neuromuscular blocking agents, cimetidine, or disulfiram.   The FDA (2016c) added a boxed warning (its strongest warning, commonly called a black box warning) related to the serious risks and possible death associated with combining benzodiazepines with opioid pain or cough medicines.   Increased effects can also occur with herbal depressants (e.g., kava, valerian, lemon verbena, l-tryptophan, melatonin, and chamomile).   Decreased effects can be noted with cigarette smoking and caffeine consumption. \*\*\*\*\*\*\*\*\*\*\*\*Diagnosis The following nursing diagnoses may be considered for patients receiving therapy with antianxiety agents:   Risk for injury related to seizures, panic anxiety, acute agitation from alcohol withdrawal (indications), abrupt withdrawal from the medication after long-term use, or effects of medication intoxication or overdose   Anxiety related to threat to physical integrity or self-concept   Risk for activity intolerance related to side effects of sedation, confusion, and/or lethargy   Disturbed sleep pattern related to situational crises, physical condition, or severe level of anxiety Safety Issues in Planning and Implementing Care The IOM (2003) identified ensuring safety as a core competency for health professions education. With that goal in mind, Table 4--3 notes some of the significant safety issues to be considered for clients taking antianxiety agents. Nursing interventions related to each side effect are noted in the right-hand column. \*\*\*\*\*\*\*\*\*\*Outcome Criteria and Evaluation The following criteria may be used for evaluating the effectiveness of therapy with antianxiety agents. The patient:   Demonstrates a reduction in anxiety, tension, and restless activity   Experiences no seizure activity   Experiences no physical injury   Tolerates usual activities without excessive sedation   Exhibits no evidence of confusion   Tolerates the medication without gastrointestinal distress   Verbalizes understanding of the need for, side effects of, and regimen for self-administration   Verbalizes possible consequences of abrupt withdrawal from the medication \*\*\*\*\*\*\*\*\*\*\*\*Antidepressants There are several types of antidepressants, some of which are also prescribed to treat anxiety disorders. The first "antidepressant" drug was a monoamine oxidase inhibitor (MAOI), isoniazid, which was used to treat tuberculosis. When patients began describing their increased feelings of well-being on these drugs, MAOIs were developed specifically for the treatment of depression. Unfortunately, they were also potentially deadly for anyone who ate foods high in tyramine while taking these drugs, and several serious interactions occurred with other drugs. Because MAOIs increase the availability of norepinephrine, researchers focused on developing drugs that affected norepinephrine without the need for food restrictions, leading to the introduction of tricyclic antidepressants (TCAs). Tricyclics were the first line of treatment for depression for many years, but not everyone responded to them (it was generally identified that about 70% of people with depression improved with treatment, but that finding has been challenged in more recent studies). In addition, because all neurotransmitters bind to various receptor sites, increasing the availability of norepinephrine with tricyclics also causes anticholinergic effects (such as rapid heart rate) and increases the potential for postural hypotension. These side effects limit their use in the elderly and those with cardiovascular problems. In the late 1980s, serotonin, an antianxiety hormone and neurotransmitter, became the latest biochemical believed to promote improvement in depression and anxiety without significant anticholinergic side effects. Consequently, a new group of drugs, SSRIs and SNRIs, became the preferred first-line treatment. Common SNRIs, which decrease reuptake of serotonin and norepinephrine, include desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), and venlafaxine (Effexor). With these developments SSRIs and SNRIs became the preferred first line of treatment for depression. Atypical antidepressants are a group of drugs that work differently and do not fit into the previously mentioned classes. The following are FDA-approved atypical antidepressants:   Bupropion (Wellbutrin)---decreases reuptake of dopamine and, to a lesser extent, serotonin and norepinephrine   Mirtazapine (Remeron)---potentiates the effects of norepinephrine and serotonin   Nefazodone---inhibits reuptake of serotonin and norepinephrine by acting as an antagonist at the central 5-HT2 receptor   Vortioxetine (Trintellix)---action not well understood   Vilazodone (Viibryd)---partial agonist at serotonergic 5-HT1A receptors   Trazodone (Desyrel)---unknown but alters the effect of serotonin TABLE 4--3    Safety Issues and Nursing Interventions for Patients Taking Antianxiety Agents SAFETY ISSUES NURSING INTERVENTIONS Tolerance and physical dependence may develop. Abrupt withdrawal can be life-threatening (except with buspirone); signs include sweating, agitation, tremors, nausea and vomiting, delirium, seizures. Instruct patient not to stop taking the drug abruptly. Assess the patient for signs of developing tolerance (requiring higher doses of medication to achieve effects). Educate the patient about symptoms of withdrawal. Contact the doctor immediately if symptoms of withdrawal are assessed. Drowsiness, confusion, and lethargy are the most common side effects. Instruct patient not to drive or operate dangerous machinery while taking this medication. Effects of other CNS depressants are increased. Instruct the patient not to drink alcohol or take other CNS depressants, antihistamines, cimetidine, antidepressants, neuromuscular blocking agents, or disulfiram while taking these drugs. The FDA (2016c) recently added a boxed warning (its strongest warning) related to the serious risks and possible death associated with combining benzodiazepines with opioid pain or cough medicines. Antianxiety agents may aggravate symptoms of depression. Assess the patient's mood and assess for suicide risk. Orthostatic hypotension may occur. Instruct the patient to rise slowly from a sitting to standing position to minimize risk for falls. Monitor lying and standing blood pressures to assess for orthostatic hypotension. Paradoxical excitement (opposite from the desired effect) may occur. Especially the elderly may be at higher risk for agitation and increased anxiety. In general, safety risks associated with benzodiazepines may be greater for the older adult (especially with long-acting benzodiazepines and long-term use), including impaired cognitive function, reduced mobility, risk for falls, and chemical dependence (Gress et al., 2020). Hold the medication and notify the doctor. Assess for other side effects and safety issues, including impaired cognition and impaired mobility. Use a patient-centered, collaborative team approach to explore options in safe management of anxiety and insomnia (lower dose, shorter-acting benzodiazepines; psychological interventions, etc.). Blood dyscrasias, although rare, can be serious or life-threatening. Assess for sore throat, fever, bruising, or unusual bleeding. Hold medication and report these symptoms immediately to the doctor. Congenital malformations have been associated with use of these drugs during the first trimester of pregnancy. Instruct the patient who is pregnant or anticipating pregnancy while on these drugs to explore alternative treatment options with their physician. CNS, central nervous system. One of the more recent additions to the pharmacological treatments for depression and anxiety are atypical antipsychotics that increase the availability of serotonin and dopamine. These medications are promoted as adjunctive to antidepressant therapy. The most popular example is aripiprazole (Abilify). In a large study sponsored by the National Institute of Mental Health, 44% of older adults who were not responding to a first-line antidepressant (venlafaxine) showed improvement in their symptoms when aripiprazole (Abilify) was added to treatment with venlafaxine. This finding has important implications for the treatment of older adult clients with depression because more than one-half of older adults with clinical depression do not respond to antidepressants alone (Lenze et al., 2015). Despite these developments and client-subjective reports of improvement with antidepressant medications, our understanding of the exact mechanisms of action remains theoretical. Currently, the levels of neurotransmitters in the brain cannot be measured and in the STAR\*D study (a large study funded by the National Institute of Mental Health), it was found that two-thirds of patients treated with an SSRI antidepressant medication did not experience full recovery (National Institute of Mental Health, 2006). Research continues with the goal of identifying antidepressant therapies that are more effective and more rapid in achieving therapeutic benefits. All antidepressant therapies (TCA, SSRI, SNRI, and MAOI) may take up to 2 weeks before signs of improvement are noted and up to 4 weeks to achieve full therapeutic benefits. Several of the newest drugs on the market for treatment of depression are not significantly different from existing products. For example, a "new" antidepressant approved by the FDA in 2016, Oleptro, is a reformulation of trazodone. But new mechanisms are being explored in clinical trials. Glutamate receptors (N-methyl-D-aspartate \[NMDA\]) and a novel GABA modulator (Gunduz-Bruce et al., 2019) are being studied for potential antidepressant effects. Ketamine and midazolam (a benzodiazepine with transient effects similar to those of ketamine) are being explored as potentially faster-acting than traditional antidepressants. In 2019, the FDA approved the nasal spray esketamine (Spravato) in conjunction with an oral antidepressant for individuals with treatment-resistant depression. In one of three short-term studies used to evaluate the drug's efficacy, Spravato demonstrated statistically significant benefit in reducing depressive symptoms, and some effect was seen within 2 days (FDA, 2019). Research into esketamine's mechanism of action, applications, and risks is ongoing. Because there are risks for serious adverse outcomes related to sedation, dissociation (difficulty with attention, judgment, and thinking), and the potential for substance misuse, this drug is classified as a schedule III controlled drug and is only available through a restricted distribution system. It must be administered in a certified medical office where the patient is under observation, and it requires a Risk Evaluation and Mitigation Strategy (REMS) (FDA, 2019). Drugs that act on melatonin receptors are currently in clinical trials for use in depression (one is already approved for use in Europe). One study found a synergistic antidepressant effect when melatonin was combined with fluoxetine (Li et al., 2018), but more research is needed. There is concern that melatonin, although it may improve sleep disturbances in people with depression, may also worsen other symptoms of depression in some individuals (Tonon et al., 2021). A new group of antidepressants called triple reuptake inhibitors that simultaneously block reuptake of serotonin, norepinephrine, and dopamine have been studied but have demonstrated mixed results with regard to any superior benefits over highly selective serotonergic agents alone (Kose & Cetin, 2018). The most current research is exploring the potential benefits of the psychedelic drugs ayahuasca, psilocybin, and lysergic acid diethylamide (LSD) for treatment-resistant depression. Studies thus far have found that when administered in a supportive setting, antidepressant and anxiolytic effects were immediate, consistent, and enduring for several months (Muttoni et al., 2019). In a recent study that incorporated two doses of psilocybin along with supportive therapy, researchers found substantial, enduring antidepressant effects at least through the follow-up period of 12 months (Gukasyan et al., 2022). The researchers caution, though, that at present the studies have been limited and small. Pharmacogenetic research is ongoing to identify factors that may influence whether an individual is more likely to respond to one type of antidepressant than another. This type of research may provide a valuable resource for making decisions about which antidepressant to prescribe first. The myriad searches for different treatment options speaks to the enormity of depression and suicide as public health concerns and the need for a more effective response. Nurses need to be informed of current, evidence-based pharmacological and nonpharmacological treatments to provide education and counseling to patients in and outside of psychiatric settings. \*\*\*\*\*\*\*\*\*\*Background Assessment Data Indications In addition to the obvious indications for antidepressant medications in the treatment of major depressive and dysthymic disorders, some SSRIs, SNRIs, and atypical antidepressants have received FDA approval for the treatment of some anxiety disorders, bulimia nervosa and other eating disorders, premenstrual dysphoric disorder, borderline personality disorder, obesity, and smoking cessation. A landmark review of the research on antidepressants (Fournier et al., 2010) found that the benefits of antidepressant therapy for clients with mild to moderate symptoms of depression may be minimal or nonexistent but that for clients with severe depression, the benefits, compared with placebo effects, are substantial. Therefore, these medications are particularly indicated when an individual is identified as having severe depression. (A table of current FDA-approved antidepressants can be found in Chapter 25, "Depressive Disorders.") Action Most antidepressants work to increase the concentration of norepinephrine, serotonin, and/or dopamine through a series of complex interactions in the body. For TCAs, SSRIs, SNRIs, and some atypical antidepressants this is believed to be accomplished by blocking the reuptake of neurotransmitters. MAOI antidepressants, on the other hand, act by inhibiting the enzyme monoamine oxidase (MAO), which is known to inactivate norepinephrine, serotonin, and dopamine. Interactions Tables 4--4 to 4--7 identify some of the significant, dangerous interactions between antidepressants and other drugs or foods. It is important to recognize that new information about drug interactions is discovered and published frequently. To fully understand safety issues related to medication administration, nurses need to access the most current, evidence-based informatics on drug interaction information. TABLE 4--4    Selected Drug Interactions With Selective Serotonin Reuptake Inhibitors (SSRIs) INTERACTING DRUGS ADVERSE EFFECTS Buspirone (BuSpar), tricyclic antidepressants (especially clomipramine), selegiline (Eldepryl), St. John's wort Serotonin syndrome\* Monoamine oxidase inhibitors Hypertensive crisis Warfarin, NSAIDs Increased risk of bleeding Alcohol, benzodiazepines Increased sedation Antiepileptics Lowered seizure threshold \*Serotonin syndrome is a potentially fatal syndrome of serotonin overstimulation with rapid onset that progresses from diarrhea, restlessness, agitation, hyperreflexia, fluctuations in vital signs to later symptoms of myoclonus, seizures, hyperthermia, uncontrolled shivering, muscle rigidity, and ultimately can lead to delirium, coma, status epilepticus, cardiovascular collapse, and death. Immediate cessation of offending drugs and comprehensive supportive intervention are essential (Boland & Verduin, 2022). NSAID, nonsteroidal anti-inflammatory drug. TABLE 4--5    Selected Drug Interactions With Tricyclic Antidepressants (TCAs) INTERACTING DRUGS ADVERSE EFFECTS Monoamine oxidase inhibitors High fever, convulsions, death St. John's wort, tramadol (Ultram) Seizures, serotonin syndrome Clonidine (Catapres), epinephrine Severe hypertension Acetylcholine blockers Paralytic ileus Alcohol and carbamazepine (Tegretol) Blocks antidepressant action, increases sedation Cimetidine (Tagamet), bupropion (Wellbutrin) Increased TCA blood levels and increased side effects TABLE 4--6    Selected Drug Interactions With Monoamine Oxidase Inhibitors (MAOIs) INTERACTING DRUGS ADVERSE EFFECTS Selective serotonin reuptake inhibitor, tricyclic antidepressants, atomoxetine (Strattera), duloxetine (Cymbalta), dextromethorphan (an ingredient in many cough syrups), venlafaxine (Effexor), St. John's wort, ginkgo biloba Serotonin syndrome Morphine and other narcotic pain relievers, antihypertensives Hypotension All other antidepressants, pseudoephedrine, amphetamines, cocaine, cyclobenzaprine (Flexeril), dopamine, methyldopa, levodopa, epinephrine, buspirone (BuSpar) Hypertensive crisis (these side effects can occur even if taken within 2 weeks of stopping MAOIs) Buspirone Psychosis, agitation, seizures Antidiabetics Hypoglycemia Tegretol Fever, hypertension, seizures TABLE 4--7    Diet Restrictions for Clients on Monoamine Oxidase Inhibitor (MAOI) Therapy FOODS CONTAINING TYRAMINE HIGH TYRAMINE CONTENT (AVOID WHILE ON MAOI THERAPY) MODERATE TYRAMINE CONTENT (MAY EAT OCCASIONALLY WHILE ON MAOI THERAPY) LOW TYRAMINE CONTENT (LIMITED QUANTITIES PERMISSIBLE WHILE ON MAOI THERAPY) Aged cheeses (cheddar, Swiss, Camembert, blue cheese, parmesan, provolone, Romano, brie) Raisins, fava beans, flat Italian beans, Chinese pea pods Red wines (chianti, burgundy, cabernet sauvignon) Liqueurs Smoked and processed meats (salami, bologna, pepperoni, summer sausage) Caviar, pickled herring, corned beef, chicken or beef liver Soy sauce, brewer's yeast, meat tenderizer (MSG) Sauerkraut Gouda cheese, processed American cheese, mozzarella Yogurt, sour cream Avocados, bananas Beer, white wine Coffee, colas, tea, hot chocolate (caffeinated beverages) Meat extracts, such as bouillon Chocolate Pasteurized cheeses (cream cheese, cottage cheese, ricotta) Figs Distilled spirits (in moderation) Sources: Complied from Boland, R., & Verduin, M. L. (2022). Kaplan & Sadock's synopsis of psychiatry (P. Ruiz, Ed.). (12th ed.). Wolters Kluwer; Vallerand, A. H., & Sanoski, C. A. (2022). Davis's drug guide for nurses (18th ed.). F.A. Davis. \*\*\*\*\*\*\*\*\*\*Drug interactions vary widely within these groups; the following are several examples:   Concomitant use with MAOIs results in serious, sometimes fatal, effects resembling neuroleptic malignant syndrome (a rare but potentially life-threatening side effect characterized by muscle rigidity, severe hyperthermia, and cardiac effects that can progress rapidly over 24 to 72 hours). Coadministration is contraindicated.   Serotonin syndrome (a potentially fatal syndrome associated with serotonin overstimulation) may occur when any of the following are used together: St. John's wort, sumatriptan, sibutramine, trazodone, nefazodone, venlafaxine, duloxetine, levomilnacipran, SSRIs, 5-HT-receptor agonists (triptans).   Increased effects of haloperidol, clozapine, and desipramine may occur with concomitant use of venlafaxine.   Increased effects of levomilnacipran may occur with concomitant use of CYP3A4 inhibitors.   Increased effects of venlafaxine may occur with concomitant use of cimetidine.   Increased effects of duloxetine may occur with concomitant use of CYP1A2 inhibitors (e.g., fluvoxamine, quinolone antibiotics) or CYP2D6 inhibitors (e.g., fluoxetine, quinidine, paroxetine).   Risk of liver injury is increased with concomitant use of alcohol and duloxetine.   Risk of toxicity or adverse effects from drugs extensively metabolized by CYP2D6 (e.g., flecainide, phenothiazines, propafenone, tricyclic antidepressants, thioridazine) is increased when these drugs are used concomitantly with duloxetine or bupropion.   Decreased effects of bupropion and trazodone may occur with concomitant use of carbamazepine.   The anticoagulant effect of warfarin may be altered with concomitant use of bupropion, venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, or trazodone.   Risk of seizures is increased when bupropion is coadministered with drugs that lower the seizure threshold (e.g., antidepressants, antipsychotics, systemic steroids, theophylline, tramadol).   Effects of midazolam are decreased with concomitant use of desvenlafaxine.   Effects of desvenlafaxine and levomilnacipran are increased with concomitant use of potent CYP3A4 inhibitors (e.g., ketoconazole). \*\*\*\*\*\*\*\*Diagnosis The following nursing diagnoses may be considered for patients receiving therapy with antidepressant medications:   Risk for suicide related to depressed mood   Risk for injury related to side effects of sedation, lowered seizure threshold, orthostatic hypotension, priapism (painful penile erection enduring for hours in the absence of stimulation), photosensitivity (increased sensitivity to ultraviolet \[UV\] rays such as sunlight), arrhythmias, hypertensive crisis (a severe increase in blood pressure to 180/120 or higher), or serotonin syndrome (a potentially fatal syndrome of serotonin overstimulation)   Social isolation related to depressed mood   Risk for constipation related to side effects of the medication   Insomnia related to depressed mood and elevated level of anxiety \*\*\*\*\*\*\*\*\*Safety Issues in Planning and Implementing Care Some of the common but manageable side effects of antidepressant medications include dry mouth, sedation, and nausea. General nursing interventions such as offering hard candies, ice, and frequent sips of water are helpful in alleviating dry mouth. Patients may find that sedation is less bothersome if they take the daily dose of antidepressant at bedtime. They should be encouraged to discuss this side effect with the prescribing physician or nurse practitioner. Taking antidepressant medication with food may help minimize nausea. Some patients taking SSRIs or SNRIs complain of sexual dysfunction. Men may report abnormal ejaculation or impotence, and women may report loss of orgasm. Because of these side effects, patients sometimes stop the medication abruptly, which may put them at risk for discontinuation syndrome and worsen symptoms of depression. Nurses must develop an open attitude regarding discussion and assessment of patient sexual concerns, and patients who are particularly troubled by this side effect can be encouraged to discuss their concerns with the prescribing physician or nurse practitioner to explore an alternative medication. Because there is so much information and new drug development is ongoing, practicing nurses should ensure that they are accessing evidence-based informatics to keep up to date on side effects as well. Many health-care organizations provide online medication resources to employees, and mobile device applications provide a readily available resource for updated drug information. Some important safety issues and nursing interventions are listed in Table 4--8. CLINICAL PEARL All antidepressants carry an FDA boxed warning for increased risk of suicidality in children, adolescents, and young adults up to 25 years of age. CLINICAL PEARL As antidepressant drugs take effect and mood begins to lift, the individual may have increased energy with which to implement a suicide plan. Suicide potential may increase as the level of depression decreases. The nurse should be particularly alert to sudden lifts or other dramatic changes in mood. TABLE 4--8    Safety Issues and Nursing Interventions for Patients Taking Antidepressants SAFETY ISSUES NURSING INTERVENTIONS Drug interactions (multiple, as discussed in the text) Instruct patients to inform their physician or nurse practitioner of all medications they are taking, including herbal preparations, over-the-counter drugs, and any medications they have stopped taking within the previous 2 weeks. Notify the physician immediately when any symptoms of serotonin syndrome are assessed. Do not administer the offending agent.   Monitor vital signs.   Protect from injury secondary to muscle rigidity or change in mental status.   Provide cooling blankets for temperature regulation.   Monitor intake and output. The condition usually resolves when the offending agent is promptly discontinued but can be fatal without intervention (Cooper & Sejnowski, 2013). Increased risk for suicide Assess frequently for presence or worsening of suicide ideation. Initiate suicide precautions as needed. Monitor patients' use of medication as prescribed, because these medications can be lethal in overdose. Sedation Instruct patients not to drive or operate dangerous machinery when experiencing sedation. Discontinuation syndrome: SSRIs---dizziness, lethargy, headache, nausea TCAs---hypomania, akathisia, cardiac arrhythmias, gastrointestinal upset, panic attacks MAOIs---flu-like symptoms, confusion, hypomania Instruct patients that all antidepressants have some potential for discontinuation syndrome and should not be stopped abruptly but rather tapered off. Paroxetine is associated with the highest risk for discontinuation syndrome (Janicak & Hussain, 2017). Photosensitivity Instruct patients of their vulnerability to severe sunburn and recommend sunscreen. Orthostatic hypotension (TCAs) Instruct patients to rise slowly from sitting to standing. Monitor blood pressure to assess for symptoms. Tachycardia, arrhythmias (TCAs) Monitor vital signs, especially in elderly with preexisting cardiovascular disorders. Hyponatremia (SSRIs), especially among the elderly Instruct patients to report any symptoms of nausea, malaise, lethargy, muscle cramps. Assess for disorientation or restlessness. Monitor sodium levels:   \0.8 mmol (or mEq)/L are associated with increased risk for renal toxicity (N-acetylcysteine may prevent lithium-induced renal damage \[Rege, 2020\]).   At blood levels \>1.2 mEq/L early signs of toxicity include vomiting and diarrhea.   At blood levels \>1.5 mEq/L gastrointestinal (increasing nausea, anorexia, diarrhea) and CNS effects (muscle weakness, drowsiness, ataxia, coarse tremor and muscle twitching) occur (Rege, 2020).   At blood levels \>2 mEq/L increasing disorientation and seizures can occur.   Blood levels ≥ 3.5 mEq/L are associated with coma, cardiovascular collapse, and death.   Chlorpromazine (Thorazine) may mask early signs of lithium toxicity (Vallerand & Sanoski, 2022).   Instruct patients to report all medications, herbals, and caffeine use to physician or nurse practitioner to evaluate for drug interactions. Encourage patients to maintain fluid intake at 2,000--3,000 mL/day and avoid activities in which excessive sweating and fluid loss are a risk because inadequate fluid intake can affect lithium levels. Instruct patients about the importance of regular monitoring of serum lithium levels. Blood levels should be drawn 12 hours after the last dose. Increased risk of suicide for antiepileptics Assess for suicide risk regularly and inform patients of risks associated with anticonvulsants. Hyponatremia (lithium, carbamazepine) Instruct patients to maintain usual dietary intake of sodium. Assess for and educate patients to report any episodes of nausea, vomiting, headache, muscle weakness, confusion, seizures, because these may be signs of hyponatremia. Stevens-Johnson syndrome (especially with lamotrigine and carbamazepine) This toxic skin necrolysis can be life-threatening. Assess for and educate patients to report any signs of rash or unusual skin breakdown. Hypotension, arrhythmias (lithium) Monitor vital signs and instruct patients to report any symptoms of dizziness or palpitations. Blood dyscrasias (valproic acid, carbamazepine) Educate patients to report infections or other illness while on these medications. Ensure that platelet counts and bleeding time are determined before initiation of therapy. Monitor for spontaneous bleeding or bruising. Increased risk of birth defects (anticonvulsant mood stabilizers) Inform female patients of the risks of birth defects and provide education about contraception as desired. Drowsiness (lithium and all anticonvulsants) Instruct patients to avoid driving or operating dangerous machinery when experiencing this side effect. Assess patients' mental status for level of alertness. Lithium Maintenance Patients who respond to lithium will typically remain on the medication indefinitely. To ensure safe maintenance and prevent lithium toxicity, patient education and regular monitoring are essential. An important component of monitoring is evaluation of serum lithium levels to ensure that they remain within the therapeutic range. Although a typical therapeutic range for lithium is from 0.6 to 1.2 mEq/L, current American Psychiatric Association clinical practice guidelines recommend that when initiating treatment, the levels should be closer to 1.2 (the higher end of the range) and that in maintenance treatment the optimum levels should be closer to 0.6 (the lower end of the range) (Rege, 2020). An international study group recently completed a systematic review and came to a consensus on a more conservative optimal range of 0.4 to 0.6 mEq/L if the patient is responding well to lithium therapy (Nolen et al., 2019). Although higher levels (closer to 1.0) may be more efficacious for patients that are prone to more manic episodes (rather than more depressive episodes), higher levels are also associated with more adverse effects. At levels over 1.5 mEq/L, increasing nausea, anorexia, and diarrhea are common as well as CNS symptoms such as muscle weakness, drowsiness, ataxia, tremors, and muscle twitching. Even higher levels can lead to delirium, seizures, cardiovascular collapse, or death. Serum lithium levels should be monitored once or twice a week after initial treatment until dosage and serum levels are stable and then monthly during maintenance therapy. Blood samples should be drawn 12 hours after the last dose. Some individuals complain that they miss the "high" feeling of being in a manic or hypomanic state once they begin mood-stabilizer medications. They may be at risk for self-adjusting medication or discontinuing it altogether. Open discussion and exploring the benefits versus disadvantages of medication treatment promote patient-centered care and enable the nurse to troubleshoot with the patient ways to minimize risks. One generally undesirable side effect of lithium is weight gain. Patients should be educated about this potential, and weight should be monitored at regular intervals. It may be helpful to discuss low-calorie diets while stressing the importance of not making significant changes in sodium intake because of its effect on serum blood levels of lithium. CLINICAL PEARL The FDA requires that all antiepileptic (anticonvulsant) drugs carry a warning label indicating that use of the drugs increases risk for suicidal thoughts and behaviors. Patients treated with these medications should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. \*\*\*\*\*\*\*\*\*Outcome Criteria and Evaluation The following criteria may be used for evaluating the effectiveness of therapy with mood-stabilizing agents. The patient:   Is maintaining stability of mood   Has not harmed self or others   Has experienced no injury from hyperactivity   Is able to participate in activities without excessive sedation or dizziness   Is maintaining appropriate weight   Exhibits no signs of lithium toxicity   Verbalizes importance of taking medication regularly and reporting for regular laboratory blood tests \*\*\*\*\*\*\*\*\*Antipsychotic Agents Antipsychotic agents are also called neuroleptics. Historically, they have been referred to as major tranquilizers and have clear sedative effects. The term antipsychotic is most descriptive because the primary benefit over time is the alleviation of psychotic symptoms, such as hallucinations and delusions. Background Assessment Data Antipsychotic agents were introduced in the United States in the 1950s with the phenothiazines. Other drugs in this classification soon followed, and these are called typical or first generation antipsychotics. Unfortunately, this group of medications has the potential for extrapyramidal side effects, also called extrapyramidal symptoms (EPS), that interfere with normal movements, including acute dystonias (muscle spasms) that can be life-threatening, Parkinson-like symptoms, and tardive dyskinesia (later-onset involuntary movement disorders primarily in the tongue, lips, and jaw that may also involve other movement disturbances). Some of these side effects can be permanent, continuing even after the drug is discontinued. The first generation, typical antipsychotics include the phenothiazines, haloperidol, loxapine, pimozide, and thiothixene. Second generation antipsychotic medications have since been developed with less potential for EPS. They have become the preferred first-line treatment. These are most often referred to as atypical antipsychotics, and they include aripiprazole, asenapine and asenapine transdermal (Secuado), clozapine, olanzapine, quetiapine, risperidone, paliperidone, iloperidone, lurasidone, ziprasidone, brexpiprazole (Rexulti), cariprazine (Vraylar), pimavanserin (Nuplazid), and lumateperone (Caplyta). Pimavanserin is indicated for hallucinations and delusions associated with Parkinson's disease psychosis. This group of drugs is used to alleviate positive symptoms hallucinations, delusions, and agitation and may be beneficial in treating some of the negative symptoms as well. The atypical antipsychotic aripiprazole (Abilify) has sometimes been described as a third generation antipsychotic because of its unique functional profile with dopamine receptors, and it has been identified as having minimal risk for EPS. In 2017 the FDA approved a novel (and controversial) formulation of aripiprazole (called Abilify MyCite), which includes a sensor device embedded in the pill that enables the patient (and others) to track whether they are taking the medication. In 2020 the FDA approved a novel antipsychotic medication, lumateperone (Caplyta), which, although the action is unknown, reportedly demonstrates benefit in treating both positive and negative symptoms of schizophrenia. \*\*\*\*\*\*\*\*\*Indications Antipsychotics are used in the treatment of schizophrenia and other psychotic disorders. Selected agents are used in the treatment of bipolar mania (see previous section, "Mood-Stabilizing Agents"). Others are used as antiemetics (chlorpromazine, perphenazine, prochlorperazine), in the treatment of intractable hiccoughs (chlorpromazine), and for the control of tics and vocal utterances in Tourette's disorder (haloperidol, pimozide). Selected atypical antipsychotics, including aripiprazole (Abilify), are also being identified as adjuncts to the treatment of major depressive disorder. (A table of current FDA-approved antipsychotics as well as antiparkinsonian agents, which are used to treat EPS caused by antipsychotic medication, can be found in Chapter 24, "Schizophrenia Spectrum and Other Psychotic Disorders.") Action First generation, typical antipsychotics are antagonists that work by blocking postsynaptic dopamine receptors in the basal ganglia, hypothalamus, limbic system, brainstem, and medulla. They also demonstrate varying affinity for cholinergic, alpha1-adrenergic, and histaminic receptors. Second generation, atypical antipsychotics are weaker dopamine receptor antagonists than conventional antipsychotics but are more potent antagonists of the serotonin type 2A (5-HT2A) receptors. They also exhibit antagonism for cholinergic, histaminic, and adrenergic receptors. As mentioned previously, aripiprazole (Abilify) is a dopamine receptor antagonist that seems to have a unique way of accomplishing its action and thus has a minimal risk of EPS. \*\*\*\*\*\*\*\*\*\*\*Contraindications and Precautions Certain individuals may be at greater risk for experiencing side effects associated with antipsychotic agents. Older adults have been identified as an at-risk population because of reports of stroke and sudden death while taking antipsychotic medication. Studies have indicated that older patients with psychosis related to neurocognitive disorder (NCD) who are treated with antipsychotic drugs are at increased risk of death, particularly from cerebrovascular events, and researchers have found a decrease in associated deaths since the FDA initiated boxed warnings about these risks for all antipsychotics (Rubino et al., 2020). All antipsychotic drugs now carry a boxed warning about these risks. A boxed warning, named for the black border around the warning text on a drug's package insert, is the highest level warning imposed by the FDA for prescription medications. Its purpose is to alert consumers about serious or life-threatening side effects the drug may have. Antipsychotic drugs are not approved for treatment of older patients with NCD-related psychosis. Rubino and associates (2020) also found that while prescriptions for antipsychotics declined in those with dementia-related psychosis since the initiation of boxed warnings, an increase in opioid and antiepileptic medication prescriptions (with other significant risks) ensued. Both first and second generation antipsychotics are contraindicated in clients with known hypersensitivity. They should not be used in clients who are comatose or when CNS depression is evident; when blood dyscrasias exist; in clients with Parkinson's disease or narrow-angle glaucoma (first generation agents); for those with liver, renal, or cardiac insufficiency; in individuals with poorly controlled seizure disorders; or in elderly clients with dementia-related psychosis. Ziprasidone, risperidone, paliperidone, asenapine, and iloperidone are contraindicated in patients with a history of QT prolongation or cardiac arrhythmias, recent myocardial infarction (MI), uncompensated heart failure, and concurrent use with other drugs that prolong the QT interval. Clozapine is contraindicated in patients with myeloproliferative disorders, a history of clozapine-induced agranulocytosis or severe granulocytopenia, or uncontrolled epilepsy. Lurasidone is contraindicated in individuals also using strong inhibitors of cytochrome P450 isozyme 3A4 (CYP3A4) (e.g., ketoconazole, an antifungal) and strong CYP3A4 inducers (e.g., rifampin, an antitubercular). Caution is indicated when administering atypical antipsychotic medications to elderly or debilitated patients; patients with cardiac, hepatic, or renal insufficiency; those with a history of seizures; patients with diabetes or risk factors for diabetes; clients exposed to temperature extremes; under conditions that cause hypotension (dehydration, hypovolemia, treatment with antihypertensive medication); and to pregnant clients (several atypical antipsychotic medications, such as olanzapine, risperidone, and quetiapine, have been associated with congenital malformations) (Anderson et al., 2020). Six atypical antipsychotic medications (aripiprazole, asenapine, olanzapine, paliperidone, quetiapine, and risperidone) have FDA approval for use in children and adolescents. Both aripiprazole and quetiapine (also approved for adjunctive treatment in depression) carry boxed warnings about increased risk for suicidal thinking in children, adolescents, and young adults. Interactions Table 4--11 highlights some drug interactions that warrant monitoring and assessment by nurses. TABLE 4--11    Selected Drug Interactions With Antipsychotic Medications DRUG INTERACTION ADVERSE EFFECT Antihypertensives, central nervous system depressants Epinephrine or dopamine in combination with haloperidol or phenothiazines Additive and potentially severe hypotension Oral anticoagulants with phenothiazines Less effective anticoagulant effects Drugs that prolong QT intervals Additive effects Drugs that trigger orthostatic hypotension Additive hypotension Drugs with anticholinergic effects, including prescription and over-the-counter drugs Additive anticholinergic effects, including anticholinergic toxicity, signs of which are   Flushing   Dry mouth   Mydriasis   Altered mental status   Fever   Decreased bowel sounds   Ileus   Tachycardia   Urinary retention   Tremulousness   Myoclonic jerking   Hypertension (Ramnarine & Ahmed, 2022) \*\*\*\*\*\*\*\*\*\*Diagnosis The following nursing diagnoses may be considered for patients receiving antipsychotic therapy:   Risk for other-directed violence related to panic anxiety and mistrust of others   Risk for injury related to medication side effects of sedation, photosensitivity, reduction of seizure threshold, agranulocytosis, EPS, tardive dyskinesia, neuroleptic malignant syndrome, or QT prolongation   Risk for activity intolerance related to medication side effects of sedation, blurred vision, and weakness   Nonadherence with medication regimen related to suspiciousness and mistrust of others Safety Issues in Planning and Implementing Care Table 4--12 discusses some significant safety issues to consider and relevant nursing interventions for patients taking antipsychotic medication. TABLE 4--12    Safety Issues and Nursing Interventions for Patients Taking Antipsychotic Medication \*\*\*\*\*\*\*\*SAFETY ISSUES NURSING INTERVENTIONS Extrapyramidal side effectsa Instruct patient to report any signs of muscle stiffness or spasms. Hold the medication if this occurs. Administer antiparkinsonian agents as ordered and immediately when signs of acute dystonia are present. Assess the patient for abnormal involuntary movements (see Box 4--2). (See "Additional Issues for Patient Education" for further discussion.) Hyperglycemia, weight gain, and diabetes (more common with atypical antipsychotic agents) Assess for a history of diabetes. Evaluate blood sugars. Instruct the patient in these risks and the importance of diet and exercise. Assess for signs of hyperglycemia including polydipsia, polyphagia, polyuria, and weakness. Hypotension Educate the patient about the risk for hypotension. Monitor blood pressure. Orthostatic hypotension Instruct patient to rise slowly from sitting to standing. Monitor blood pressure lying and then standing to assess for postural changes. Lower seizure threshold (especially with clozapine) Assess patient for history of seizure disorder. Monitor the patient for evidence of seizure activity and report to prescribing physician or nurse practitioner. Prolonged QT interval,b especially ziprasidone, thioridazine, pimozide, haloperidol, paliperidone, iloperidone, asenapine, and clozapine. Assess for history of arrhythmias, recent myocardial infarction, heart failure, and report to prescribing physician or nurse practitioner because these events are contraindications. Assess for other medications the patient is taking that prolong QT interval (there are many online resources), but note that erythromycin and clarithromycin are two that are commonly prescribed. Instruct patient to report any rapid heartbeat, dizziness, or fainting. Check baseline electrocardiogram (ECG) before beginning treatment. Anticholinergic effects Instruct patient about additive effects of other anticholinergic drugs in combination with antipsychotics, and to report any other medications taken including over-the-counter and herbal remedies. For minor symptoms such as dry mouth, recommend hard candies and sips of water. Instruct patient about the importance of good oral hygiene. Instruct patient to report and assess for any evidence of urinary retention, tachycardia, tremulousness, or hypertension, which may be signs of anticholinergic toxicity. Sedation Educate patient about this side effect and instruct patient not to drive or operate dangerous machinery if experiencing sedation. Photosensitivity Instruct patient to use sunblock and sunglasses and to wear protective clothing when in the sun because of the increased risk for severe sunburn while on these medications. Agranulocytosis (more common with typical antipsychotics but especially with the atypical antipsychotic agent clozapine) Instruct the patient receiving clozapine that regular monitoring of white blood cell and absolute neutrophil counts is essential. Instruct patient to report any signs of sore throat, fever, or malaise. (See additional guidelines in the section "Issues in Antipsychotic Maintenance Therapy.") Neuroleptic malignant syndrome (NMS)c Instruct patient to report immediately any fever, muscle rigidity, diaphoresis, tachycardia. Assess vital signs regularly, including temperature. Assess for deteriorating mental status or any other sign of NMS. Presence of any of these signs requires holding the medication and contacting the prescribing physician or nurse practitioner immediately, as well as monitoring vital signs and intake and output. Drug reaction with eosinophilia and systemic symptoms (DRESS) (olanzapine)d (FDA, 2016b) New impulse control problems such as compulsive or uncontrollable urges to gamble, binge eat, shop, and have sex (aripiprazole) (FDA, 2016a) Assess for symptoms of DRESS including fever, rash, swollen lymph glands, swelling in the face. Hold medication and contact physician immediately. Assess for newly developing impulse control problems for patients taking aripiprazole. Closely monitor patients who may be at increased risk for impulse control problems such as those with personal or family history of obsessive-compulsive disorder, bipolar disorder, impulsive personality, alcohol, drug, or other addictive behaviors. aAcute dystonias can be life-threatening (more common with typical antipsychotic agents). bPotentially life-threatening. cRare but potentially life-threatening side effect characterized by muscle rigidity, severe hyperthermia, and cardiac effects that can progress rapidly over 24--72 hours. dRare but serious; can lead to organ injury and even death. Additional Issues for Patient Education Patients should be apprised of health risks when taking antipsychotic agents, including the following:   Smoking increases the metabolism of antipsychotics, requiring an adjustment in dosage to achieve a therapeutic effect. Patients should be encouraged to discuss this issue with the prescribing physician or nurse practitioner.   Body temperature is harder to maintain with antipsychotic medication, so patients should be encouraged to dress warmly in cold weather and avoid extended exposure to very high or low temperatures.   Antipsychotic medications increase photosensitivity to sunlight. Patients should be advised to wear sunscreen and protective clothing when exposed to the sun.   Alcohol and antipsychotic drugs potentiate each other's effects, so patients should be advised to avoid drinking alcohol while on antipsychotic therapy.   Many medications contain substances that interact with antipsychotics in a way that may be harmful. Patients should avoid taking other medications, including over-the-counter products, without first discussing it with the prescriber.   A significant number of patients on clozapine report excessive salivation. Sugar-free gum and medications (anticholinergic or alpha2-adrenoceptor agonists) may alleviate symptoms. Patients should be encouraged to discuss these options with the prescribing physician or nurse practitioner.   Safe use of antipsychotics during pregnancy has not been established. Antipsychotics are thought to readily cross the placental barrier; if so, a fetus could experience adverse effects of the drug. Patients should be aware of the possible risks and should inform the physician immediately if pregnancy occurs, is suspected, or is planned.   Clozapine carries a particular risk for agranulocytosis, which increases risk for severe infection. Patients should be instructed that regular measurement of neutrophils is essential (this is discussed in more detail later).   Clozapine also carries a risk for ileus (intestinal blockage) with a 15% to 28% fatality rate. Eighty percent of clozapine-treated patients have some hypomotility in their bowels, and in 2020 the FDA strengthened its warning on the risks of ileus (FDA, 2020). Patients should be instructed to report any change in bowel habits to their physician and to explore diet and medications to reduce constipation. Issues in Antipsychotic Maintenance Therapy The nurse must understand the management of side effects associated with antipsychotic medication to conduct a thorough assessment and minimize risks. In addition, some of these side effects can be difficult for patients to manage or understand, particularly when they are struggling with impaired mental status including psychosis and cognitive deficits. Three of these are discussed here. Clozaril and the Risk for Agranulocytosis The FDA requires close monitoring of patients on medications that increase the risk for life-threatening side effects. Clozaril is one such drug. Due to the risk of agranulocytosis, the FDA requires that clozapine be part of a REMS program to ensure that risk for agranulocytosis is monitored, managed, and reported. Agranulocytosis is a potentially fatal blood disorder in which the patient's absolute neutrophil count (ANC) drops to extremely low levels (less than or equal to 500 µL). This condition is called neutropenia. An ANC must be assessed before initiation of treatment with clozapine and weekly for the first 6 months of treatment. Initially, only a 1-week supply of medication is dispensed at a time. If the ANC remains within acceptable levels (i.e., ANC at least 1,500 µL) during the first 6 months, blood counts may be monitored biweekly for another 6 months and monthly thereafter. Some individuals with dark skin, particularly those of African and Middle Eastern descent, have normally lower ANC (benign ethnic neutropenia); in such cases the parameters for identifying clinically significant neutropenia are altered (Clozapine REMS, 2015). Although the benefits of clozapine can be profound, this medication is typically used when patients fail to respond to other antipsychotics because of the strict protocols for adherence. If the patient agrees to this option, the nurse can be a vital resource in ensuring that support services, both professional and personal (such as family members or peers), are engaged to assist the patient with follow-through as needed. \*\*\*\*\*\*\*\*\*Extrapyramidal Side Effects To conduct a thorough assessment, the nurse must be familiar with several distinct types of extrapyramidal side effects of antipsychotic medications:   Pseudoparkinsonism: Symptoms of pseudoparkinsonism---tremor, shuffling gait, drooling, rigidity---may appear 1 to 5 days after initiation of antipsychotic medication. This side effect occurs most often in women, the elderly, and dehydrated individuals.   Akinesia: Absence or impairment in voluntary movement is termed akinesia.   Akathisia: Continuous restlessness and fidgeting, or akathisia, occurs most often in women and may manifest 50 to 60 days after therapy begins. Combining atypical antipsychotics and administration at doses greater than target ranges increases the incidence of akathisia (Chow et al., 2020)   Dystonia: This side effect---involuntary muscle spasms in the face, arms, legs, and neck---occurs most often in men and those younger than age 25. Dystonia should be treated as an emergency because laryngospasm follows these symptoms and can be fatal. The physician should be contacted, and intravenous or intramuscular benztropine mesylate (Cogentin) is commonly administered (see Chapter 24, "Schizophrenia Spectrum and Other Psychotic Disorders," for a list of antiparkinsonian agents used to treat EPS). Nurses should stay with the patient and offer reassurance.   Oculogyric crisis: Uncontrolled rolling back of the eyes, or oculogyric crisis, is a symptom of acute dystonia and can be mistaken for seizure activity. As with other symptoms of acute dystonia, this side effect should be treated as a medical emergency.   Tardive dyskinesia: This extrapyramidal side effect involves bizarre face and tongue movements, stiff neck, and difficulty swallowing. It may occur with all classifications but most commonly takes place with typical antipsychotics. All clients receiving antipsychotic therapy for months or years are at risk. Symptoms are potentially irreversible. Nurses should immediately report early signs of tardive dyskinesia (usually vermiform movements of the tongue) to the prescribing physician or nurse practitioner. Often, the drug is discontinued, changed to a different antipsychotic, or the dosage is altered. In 2017 the FDA approved the first drug for treating tardive dyskinesia, valbenazine (Ingrezza). It is hoped that this novel drug will effectively reduce this troubling condition and its sometimes stigmatizing effects (FDA, 2017). The involuntary movements associated with tardive dyskinesia can be measured by the Abnormal Involuntary Movement Scale (AIMS), developed in the 1970s by the National Institute of Mental Health. AIMS aids in early detection of movement disorders and provides means for ongoing surveillance. AIMS is featured in Box 4--3. Some EPS can be life-threatening, and those that are not can sometimes be permanent. The abnormal movements in the tongue and lips are sometimes very visible and severe enough to interfere with a person's ability to speak or swallow. The nurse's empathic approach in listening to the patient's wishes regarding medication and advocating for exploring other options for management of symptoms is one way to promote patient-centered care, an essential nursing competency (IOM, 2003), and to promote a recovery model that empowers the patient to make decisions about management of the illness. There is evidence (Forma et al., 2020; Haddad et al., 2014) that remaining on antipsychotic medication can reduce the frequency of hospitalizations, and early treatment at the first psychotic episode may reduce some long-term consequences of illness. Educating patients about these risks and benefits is important in assisting them to make informed decisions about medication treatment. \*\*\*\*\*\*\*\*\*\*Hormonal Side Effects The following are sexual side effects that may accompany antipsychotic medications:   Decreased libido, retrograde ejaculation (the discharge of seminal fluid into the bladder rather than through the urethra); gynecomastia (breast enlargement in men)   Amenorrhea (absence of menses in women); galactorrhea (milky discharge from breasts of nonbreastfeeding women that may also occur in men) These side effects can be troubling for anyone, but for a patient struggling with thought disturbances, they can become the foundation for delusions. A male patient with gynecomastia, for example, might begin to believe that external forces are taking over his body and turning him into a woman. An amenorrheic woman may begin to believe that she has been divinely impregnated. It is important for the nurse to clarify that these are side effects of the medication and offer reassurance that they are reversible. Women with amenorrhea should be instructed that this side effect does not indicate cessation of ovulation, so contraception use should continue as usual. Patients should be encouraged to explore alternative treatment if these side effects are deemed intolerable. \*\*\*\*\*\*\*\*\*Current Developments in Psychopharmacological Treatment of Schizophrenia One of the identified limitations of medication treatments available for schizophrenia is the cognitive deficits that are core symptoms of this illness, including deficits in working memory and long-term memory, reduced processing speed, limited verbal fluency, and impaired executive functions. Some atypical antipsychotics have demonstrated efficacy in lessening cognitive deficits but do not eliminate residual effects. Cariprazine (Vraylar) has demonstrated some efficacy in treating the negative symptoms of schizophrenia, including flat affect, social withdrawal, and apathy (Correll et al., 2020). Although cariprazine is similar to other atypical antipsychotics, its particular affinity for certain dopamine receptors (D3) is believed to be associated with its superior effect on negative symptoms, particularly improving social behavior and self-care. In addition, cariprazine has demonstrated effectiveness in reducing substance misuse, a common comorbidity in patients with schizophrenia, and its long half-life enables maintenance of therapeutic levels even when a few doses are missed (Scarff, 2017). Negative symptoms can complicate the prognosis in treatment of schizophrenia and as Scarff (2017) pointed out, the evidence supports "cautious optimism" that cariprazine may become the first-line treatment for patients with "disabling negative symptoms or impairment in self-care and interpersonal relationships" (p. 237). As mentioned previously, an even newer medication, lumateperone (Caplyta), is also being advanced as effective for treating both positive and negative symptoms of schizophrenia, although its action is unknown. BOX 4--3 Abnormal Involuntary Movement Scale (AIMS) Source: U.S. Department of Health and Human Services. Available for use in the public domain from Guy W. ECDEU Assessment Manual for Psychopharmacology: Revised (DHEW publication number ADM 76-338). Rockville, MD, US Department of Health, Education and Welfare, Public Health Service, Alcohol, Drug Abuse and Mental Health Administration, NIMH Psychopharmacology Research Branch, Division of Extramural Research Programs, 1976: 534--537. \*\*\*\*\*\*\*\*\*\*Outcome Criteria and Evaluation The following criteria may be used for evaluating the effectiveness of therapy with antipsychotic medications. The patient:   Has not harmed self or others   Has not experienced injury secondary to lowered seizure threshold or photosensitivity   Maintains an ANC within normal limits   Exhibits no symptoms of EPS, tardive dyskinesia, neuroleptic malignant syndrome, or hyperglycemia   Maintains weight within normal limits   Tolerates activity unaltered by the effects of sedation or weakness   Adheres to medication schedule   Verbalizes understanding of medication regimen and the importance of regular administration   Demonstrates improvement in self-care and prosocial behavior \*\*\*\*\*\*\*\*\*\*Sedative-Hypnotic Agents Background Assessment Data Indications Sedative-hypnotic agents are used in the short-term management of various anxiety states and to treat insomnia. Selected agents are used as anticonvulsants (pentobarbital, phenobarbital) and preoperative sedatives (pentobarbital, secobarbital) and in the management of alcohol withdrawal. Examples of commonly used sedative-hypnotics are presented in Table 4--13. Clinical guidelines typically recommend CBT as the first choice of treatment for insomnia, but there are currently four categories of medications approved by the FDA for this purpose (Neubauer, 2020):   Benzodiazepines (estazolam, flurazepam, quazepam, temazepam, and triazolam) and alternative structured medications (eszopiclone, zaleplon, and zolpidem) with benzodiazepine-like properties   Melatonin receptor agonists (ramelteon, tasimelteon)   Histamine receptor antagonist (low-dose doxepin)   Orexin receptor antagonists (suvorexant and lemborexant) \*\*\*\*\*\*\*\*\*Action Sedative-hypnotics cause generalized CNS depression. They may produce tolerance with chronic use and have the potential for psychological or physical dependence. Exception: Ramelteon (Rozerem) is not a controlled substance. It does not produce tolerance or physical dependence. Sleep-promoting properties are the result of ramelteon's agonist activity on selective melatonin receptors. TABLE 4--13    Sedative-Hypnotic Agents CHEMICAL CLASS GENERIC (TRADE) NAME CONTROLLED CATEGORIES DAILY DOSAGE RANGE Barbiturates Amobarbital CII 60--200 mg   Butabarbital (Butisol) CIII 45--120 mg   Pentobarbital (Nembutal) CII 150--200 mg   Phenobarbital (Luminal; Solfoton) CIV 30--200 mg   Secobarbital (Seconal) CII 100 mg (hypnotic); 200--300 mg (preoperative sedation) Benzodiazepines Estazolam CIV 0.5--2 mg   Flurazepam CIV 15--30 mg   Temazepam (Restoril) CIV 7.5--30 mg   Triazolam (Halcion) CIV 0.125--0.5 mg Miscellaneous Eszopiclone (Lunesta) CIV 1--3 mg   Ramelteon (Rozerem) N/A 8 mg   Zaleplon (Sonata) CIV 5--20 mg   Zolpidem (Ambien) CIV 5--10 mg (immediate release) 6.25--12.5 mg (extended release   Lemborexant (Dayvigo) (pending) 5--10 mg \*\*\*\*\*\*\*\*\*\*\*Contraindications and Precautions Sedative-hypnotics are contraindicated in individuals with hypersensitivity to the drug or to any drug within the chemical class; in pregnancy (exceptions may be made in certain cases based on benefit-to-risk ratio); during lactation; in severe hepatic, cardiac, respiratory, or renal disease; and in children younger than age 15 years for flurazepam and those younger than age 18 years for estazolam, quazepam, temazepam, and triazolam. Triazolam is contraindicated with concurrent use of medications that impair the metabolism of triazolam by cytochrome P4503A (CYP3A), such as ketoconazole, itraconazole, and nefazodone. Ramelteon is contraindicated with concurrent use of fluvoxamine. Zolpidem, zaleplon, eszopiclone, and ramelteon are contraindicated in children. Caution should be used in administering these drugs to patients with cardiac, hepatic, renal, or respiratory insufficiency. They should be used with caution in patients who may be suicidal or who previously may have been addicted to drugs. Hypnotic use should be short term. Elderly patients may be more sensitive to CNS depressant effects, and dosage reduction may be required. \*\*\*\*\*\*\*\*\*\*Interactions   Barbiturates: The effects of barbiturates are increased with concomitant use of alcohol, other CNS depressants, MAOIs, or valproic acid. The effects of barbiturates may be decreased with rifampin. Possible decreased effects of the following drugs may occur when used concomitantly with barbiturates: anticoagulants, beta blockers, carbamazepine, clonazepam, oral contraceptives, corticosteroids, digitoxin, doxorubicin, doxycycline, felodipine, fenoprofen, griseofulvin, metronidazole, phenylbutazone, quinidine, theophylline, or verapamil. Concomitant use with methoxyflurane may enhance renal toxicity.   Benzodiazepines: The effects of the benzodiazepine hypnotics are increased with concomitant use of alcohol or other CNS depressants, cimetidine, oral contraceptives, disulfiram, isoniazid, or probenecid. Concomitant use with opioids increases the risk of respiratory depression, coma, and death. The effects of the benzodiazepine hypnotics are decreased with concomitant use of rifampin, theophylline, carbamazepine, or St. John's wort and with cigarette smoking. The effects of digoxin or phenytoin are increased when used concomitantly with benzodiazepines. Bioavailability of triazolam is increased with concurrent use of macrolides.   Eszopiclone (Lunesta): Additive effects of eszopiclone occur with alcohol or other CNS depressants. Decreased effects of eszopiclone occur with CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital), with lorazepam, or after a high-fat or heavy meal. Increased effects of eszopiclone occur with CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir, and nelfinavir). The effects of lorazepam are decreased when used concomitantly with eszopiclone.   Zaleplon (Sonata): Additive effects of zaleplon occur with alcohol or other CNS depressants. Decreased effects of zaleplon occur with CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital) or after a high-fat or heavy meal. The effects of zaleplon are increased when used concomitantly with cimetidine.   Zolpidem (Ambien, Ambien CR, Edluar, Intermezzo, Zolpimist): Increased effects of zolpidem occur with alcohol or other CNS depressants, azole antifungals, ritonavir, or SSRIs. Decreased effects of zolpidem occur with flumazenil, rifampin, and with food. There is a risk of life-threatening cardiac arrhythmias with concomitant use of amiodarone.   Ramelteon (Rozerem), tasimelteon (Hetlioz): Increased effects occur with alcohol, ketoconazole (and other CYP3A4 inhibitors), and fluvoxamine (and other CYP1A2 inhibitors). Decreased effects occur with rifampin (and other CYP3A4 inducers) and after a heavy or high-fat meal. \*\*\*\*\*\*\*\*\*Diagnosis The following nursing diagnoses may be considered for patients receiving therapy with sedative-hypnotics:   Risk for injury related to abrupt withdrawal from long-term use or decreased mental alertness caused by residual sedation   Disturbed sleep pattern or insomnia related to situational crises, physical condition, or severe level of anxiety   Risk for activity intolerance related to side effects of lethargy, drowsiness, and dizziness   Risk for acute confusion related to action of the medication on the CNS \*\*\*\*\*\*\*\*\*\*Safety Issues in Planning and Implementing Care Refer to the earlier discussion of safety issues in the previous section "Antianxiety Agents." In addition to the side effects listed in that section, abnormal thinking and behavioral changes, including aggressiveness, hallucinations, and suicidal ideation, have also been noted in some individuals taking sedative-hypnotics. Certain complex behaviors, such as sleep-driving, preparing and eating food, and making phone calls, with amnesia for the behavior, have occurred. In 2019, the FDA added a boxed warning to prescribing information for eszopiclone, zaleplon, and zolpidem related to serious injuries and death associated with complex sleep behaviors that may occur with these medications. The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation. \*\*\*\*\*\*\*\*\*\*\*Outcome Criteria and Evaluation The following criteria may be used for evaluating the effectiveness of therapy with sedative-hypnotic medications. The patient:   Demonstrates reduced anxiety, tension, and restless activity   Falls asleep within 30 minutes of taking the medication and remains asleep for 6 to 8 hours without interruption   Is able to participate in usual activities without residual sedation   Experiences no physical injury   Exhibits no evidence of confusion   Verbalizes understanding of taking the medication on a short-term basis   Verbalizes understanding of potential for development of tolerance and dependence with long-term use \*\*\*\*\*\*\*\*\*\*Attention Deficit-Hyperactivity Disorder Agents Background Assessment Data Indications Attention deficit-hyperactivity disorder (ADHD) agents include CNS stimulants and nonstimulants. Amphetamines (which are CNS stimulants) are schedule II controlled substances indicating their high potential for misuse and dependence. They are also used in the treatment of narcolepsy and exogenous obesity. Nonstimulant medications include atomoxetine and bupropion (used off-label in ADHD treatment), which are also used in the treatment of major depression and for smoking cessation (Zyban only), and clonidine and guanfacine (also used to treat hypertension). (A table of current FDA-approved agents for ADHD can be found in Chapter 32, "Children and Adolescents.") \*\*\*\*\*\*\*\*\*\*Action CNS stimulants increase levels of neurotransmitters (probably norepinephrine, dopamine, and serotonin) in the CNS. They produce CNS and respiratory stimulation, vasoconstriction, dilated pupils, increased motor activity, mental alertness, decreased fatigue, and improved attention span in ADHD. The CNS stimulants discussed in this section include dextroamphetamine sulfate, methamphetamine, lisdexamfetamine, amphetamine mixtures, methylphenidate, and dexmethylphenidate. Their mechanism of action in the treatment of ADHD is unclear; however, it is believed that increasing dopamine and norepinephrine activity in the prefrontal cortex may explain the drugs' benefits because deficits in prefrontal functioning have been associated with ADHD, and dopamine and norepinephrine are key to enhancing prefrontal cortex functions (Guzman, 2021). Atomoxetine inhibits the reuptake of norepinephrine, and bupropion blocks the neuronal uptake of serotonin, norepinephrine, and dopamine. Clonidine and guanfacine stimulate central alpha-adrenergic receptors in the brain, resulting in reduced sympathetic outflow from the CNS. The exact mechanism by which these nonstimulant drugs produce the therapeutic effect in ADHD is unclear. One recent FDA approval in 2020 for the treatment of ADHD was not a drug but instead a novel interactive video game, EndeavorRx. Its developers identify that it directly targets neurological function, and studies support its effectiveness in improving attention (Tumolo, 2020). It requires a prescription and is currently advanced as a nondrug adjunctive treatment option. A second FDA-approved device is the Monarch external trigeminal nerve stimulation (eTNS) system, a trigeminal nerve stimulator. As Greenhill (2022) noted, FDA approvals for devices only require evidence of safety (unlike medications, which also require evidence of efficacy). More research is needed to evaluate the therapeutic benefits of these treatments. Other advances in the treatment of ADHD include a delayed-release stimulant (methylphenidate hydrochloride) given at bedtime so that it reaches effectiveness levels in the morning; FDA approval of an SNRI, viloxazine (Qelbree), as another nonstimulant option; and a combination CNS stimulant drug (serdexmethylphenidate and dexmethylphenidate \[Azstarys\]) that is advanced as offering all-day relief in a single daily dose. \*\*\*\*\*\*\*\*\*\*\*Contraindications and Precautions CNS stimulants are contraindicated in individuals with hypersensitivity to sympathomimetic amines. They should not be used in clients with advanced arteriosclerosis, cardiovascular disease, hypertension, hyperthyroidism, glaucoma, or agitated or hyperexcitability states; in clients with a history of substance misuse; during or within 14 days of receiving therapy with MAOIs; in children younger than age 3; or during pregnancy and lactation. Atomoxetine and bupropion are contraindicated in clients with hypersensitivity to the drugs or their components, in lactation, and in concomitant use with or within 2 weeks of using MAOIs. Atomoxetine is contraindicated in clients with narrow-angle glaucoma. Bupropion is contraindicated in individuals with known or suspected seizure disorder, in the acute phase of MI, and in people with bulimia or anorexia nervosa. Because bupropion reduces the seizure threshold, doses should be given in equally spaced time increments during the day to minimize the risk of seizures. Risk of seizures increases fourfold in doses greater than 450 mg per day (Vallerand & Sanoski, 2022). Alpha-agonists are contraindicated in clients with known hypersensitivity to the drugs. Caution is advised in using CNS stimulants in children with psychosis; in Tourette's disorder; in clients with anorexia or insomnia; in elderly, debilitated, or asthenic clients; and in clients with a history of suicidal or homicidal tendencies. Prolonged use may result in tolerance and physical or psychological dependence. Atomoxetine and bupropion should be used with caution in clients with urinary retention, hypertension, or hepatic, renal, or cardiovascular disease; in suicidal clients; during pregnancy; and in older and debilitated clients. Alpha-adrenergic agonists should be used with caution in clients with coronary insufficiency, recent MI, or cerebrovascular disease; in chronic renal or hepatic failure; in older adults; and in pregnancy and lactation. \*\*\*\*\*\*\*\*\*\*Interactions   CNS Stimulants (Amphetamines): Effects of amphetamines are increased with furazolidone or urinary alkalinizers. Hypertensive crisis may occur with concomitant use of (and up to several weeks after discontinuing) MAOIs. Increased risk of serotonin syndrome occurs with coadministration of SSRIs. Decreased effects of amphetamines occur with urinary acidifiers, and decreased hypotensive effects of guanethidine occur with amphetamines.   Dexmethylphenidate and Methylphenidate: Effects of antihypertensive agents and pressor agents (e.g., dopamine, epinephrine, phenylephrine) are decreased with concomitant use of methylphenidates. Effects of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), TCAs, and SSRIs are increased with the methylphenidates. Hypertensive crisis may occur with coadministration of MAOIs.   Atomoxetine and Viloxazine (SNRIs): Effects are increased with concomitant use of CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine). Potentially fatal reactions may occur with concurrent use of (or within 2 weeks of discontinuation of) MAOIs. Risk of cardiovascular effects is increased with concomitant use of albuterol or vasopressors.   Bupropion (Nonstimulant, Antidepressant): Effects of bupropion are increased with amantadine, levodopa, or ritonavir. Effects of bupropion are decreased with carbamazepine. There is an increased risk of acute toxicity with MAOIs. Increased risk of hypertension may occur with nicotine replacement agents, and adverse neuropsychiatric events may occur with alcohol. Increased anticoagulant effects of warfarin and increased effects of drugs metabolized by CYP2D6 (e.g., nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline, haloperidol, risperidone, thioridazine, metoprolol, propafenone, and flecainide) occur with concomitant use.   Alpha-adrenergic Agonists: Synergistic pharmacological and toxic effects, possibly causing atrioventricular block, bradycardia, and severe hypotension, may occur with concomitant use of calcium channel blockers or beta blockers. Additive sedation occurs with CNS depressants, including alcohol, antihistamines, opioid analgesics, and sedative-hypnotics. Effects of clonidine may be decreased with concomitant use of TCAs and prazosin. Decreased effects of levodopa may occur with clonidine, and effects of guanfacine are decreased with barbiturates or phenytoin. \*\*\*\*\*\*\*\*\*\*Diagnosis The following nursing diagnoses may be considered for patients receiving therapy with agents for ADHD:   Risk for injury related to overstimulation and hyperactivity (CNS stimulants) or seizures (possible side effect of bupropion)   Risk for suicide secondary to major depression related to abrupt withdrawal after extended use (CNS stimulants)   Risk for suicide (children, adolescents, and young adults) as a side effect of atomoxetine and bupropion (boxed warning)   Imbalanced nutrition, less than body requirements, related to side effects of anorexia and weight loss (CNS stimulants)   Insomnia related to side effects of overstimulation   Nausea related to side effects of atomoxetine or bupropion   Pain related to side effect of abdominal pain (atomoxetine, bupropion) or headache (all agents)   Risk for activity intolerance related to side effects of sedation and dizziness with atomoxetine or bupropion \*\*\*\*\*\*\*\*\*\*\*Safety Issues in Planning and Implementing Care The plan of care should include monitoring for the following side effects from agents for ADHD. Nursing interventions related to each side effect are discussed in sub-bullets after each side effect.   Overstimulation, restlessness, insomnia (CNS stimulants)   Assess mental status for changes in mood, level of activity, degree of stimulation, and aggressiveness.   Ensure that the patient is protected from injury.   Keep stimuli low and environment as quiet as possible to discourage overstimulation.   Administer the last dose at least 6 hours before bedtime to prevent insomnia. Administer sustained-release forms in the morning.   Palpitations, tachycardia (CNS stimulants, atomoxetine, bupropion, clonidine), or bradycardia (clonidine, guanfacine)   Monitor and record vital signs at regular intervals (two or three times a day) throughout therapy. Report significant changes to the physician immediately. Note: The FDA has issued warnings for CNS stimulants and atomoxetine about the risk for sudden death in patients who have cardiovascular disease. A careful personal and family history of heart disease, heart defects, or hypertension should be obtained before these medications are prescribed. Careful monitoring of cardiovascular function during administration must be ongoing.   Anorexia, weight loss (CNS stimulants, atomoxetine, bupropion)   Administer the medication immediately after meals to reduce anorexia.   Weigh the patient regularly (at least weekly) when receiving therapy with CNS stimulants, atomoxetine, or bupropion because of the potential for anorexia and weight loss and temporary interruption of growth and development.   Tolerance, physical and psychological dependence (CNS stimulants)   Attempt a drug "holiday" periodically in children with ADHD, under the direction of the physician to determine the effectiveness of the medication and the need for continuation.   Do not abruptly withdraw CNS stimulants. To do so could initiate a syndrome of symptoms with nausea, vomiting, abdominal cramping, headache, fatigue, weakness, mental depression, suicidal ideation, increased dreaming, and psychotic behavior.   Nausea and vomiting (atomoxetine and bupropion) \*\*\*\*\*\*\*\*\*\*  Recommend taking medication with food to minimize gastrointestinal upset.   Constipation (atomoxetine, bupropion, clonidine, guanfacine)   Recommend increasing fiber and fluid in diet if not contraindicated.   Dry mouth (clonidine and guanfacine)   Offer the patient sugarless candy, ice, and frequent sips of water.   Advise the patient that strict oral hygiene is very important.   Sedation (clonidine and guanfacine)   Warn the patient that this effect is increased by concomitant use of alcohol and other CNS drugs.   Warn the patient to refrain from driving or performing hazardous tasks until response has been established.   Potential for seizures (bupropion)   Protect the patient from injury if seizure should occur.   Instruct family and significant others of patients on bupropion therapy how to protect the patient during a seizure if one should occur.   Ensure that doses of the immediate-release medication are administered at least 4 to 6 hours apart and doses of the sustained-release medication at least 8 hours apart.   Severe liver damage (with atomoxetine)   Monitor for the following side effects and report to the physician immediately: itch