Mental Health Prescribing Nursing CE Course for APRNs

m during school hours. Once a child reaches adolescence, medications are often used, but behavioral therapy may still be a helpful adjunct. Medications should be started at the lowest dose possible and titrated up as needed until the child reaches the maximum benefit while avoiding significant adverse effects. If the child has a "medication vacation" and does not take their medicine for a period, such as during a school break, the dose should be reduced when the medication is restarted and titrated back up slowly (Wolraich et al., 2019).

Pharmacologic treatment should only be considered if behavioral therapy is ineffective or does not provide significant improvement and there is a moderate-to-severe continued disturbance in the 4- to 5-year-old child's functioning. The guidelines encourage providers to weigh the risks of prescribing medication before age 6 against the harm of delaying treatment. Elementary and middle school-aged children (6-12) should receive treatment with PTBM, behavioral classroom intervention, and medication. Educational interventions and individualized instructional support should be provided within the school environment, classroom placement, and additional essential components of the treatment plan, often including an individualized education program (IEP) or a rehabilitation plan. Adolescents (ages 12-18) should receive medications approved by the FDA with their consent, preferably with the same behavioral and educational interventions outlined above. Medications are also commonly used during adulthood, as up to one-third of children with ADHD continue to have symptoms into adulthood. There is no cure for ADHD; therefore, medication use aims to lessen hyperactivity and impulsivity symptoms and improve the patient’s ability to concentrate, focus, work, and learn (CDC, 2022b; CHADD, n.d.-b; Wolraich et al., 2019).

The pathophysiology of ADHD is not entirely clear but is premised on a complex neurobiological basis involving multiple brain pathways. Neurotransmitters are endogenous chemical messengers within the brain that help transmit signals necessary for normal functioning, and they are thought to play a role in ADHD disorders. Dopamine, norepinephrine, and serotonin are the three neurotransmitters implicated in ADHD disorders, and a deficiency in these vital chemical messengers may be linked to the development of ADHD symptoms. Dopamine influences movement, attention, and motivation; norepinephrine plays a role in maintaining mental activity, regulating mood and excitability, problem-solving, and memory; and serotonin influences mood, sleep, memory, and social behavior. Therefore, medications targeting these neurotransmitters are considered the mainstay of pharmacological treatment (Tarraza, 2023).

Two classes of medications are commonly prescribed for treating ADHD: stimulants and non-stimulants. These medications work primarily by blocking the reuptake and increasing the release of dopamine and norepinephrine neurotransmitters, improving cognition and attention. Stimulants are the most widely used and well-known class of medications for managing ADHD-related symptoms and have been shown to reduce symptoms in 70% to 80% of children with ADHD. Non-stimulants were approved for the treatment of ADHD in 2003, and their effects can last longer, up to 24 hours, but are slower to take effect. Stimulants consist of both amphetamines and methylphenidates, and they are available in immediate-release (IR), sustained- or extended-release (SR, ER, XR), and long-acting (LA) formulations. The development of longer-acting ER stimulants is relatively new and provides increased patient treatment options. Longer-acting agents are associated with improved compliance with treatment, as they are only dosed once a day instead of the 2 to 3 times per day (BID or TID) required with IR formulations (CDC, 2022b; NIMH, 2022e).

Stimulants

The most common medications used to treat ADHD are stimulants. Most children (70% to 80%) diagnosed with ADHD and medicated with a stimulant exhibit significantly improved ADHD behaviors. Stimulants are all categorized by the US Drug Enforcement Administration (DEA) as Schedule II with high abuse potential and previously by the FDA as pregnancy Category C (i.e., risk cannot be ruled out). These medications were first administered to children with behavioral and learning disorders in 1937. Hundreds of controlled studies have been conducted (involving more than 6,000 children, adolescents, and adults) to determine the short-term effects of these medications. There are no long-term studies (i.e., more than a few years) on the effects of these medications, as this research would necessitate withholding treatment over many years for patients with significant impairment, which has been deemed unethical. However, individuals have used these medications for many years without serious adverse effects. Stimulants generally contain different types of methylphenidate and amphetamines and produce a calming effect on hyperactivity by increasing brain dopamine levels. The most common stimulants used for ADHD are methylphenidate (Ritalin, Concerta, Aptensio, Jornay PM), dextroamphetamine (Dexedrine), and dextroamphetamine/amphetamine (Adderall). They are available as IR formulas (lasting about 4 hours), LA formulas (ranging from 6 to 12 hours), and ER preparations (lasting up to 24 hours). Many caregivers and patients prefer LA or ER formulations, as these may reduce the "ups and downs" experienced throughout the day and eliminate the need to dose medication at school or work (CHADD, n.d.-a; Wolraich et al., 2019).

Amphetamines induce central nervous system (CNS) activity, activating the acute stress response (fight or flight) and producing a paradoxical calming effect. CNS activation creates physiological changes as if the body were stressed or threatened. Amphetamines stimulate the release of adrenaline and raise cortisol and other stress hormone levels, causing increased heart rate and blood pressure. As a result, blood flow is redirected to the muscles and away from the brain. In small doses, amphetamines can alleviate tiredness and help patients feel alert and refreshed. Some common types include dextroamphetamine (Dexedrine), dextroamphetamine/amphetamine (Adderall), amphetamine salt combo XR (Adderall XR), and lisdexamfetamine (Vyvanse; Wolraich et al., 2019; Woods, 2023).

Dextroamphetamine/amphetamine (Adderall) is considered the first-line pharmacological treatment for ADHD and is widely used in individuals 6 years and older. Initial dosing for patients 6 and older is 5 mg (IR tabs) by mouth once or twice daily, increasing the dose by 5 mg weekly until optimal symptom management is achieved up to 40 mg/day. IR dosing for children ages 3 to 5 is 2.5 mg by mouth once daily, increasing the dose by 2.5 mg weekly in 1 to 3 divided doses per day until optimal results are achieved. With ER tabs, the initial dosing for children ages 6 to 12 is 5 to 10 mg by mouth once daily in the morning, increasing the dose by 5 or 10 mg weekly up to 30 mg/day. For adolescents ages 13 to 17, the initial dosing is 10 mg by mouth daily in the morning, increasing to 20 mg/day after a week if symptoms are not controlled. The adult dose is 20 mg daily in the morning, with a maximum dose of 30 mg/day. Proton pump inhibitors (PPIs) such as omeprazole (Prilosec) and esomeprazole (Nexium) can interfere with the absorption of this medication, and there is a rare risk of sudden death in patients with a cardiac history. Dextroamphetamine/ amphetamine (Adderall) can be administered with or without food but should be taken in the morning to avoid insomnia. Patients taking the ER formulation should swallow capsules whole, or the contents can be sprinkled on a bite of food that does not require chewing (e.g., applesauce or pudding; Wolraich et al., 2019; Woods, 2023).

Dextroamphetamine (Dexedrine) is similar to dextroamphetamine/amphetamine (Adderall) but without pure amphetamine. Initial dosing for children 6 and older is 5 mg by mouth once or twice daily, increasing by 5 mg weekly until optimal results are obtained. The dose rarely needs to exceed 40 mg/day. For children ages 3 to 5, the initial dosing is 2.5 mg orally once daily, increasing by 2.5 mg weekly until optimal response is obtained. Dextroamphetamine (Dexedrine) should not be administered in the late evening due to the risk of insomnia. This medication interacts with antihypertensives (diminishes effects), monoamine oxidase inhibitors (MAOIs; may cause severe hypertension), and acidic foods or fruit juices due to delayed absorption and decreased effectiveness. It should be used cautiously in patients experiencing agitation, motor or phonic tics, or Tourette syndrome (Woods, 2023).

Lisdexamfetamine (Vyvanse) is a LA preparation and differs from other medications in this class due to its pharmacokinetics. It is considered a prodrug, which means it must undergo chemical conversion by metabolic processes before becoming an active agent. It does not convert to its active formulation until it reaches the gastrointestinal tract; therefore, its effects take 60 to 90 minutes. The drug has less abuse potential than dextroamphetamine/amphetamine (Adderall), as it cannot be absorbed intravenously or transmucosally. For adults and children ages 6 to 17, the initial dose is 30 mg orally once daily in the morning, increasing by 10 to 20 mg weekly to a maximum dose of 70 mg daily. Dosing must be adjusted for patients with severe renal impairment. For patients with a glomerular filtration rate (GFR) of 15-30 mL/min/m², the maximum dose is 50 mg/day. For those with end-stage renal disease (ESRD) or a GFR below 15 mL/min/m², the maximum dose is 30 mg/day. Lisdexamfetamine (Vyvanse) should be taken in the morning with or without food to prevent insomnia (Wolraich et al., 2019; Woods, 2023).

Methylphenidate stimulates the release of terminal norepinephrine stores, promoting nerve impulse transmission. At high doses, the effects are mediated by dopamine. The most common is methylphenidate (Ritalin, Concerta, Aptensio, Jornay PM), which is available orally. Methylphenidate is also available as a transdermal patch called Daytrana. Dosing instructions for each formulation of methylphenidate are listed in Table 1. Chewable tablets must be taken with at least 240 mL of water. IR formulations should be administered in divided doses throughout the day, at least 30 to 45 minutes before meals and no later than 6 p.m., due to the risk of insomnia. The exception is Jornay PM which should be administered between 6:30 and 9:30 p.m. If using methylphenidate (Daytrana), the patch should not be placed along the waistline or where tight clothing could pull the patch away from the skin. When changing patches, the site should be moved to the alternate side of the body. Drug interactions include antacids (i.e., H2 blockers, PPIs) and MAOIs. Because methylphenidate (Concerta) does not dissolve after ingestion, it is contraindicated in patients with a history of peritonitis or conditions that cause gastrointestinal tract narrowing (e.g., short-gut syndrome, cystic fibrosis, or small-bowel inflammatory disease). These medications should be used cautiously in patients with a history of bipolar disorder, electroencephalogram (EEG) abnormalities, psychosis, or emotional disorders (Woods, 2023).

Table 1

Dosing of Methylphenidate 

Drug	Initial Dose	Titration	Considerations
Concerta	Adults ages 18 to 65 not taking other stimulants: 18 mg or 36 mg by mouth daily	May increase the dosage in 18 mg increments weekly to a maximum dose of 72 mg daily	No considerations
	Adolescents age 13 to 17 not currently taking methylphenidate or those taking other stimulants: 18 mg by mouth once daily in the morning	Increase dose by 18 mg at weekly intervals to a maximum of 72 mg daily
	For children ages 6 to 12 not currently taking methylphenidate or those taking other stimulants: 18 mg by mouth once daily	Adjust the dose by 18 mg at weekly intervals to a maximum of 54 mg daily
	Adults and adolescents ages 13 to 17 currently taking methylphenidate: if the previous dose was 5 mg BID or TID, start 18 mg by mouth once daily if the previous dose was 10 mg BID or TID, start 36 mg by mouth once daily if the previous dose was 15 mg BID or TID, give 54 mg by mouth once daily if the previous dose was 20 mg BID or TID, give 72 mg by mouth once daily	The maximum conversion dose is 72 mg daily
	Children age 6 to 12 currently taking methylphenidate: if the previous dose was 5 mg BID or TID, give 18 mg by mouth once daily if the previous dose was 10 mg BID or TID, give 36 mg by mouth once daily if the previous dose was 15 mg BID or TID, give 54 mg by mouth once daily	The maximum conversion dose is 54 mg daily
Ritalin LA	Adults and children ages 6 and older: 20 mg by mouth once daily	Increase dosage by 10 mg at weekly intervals to a maximum dose of 60 mg daily	If replacing methylphenidate BID, give the same daily dosage once daily
Aptensio XR	Adults and children ages 6 and older: 10 mg by mouth daily in the morning	Increase dosage by 10 mg at weekly intervals to a maximum dose of 60 mg daily	No considerations
Jornay PM	For children ages 6 and older: 20 mg by mouth once daily in the evening	Increase dosage by 20 mg at weekly intervals to a maximum dose of 100 mg daily	Can adjust the timing of administration between 6:30 and 9:30 p.m.
Daytrana	Adults and children age 6 to 17: apply one 10 mg patch daily	Increase the dose weekly as needed to a maximum of 30 mg daily	Apply the patch 2 hours before the desired effect and remove 9 hours later

(Woods, 2023)

The side effects of stimulants include hypertension, tachycardia, anxiety, decreased appetite, sleep problems, personality changes, tics, stomach pain, and headaches. Less commonly reported side effects include allergic reactions, fever, arthralgia, psychosis, and depression. Sudden death is a rare adverse effect in patients with preexisting cardiac conditions. These drugs should be used cautiously in patients with hypertension, seizures, a history of myocardial infarction, stroke, liver disease, kidney disease, or anxiety disorders. Stimulants are contraindicated for patients with advanced arteriosclerosis, hyperthyroidism, symptomatic cardiovascular disease, structural cardiac abnormalities, cardiomyopathy, serious arrhythmia, or glaucoma. APRNs should counsel patients on strategies to manage insomnia, including taking the medication before noon, limiting or avoiding caffeine, and maintaining healthy sleep hygiene. When insomnia requires pharmacological management, melatonin is encouraged as the initial intervention, as it naturally occurs in the body and is non-addicting. Some patients may require adjunctive prescriptive sleep aids, such as clonidine (Catapres, Kapvay) or trazodone (Desyrel), which may be used in children and adults. Medications such as eszopiclone (Lunesta) and zolpidem (Ambien) should only be prescribed for adults and should be taken 30 to 60 minutes before bedtime (NIMH, 2022e; Tarraza, 2023; Woods, 2023).

Determining which medication to use to treat ADHD depends on a range of factors, including but not limited to the presence of comorbidities, the risk of experiencing side effects, consideration of the individual's compliance potential, and the potential for drug diversion. Stimulants carry a risk for diversion (i.e., when legitimate stimulant prescriptions for ADHD are diverted and used for reasons other than treating ADHD). When taken at doses and via routes other than those prescribed, stimulants can increase dopamine levels in the brain in a rapid and highly amplified manner (similar to other drugs commonly abused, such as opioids), thereby disrupting communication between brain cells and producing euphoria. As a result, these biochemical processes and subsequent euphoric effects increase the risk of addiction. Therefore, before prescribing these medications, providers must assess each patient's risk for diversion and continue to reassess at each follow-up visit while continuing treatment. Following drug selection, providers are advised to "start low and go slow" when prescribing these agents, initially prescribing the lowest dose possible and gradually titrating the dose upward to minimize side effects. Most side effects of stimulants can be eliminated or decreased with this medication initiation plan. Some people describe a stimulant rebound during the period between dosing as the medication is wearing off, in which they can experience a negative mood, fatigue, or hyperactivity. These symptoms can be managed by changing the dose or schedule of IR formulas or switching to an LA formula if possible (CHADD, n.d.-b; Wolraich et al., 2019).

Patients prescribed stimulants should have specific monitoring performed by prescribers at particular points during treatment. All patients should have their blood pressure, heart rate, height, and weight evaluated at baseline. Height should be monitored when taking stimulants, especially in children who have not reached their full adult height, as stimulants can slow their growth rate. During dose adjustments, a weekly phone check-in or follow-up appointment is advised to monitor for side effects and assess patients for tics or adverse effects. This follow-up allows the prescriber to track changes and symptom severity closely. Once the optimal dose is established, patients should have follow-up visits every 1 to 3 months. Routine laboratory testing is not advised unless there are specific concerns based on the patient's clinical presentation. When applicable, patients should be educated that amphetamines may increase plasma corticosteroid levels and interfere with urine steroid test results (Wolraich et al., 2019; Woods, 2023).

Non-Stimulants

Non-stimulants are also highly effective in reducing ADHD symptoms but generally take longer to start working. Non-stimulants are often used instead of stimulants in patients with unacceptable adverse effects or inadequate results or combined with stimulants to enhance effects. Non-stimulants can help improve focus and attention and decrease impulsivity. Some of the most common non-stimulant medications include atomoxetine (Strattera) and guanfacine ER (Intuniv). Atomoxetine (Strattera) alleviates inattention and hyperactivity symptoms of ADHD by selectively inhibiting the reuptake of norepinephrine. It is not a controlled substance and is thus determined to have low abuse potential. Atomoxetine (Strattera) has a slower onset, taking up to 4 weeks to see the full effects of the medication. Initial dosing for adults and children older than 6 and adolescents weighing more than 70 kg is 40 mg by mouth daily, increasing after at least 3 days to a total of 80 mg/day as a single dose in the morning or two evenly divided doses. For children 6 or older and adolescents weighing less than 70 kg, initial dosing is 0.5 mg/kg by mouth daily, increasing after at least 3 days to a target total daily dose of 1.2 mg/kg given either once daily in the morning or BID in equally divided doses. Atomoxetine (Strattera) should not be used with albuterol (which may increase cardiovascular effects) or MAOIs (which may cause hyperthermia, rigidity, and myoclonus). Adverse effects include headaches, insomnia, dizziness, irritability, fatigue, abnormal dreams, sleep disorder, anxiety, orthostatic hypotension, tachycardia, palpitations, hot flashes, abdominal pain, constipation, dyspepsia, nausea, vomiting, anorexia, urinary retention, and ejaculatory problems. Due to these effects, atomoxetine (Strattera) should be used cautiously in patients with hypertension, tachycardia, hypotension, urinary retention, or cerebrovascular disease (NIMH, 2022b; Wolraich et al., 2019; Woods, 2023).

Antihypertensives such as clonidine (Catapres, Kapvay) and guanfacine (Tenex, Intuniv) have been approved for ADHD symptoms in children, such as hyperactivity and aggression; they may help adults, but studies are limited at this point. Clonidine (Catapres, Kapvay) is an alpha-2 noradrenergic agent, and guanfacine (Tenex, Intuniv) is an alpha-2a noradrenergic agent. However, both are believed to work by affecting the available levels of norepinephrine and dopamine. Dosing of clonidine ER (Kapvay) for ADHD in children ages 6 to 17 is initially 0.1 mg by mouth at bedtime. The dose can be adjusted by 0.1 mg weekly until desired effects are reached up to 0.4 mg/day. Only the ER form of guanfacine (Intuniv) is approved to treat ADHD. Initial dosing in children ages 6 to 17 is 1 mg by mouth once daily in the AM or PM at the same time each day. If needed, the dose can be adjusted by 1 mg per week. Dosages over 4 mg/day in children 6 to 12 or above 7 mg in children 13 to 17 have not been evaluated. These drugs risk significant adverse effects, such as hypotension, sedation, and hypertensive rebound. Another treatment option for adult ADHD patients is modafinil (Provigil), a wake-promoting agent that the FDA currently approves for narcolepsy and extreme fatigue in patients with multiple sclerosis. It does not seem to affect central dopamine or norepinephrine pathways but indirectly activates the frontal cortex. A small study of adults with ADHD showed favorable results from modafinil (Provigil) after a 2-week trial in 48% of patients. Data are limited and preliminary but warrant further long-term studies and consideration (CHADD, n.d.-a; Woods, 2023).

Antidepressants that target the neurotransmitter norepinephrine are sometimes used to treat ADHD, but they are not FDA-approved for this indication and are thus considered off-label. Venlafaxine (Effexor) inhibits the reuptake of norepinephrine, serotonin, and dopamine. Bupropion (Wellbutrin) is a norepinephrine and dopamine reuptake inhibitor (NDRI) that helps improve concentration and focus and reduces hyperactivity. Since it does not influence serotonin, it differs from many other antidepressants. Possible side effects of bupropion (Wellbutrin) include anxiety, agitation, increased motor activity, insomnia, tremors or tics, dry mouth, headaches, nausea, and an increased risk for seizures in susceptible individuals or those with a history of eating disorders. Less commonly, duloxetine (Cymbalta) may be used; it works by blocking the reuptake of norepinephrine and serotonin. Like atomoxetine (Strattera), these drugs are not controlled substances and have low abuse potential but should be used with caution and in conjunction with extensive patient counseling regarding the possible side effects and risks. They are not recommended for children with depression and should be used cautiously in adolescents due to the increased risk of suicide accompanying antidepressant use (CHADD, n.d.-a; WHO, 2022).

In June 2020, the FDA approved EndeavorRx, a new treatment option for ADHD in children. EndeavorRx is presented as an immersive video game played on a mobile device. The game is approved for children ages 8 to 12. To access the game, the patient must have the treatment prescribed by their primary ADHD treatment provider. The game is considered a medical device designed to be used with other therapies and should not be used as monotherapy. EndeavorRx uses sensory stimuli and motor challenges to stimulate areas of the brain that are involved in attention. The game challenges players to multitask while ignoring distractions by navigating courses, collecting tokens, and avoiding obstacles. The game measures the player's performance and adjusts the gameplay to meet the player's real-time needs. Suggested use is 5 days a week for 25 minutes each day. The game should be played for at least 4 consecutive weeks; a clinical trial conducted in 2021 demonstrated that using EndeavorRx for an additional 4 weeks can lead to optimal results. Results of five randomized clinical control studies, including over 600 children, showed that 68% of parents reported improvement in their children's symptoms after 2 months of this treatment, and 73% of child participants self-reported improved attention. No serious adverse effects were experienced by any participants across all five studies (Akili Interactive Labs, n.d.-a, n.d.-b). For more information on ADHD, see the NursingCE course Attention Deficit Hyperactivity Disorder.

 

Depression

According to the WHO, as much as 3.8% of the global population is affected by depression (approximately 280 million people), including 5% of adults and 5.7% of adults over 60. In the US, an estimated 21 million adults (8.4%) experience at least one major depressive episode (MDE) per year. The prevalence is increased in individuals ages 18 to 25 at 17%, and females are affected more frequently than men at 10.5% and 6.2%, respectively. Approximately 2.9 million (12%) adolescents aged 12 to 17 experienced at least one MDE the previous year. Despite the prevalence of depression, only 66% of adults over 18 and 41.6% of adolescents who experienced an MDE in 2020 received medical treatment that same year. Severe depression, when treated or untreated, can lead to suicide (NIMH, 2022d; WHO, 2021a).

The DSM-5-TR states that all forms of depressive disorders include a sad, empty, or irritable mood alongside somatic and cognitive changes that significantly impact the patient's functional capacity. Depression can occur in children and adolescents but is most common in adults and often presents as irritability or anxiety in children. Their major distinctions are limited to symptom duration, timing, or presumed etiology (APA, 2022; NIMH, 2022c). There are different classifications of depression, including:

• persistent depressive disorder (PDD), or dysthymia, lasts at least two years in adults and one year in children
• substance/medication-induced depressive disorder: depression-like phenomena caused by substance abuse, abuse of prescription medications (e.g., opioids), or illicit drug use
• disruptive mood dysregulation disorder: characterized by temper outbursts that occur three times per week for at least one year
• premenstrual dysphoric disorder: hormonal-induced depression that occurs the week before meses
• depression with peripartum onset: characterized by symptoms of depression that make it difficult to care for oneself and the baby (or other children)
• depression with psychosis: characterized by an MDE combined with concurrent psychotic symptoms, including delusions or hallucinations
• seasonal affective disorder (SAD): depression that has an onset during the winter months when there is less natural sunlight and is accompanied by increased sleep, weight gain, and social withdrawal
• bipolar disorder: a separate mood disorder with episodes of extremely low mood that meets the criteria for major depression but which includes periods of depression (APA, 2022; NIMH, 2022c)

The exact cause of depression is unknown and is likely due to a combination of risk factors. While depression is a psychological disorder, several contributing influences include environmental, genetic, and psychological or biochemical elements. Different chemicals in the brain can contribute to depressive symptoms and are the focus of pharmacological treatments. A previously accepted theory that depression stems from a chemical imbalance in the brain of the monoamines serotonin, norepinephrine, and dopamine has shifted over the last 15 to 20 years. Theories regarding alterations in brain architecture and complex circuitry have led researchers to question whether these neurotransmitters are not simply a messenger of information or symptom of depression as opposed to the cause itself. Advancements in genetics and functional neuroimaging have opened new and exciting investigational possibilities and altered how depression is viewed in the last 20 years, leading to changes in treatment options (APA, 2020, 2022).

An individualized treatment plan should be developed using shared decision-making and will vary based on the severity of the patient’s depression (mild, moderate, moderate-severe, or severe). Treatment for depression may include counseling, therapy, and/or medication. Adequate treatment can prevent suicide related to depression. The most effective treatment for depression is a combination of psychotherapy with pharmacological treatment, such as antidepressant medication (NIMH, 2022c).

Psychotherapy is a successful, beneficial, and cost-effective treatment for depression. The APA (2022) defines psychotherapy as any psychological service moderated by a trained professional (i.e., psychotherapist) that employs communication and interaction principles to assess, diagnose, and treat mental health disorders. Also referred to as talk therapy, psychotherapy is premised on establishing a supportive environment and collaborative relationship between a patient and a psychotherapist to foster open discussion in an objective, neutral, and nonjudgmental manner. A psychotherapist includes any individual professionally trained and licensed according to their respective governing state-licensing boards to treat mental health conditions (e.g., psychologist, psychiatrist, psychiatric nurse, APRN, counselor, therapist, or social worker). Research demonstrates that depressed individuals who receive psychotherapy achieve more durable treatment responses (i.e., are less prone to relapse) and better symptom control than when medication is used alone (Luo et al., 2020).

While there are several types of psychotherapy, the most effective options for depression include cognitive-behavioral therapy (CBT), mindfulness-based cognitive therapy (MBCT), problem-solving therapy (PST), behavioral activation (BA), and interpersonal therapy (IPT). Each patient and psychotherapist are encouraged to set mutually agreed upon and realistic goals that are periodically reevaluated. Patient response varies based on the presenting issue, severity, complexity, interference with functioning, openness to receiving treatment, and specific interventions. If patient improvement does not occur within the planned duration of treatment, the intervention should be reassessed, and other therapeutic strategies should be considered. There is no universally effective approach to treating depression. Experienced psychotherapists typically blend modalities and tailor the treatment to meet each patient's needs, often altering the treatment course when underlying issues are revealed as the patient progresses through therapy (APA, 2019; Luo et al., 2020; Wampold, 2019).

While mild to moderate depression can be effectively treated with therapy alone (CBT, psychotherapy), moderate to severe cases of depression often requires the addition of medication. It is important to note that numerous complementary and alternative treatments can be used as an adjunct to other evidence-based treatments for depression, such as exercise and yoga, light therapy, acupuncture, and mindfulness training. When combined with evidence-based treatment options, such as prescription medications and psychotherapy, these interventions can contribute positively to the overall treatment plan for depression (National Center for Complementary and Integrative Health [NCCIH], 2021).

There are pharmacological agents available over-the-counter (OTC) for the management of depression, such as hypericum perforatum (St. John's wort), omega-3 fatty acid (fish oil), and s-adenosyl methionine (SAM-e). However, these agents are not FDA-approved for depression, nor does the FDA regulate them to ensure their safety and efficacy. The lack of FDA oversight and regulation of these agents poses concerns regarding the consistency of formulations, the purity of their ingredients, and safety profiles. Although patients do not require a prescription to obtain these drugs, they still pose a risk of significant adverse effects and dangerous drug interactions. Hypericum perforatum (St. John’s wort) is notorious for interacting with several prescription drugs, either expediting or diminishing the metabolism of the prescribed agent leading to reduced efficacy or higher toxicity. For example, patients should be warned never to take hypericum perforatum (St. John’s wort) with a prescribed antidepressant, as the combination leads to increased levels of serotonin in the body, which can cause mild to severe effects. Studies have shown that adding a folate supplement such as L-methyl folate (Folic acid) can enhance the effectiveness of antidepressant medications without causing dangerous drug interactions. Furthermore, some studies have demonstrated that L-methyl folate (Folic acid) supplementation may be an effective adjunctive therapy or a stand-alone treatment for reducing depressive symptoms and improving cognitive function (NCCIH, 2021).

Antidepressant medications are the pharmacological treatment of choice for depression. Medication therapy aims to help reduce or control the symptoms of depression. The bulk of medications currently FDA-approved for treating depression target the three neurotransmitters historically associated with depression: serotonin, norepinephrine, and dopamine. Due to their side effect profiles, most antidepressants should be initiated at a low dose, tapered up slowly, and tapered down before discontinuing. If they are stopped abruptly, withdrawal symptoms such as dizziness, headaches, flu-like syndrome (tiredness, chills, muscle aches), agitation, irritability, insomnia, nightmares, diarrhea, and nausea may ensue. Discontinuation can also lead to the return of depressive symptoms. Regardless of the medication prescribed, patients must be counseled that antidepressants may take at least 2 to 4 weeks to have an effect and 12 weeks to achieve full benefits. Disturbances in sleep, appetite, and concentration often improve before a notable change in mood. While mild-to-moderate depression can often be treated with therapy alone, moderate-to-severe cases of depression often require the addition of medication. Women of childbearing age should be advised that most antidepressants were previously categorized by the FDA as pregnancy category C (risk cannot be ruled out) except for paroxetine (category D) and bupropion (category B), with slight variations between the medications' safety for lactating mothers (NIMH, 2022c, 2022e; Sheffler et al., 2023).

In 2004, the FDA required a warning to be printed on the labels of all antidepressant medications regarding the risk of increased suicidality among children and adolescents taking these medications. The warning was expanded in 2007 to include all young adults, especially those under 25, stating that these individuals may experience increased suicidal thoughts or behaviors during the first few weeks of taking an antidepressant. Before starting medication therapy, the individual may have been too paralyzed by depression to make a suicide plan. Therefore, the risk of suicide rises as symptoms begin to improve on antidepressant therapy. An increase in suicidal thoughts has also been documented in patients taking antidepressants for other conditions or indications. As antidepressants became more commonly prescribed for anxiety and other mental health conditions, reports of patients' suicidal thoughts and actions became more worrisome to providers and family members. If a depressed person on antidepressants becomes suicidal, it is always a cause for concern. However, if someone not previously depressed and taking antidepressants for another indication becomes suicidal, it raises additional questions about these medications' safety. Researchers found evidence that individuals taking antidepressant medication may have an even higher risk of suicide than individuals whose depression improves for other reasons (Fornaro et al., 2019). The FDA also requires manufacturers of antidepressants to provide a Patient Medication Guide (MedGuide) to distribute to patients advising them of precautions to reduce the risk of suicide. Healthcare professionals (HCPs) should ask patients, especially young persons, about suicidal thoughts before prescribing antidepressants (FDA, 2018). Table 2 lists the points that must be included in the boxed warning.

Table 2

FDA Antidepressants Boxed Warning Points

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) for children and adolescents with MDD and other psychiatric disorders.

Anyone considering an antidepressant for a child or adolescent for any clinical indication must balance the risk of increased suicidality with the clinical need.

Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Families and caregivers should be advised to observe the patient closely and communicate with the prescriber.

A statement must be made regarding whether the prescribed drug is approved for any pediatric indication(s) and, if so, which one(s).

 (FDA, 2018)

The current evidence does not recommend one prescribed agent over another. However, selective serotonin reuptake inhibitors (SSRIs) are typically cited as the safest initial choice that causes the fewest side effects, followed by selective norepinephrine reuptake inhibitors (SNRIs). While antidepressants typically do not require routine laboratory or drug-level monitoring, providers should remain alert to the potential side effects and adverse effects outlined in each category below. Providers should counsel patients that side effects typically improve after the first 2 weeks of treatment. As a drug class, the most common adverse effects of antidepressants include nausea, weight gain, diarrhea, sleepiness, and sexual dysfunction (i.e., loss of libido or impotence; Coryell, 2022b; NIMH, 2022e).

SSRIs and SNRIs

SSRIs selectively block serotonin reuptake, increasing serotonin available within the brain. SSRIs include medications such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and vortioxetine (Trintellix). Prozac (fluoxetine) is the only antidepressant that is FDA-approved for use in children with depression. Common side effects of SSRIs include nausea, vomiting, diarrhea, headaches, dry mouth, drowsiness, insomnia, nervousness, agitation, restlessness, sexual dysfunction, and appetite changes leading to weight loss or weight gain. Less common side effects include hyponatremia, abnormal bleeding or bruising, and declining bone mineral density. Providers should routinely evaluate patients on SSRIs, including a baseline sodium level (Coryell, 2022b; Woods, 2023).

SNRIs include duloxetine (Cymbalta), venlafaxine (Effexor), desvenlafaxine (Pristiq), and levomilnacipran (Fetzima). Side effects include nausea, headaches, dizziness, excessive sweating, dry mouth, tiredness, constipation, insomnia, sexual dysfunction, and anorexia. Patients prescribed venlafaxine (Effexor) should have their blood pressure checked at baseline and periodically after starting and following any dose increase to monitor for hypertension. The risk for hypertension with this medication is dose-dependent and typically heightens with doses higher than 225 mg. Patients taking duloxetine (Cymbalta) should have liver function tests performed at least annually due to the low risk of elevated alanine transaminase levels (ALT; Coryell, 2022b; Woods, 2023).

SSRIs and SNRIs can increase serotonin levels in the body, posing a risk for serotonin syndrome. Serotonin syndrome is characterized by agitation, anxiety, confusion, a high fever, sweating, tremors, a lack of coordination, dangerous fluctuations in blood pressure, and rapid heart rate. Patients must seek immediate medical attention because this is a potentially life-threatening condition. Furthermore, SSRIs and SNRIs increase suicide risk and withdrawal symptoms if stopped abruptly. These medications should not be used within 14 days of an MAOI (Coryell, 2022b; Woods, 2023).

Tricyclic Antidepressants and Tetracyclic Antidepressants

Tricyclic antidepressants (TCAs) and tetracyclic antidepressants are an older class of medications that include nortriptyline (Pamelor), imipramine (Tofranil), amitriptyline (Elavil), and desipramine (Norpramin). TCAs inhibit norepinephrine and serotonin reuptake but with significantly more adverse effects, such as sedation, increased appetite, weight gain, dry mouth, constipation, hypotension, lightheadedness, drowsiness, blurred vision, tremors, excessive sweating, and sexual dysfunction. Less common but serious side effects include life-threatening irregular heart rate, urinary retention, and seizures. Before being prescribed TCAs, patients should be evaluated for any cardiac history, and a baseline electrocardiogram (ECG) should be performed. An ECG should be performed again once the therapeutic dose is achieved. These medications should be used cautiously in patients receiving electroconvulsive therapy (ECT). If signs of psychosis occur, the daily dose should be reduced until symptoms subside. TCAs also carry a risk for serotonin syndrome, suicide risk, and withdrawal symptoms if discontinued abruptly. These medications should also be avoided within 14 days of MAOI use (Moraczewski & Aedma, 2022; Woods, 2023).

Mirtazapine (Remeron) is an atypical tetracyclic antidepressant that antagonizes alpha-2 adrenergic and serotonin receptors. It can cause increased cholesterol and triglyceride levels and should be used cautiously by patients with a personal or family history of heart disease or irregular heart rhythm. Mirtazapine (Remeron) should not be taken within 14 days of an MAOI due to the heightened risk for serotonin syndrome. Other common side effects include sedation, increased appetite, weight gain, and dizziness. Rare and severe side effects include agranulocytosis (low white blood cells) and angle-closure glaucoma (eye pain, changes in vision, swelling, or redness in or around the eye). APRNs should advise patients to take the medication before bedtime to avoid daytime drowsiness, especially if performing tasks that involve alertness, such as operating heavy machinery (Coryell, 2022b; National Alliance on Mental Illness [NAMI], 2023; Woods, 2023).

Monoamine Oxidase Inhibitors 

MAOIs were the first type of antidepressant developed. They impair the metabolism of serotonin and block monoamine oxidase, an enzyme that breaks down excess tyramine in the body. Tyramine is an amino acid that helps regulate blood pressure and is found naturally in the body and certain foods. MAOIs include tranylcypromine (Parnate), phenelzine (Nardil), isocarboxazid (Marplan), and a transdermal skin patch selegiline (Emsam). Due to the risk of serious adverse effects, the use of MAOIs for treating depression is reserved for patients who have failed all other treatment options. MAOIs have dangerous drug and food interactions; APRNs must warn patients to avoid foods containing high levels of tyramine, such as aged cheese (aged cheddar, swiss, parmesan, and blue cheeses); cured, smoked, or processed meats (pepperoni, salami, hotdogs, bologna, bacon, corned beef, smoked fish); pickled or fermented foods (sauerkraut, kimchi, tofu); sauces (soy sauce, miso, and teriyaki sauce); soybean products; and alcoholic beverages (beer, red wine, liquors). Other side effects of MAOIs include dry mouth, nausea, diarrhea or constipation, headaches, drowsiness, insomnia, dizziness, lightheadedness, hypotension, loss of libido, weight gain, urinary retention, involuntary muscle jerks, muscle cramps, and paresthesia. MAOIs are associated with increased suicidality and withdrawal symptoms if stopped abruptly. Before prescribing MAOIs, the APRN must ensure all other antidepressants have been discontinued for at least 14 days due to the heightened risk for serotonin syndrome. Patients should also be counseled to avoid OTC decongestants and other cold medications due to the heightened risk for dangerous hypertensive crises (Coryell, 2022b; Sub Laban & Saadabadi, 2022; Woods, 2023). Table 3 outlines the dosing and patient information for various classes of antidepressants.

Table 3

Antidepressants by Medication Class

   

Drug Class

SSRIs

Drug

Citalopram (Celexa)

Escitalopram (Lexapro)

Fluoxetine (Prozac)

Paroxetine (Paxil)

Sertraline (Zoloft)

Vortioxetine (Trintellix)

Dosing

initial adult dose: 20 mg orally once daily; can increase to 40 mg daily after a week for patients older than 60 or with hepatic failure, the maximum dose is 20 mg daily

initial dose for adolescents older than 12 and adults: 10 mg orally once daily; can increase to 20 mg after a week in adults or 3 weeks in adolescents

initial adult dose: 20 mg orally once daily, increasing the dose after several weeks based on patient response; if dose above 20 mg/day, can divide the dose; maximum dose is 80 mg/day for children ages 8 to 18, initial dose: 10 mg orally once daily for one week, then increase to 20 mg daily; may increase to 20 mg/day after several weeks if clinical improvement is not seen

initial dose: 20 mg orally once daily; may increase the dose by 10 mg/day at 1-week intervals up to a maximum dose of 50 mg/day if using a controlled-release formulation initial dose is 25 mg orally once daily; may increase the dose by 12.5 mg/day at 1-week intervals up to a maximum of 62.5 mg/day

initial dose: 50 mg orally once daily; if symptoms are not relieved, the dose can be increased weekly up to a maximum of 200 mg/day

initial dose: 10 mg orally once daily; increase as tolerated to a target dose of 20 mg/day if 10 mg is not tolerated, the dose can be reduced to 5 mg/day

Side Effects

More likely to cause QTc prolongation and sexual dysfunction

More likely to cause sexual dysfunction; QTc prolongation possible

More likely to cause sexual dysfunction or insomnia/agitation

More likely to cause sexual dysfunction, orthostatic hypotension, and/or weight gain

More likely to cause sexual dysfunction, GI disturbance, and/or insomnia/agitation

Patient Education

continue therapy even after symptoms improve avoid alcohol females of reproductive age must use contraception be cautious when operating heavy machinery

Drug Class

SNRIs

Drug

Duloxetine (Cymbalta)

Desvenlafaxine (Pristiq)

Levomilnacipran (Fetzima)

Venlafaxine (Effexor)

Dosing

initial dose: 20 mg orally BID up to 60 mg either once daily or BID in divided doses; maximum dose 120 mg/day

adult dose: 50 mg orally once daily dose adjustment: patients with a CrCl of 30 to 50 mL/min can receive 50 mg/day for CrCl below 30 mL/min or end-stage renal disease (ESRD), give 25 mg/day or 50 mg every other day

initial dose: 20 mg orally once daily for 2 days, then increase to 40 mg/day; may continue to increase the dose in increments of 40 mg/day every 2 days to a maximum of 120 mg once daily dose adjustment: for patients with a CrCl of 30 to 59 mL/min, the maximum dose is 80 mg once daily; for patients with a CrCl of 15 to 29 mL/min, the maximum dose is 40 mg once daily should not be used for patients with ESRD

initial dose: IR 75 mg orally daily in 2 to 3 divided doses; the dose can be increased by 75 mg daily every 4 days to a maximum of 225 mg/day for moderately depressed patients and 375 mg/day for severely depressed patients ER - 75 mg orally once daily; some patients may need to be started on 37.5 mg orally once daily for 4 to 7 days, then increased to 75 mg/day; the dosage can be increased by 75 mg/day every 4 days to a maximum of 225 mg/day may switch from IR to ER by using the closest equivalent dose per day dose adjustment: for patients with mild to moderate renal impairment per a creatinine clearance (CrCl) of 30 to 80 mL/min, reduce IR daily dose by 25% or ER daily dose by 25% to 50% for patients with a CrCl below 30 mL/min or on hemodialysis, reduce the daily dose by 50%

Side Effects

More likely to cause GI disturbance, may cause insomnia

More likely to cause GI disturbance, may cause insomnia

More likely to cause GI disturbance

More likely to cause sexual dysfunction or GI disturbance, may cause insomnia, QTc prolongation, or drowsiness

Patient Education

do not stop therapy abruptly avoid activities that are hazardous or require mental alertness avoid alcohol consumption sexual dysfunction may occur

Drug Class

TCAs and Tetracyclic Antidepressants

Drug

Amitriptyline (Elavil)

Nortriptyline (Pamelor)

Imipramine (Tofranil)

Desipramine (Norpramin)

Mirtazapine (Remeron)

Dosing

outpatient initial dose: 75 mg orally daily in divided doses or 50 mg to 100 mg once daily; may increase the dose by 25 mg to 50 mg as needed to a maximum of 150 mg/day older adults or adolescents should have an initial dose of 10 mg orally TID plus 20 mg at bedtime inpatient initial dose: 100 mg orally once daily; can be increased to 200 mg to 300 mg daily maintenance dose: 40 to 100 mg/day for at least 3 months

initial dose: 25 mg orally 3 to 4 times daily, increasing gradually to 150 mg/day as needed; the entire dose can also be given at bedtime instead of divided doses older adults and adolescents: 30 to 50 mg orally daily once daily or in divided doses

adult outpatient dosing: 75 mg orally daily in divided doses or as a single dose at bedtime; maximum dose is 200 mg/day adult inpatient dosing: 100 mg orally per day in divided doses; maximum dose is 300 mg/day adolescents and older adults: 30 to 40 mg orally once daily at bedtime or in divided doses if necessary; doses above 100 mg/day are generally unnecessary

adult Initial dose: 25 mg to 50 mg orally once daily or in divided doses; increase based on clinical response to 100 to 200 mg daily in a single or divided dose; maximum dose 300 mg/day adolescent and older adult dosing: 25 mg to 100 mg once daily or in divided doses, increasing gradually based on clinical response to a maximum of 150 mg/day

initial dose: 15 mg orally at bedtime; maintenance dose is 15 to 45 mg daily; dose can be increased weekly

Side Effects

Most likely to cause anticholinergic effects, drowsiness, weight gain, and sexual dysfunction

May cause anticholinergic effects, drowsiness, or QTc prolongation in some

Most likely to cause orthostatic hypotension, weight gain, drowsiness anticholinergic effects, QTc prolongation, or sexual dysfunction

May cause drowsiness, orthostatic hypotension, or QTc prolongation in some

Most likely to cause drowsiness and weight gain

Patient Education

for higher doses, administer in the late afternoon or evening to prevent daytime sedation when taken at bedtime, morning orthostatic hypotension may occur; change positions slowly when getting out of bed avoid activities that require alertness or psychomotor coordination can combat dry mouth by sucking on hard candies or chewing gum

Drug Class

MAOIs

Drug

Tranylcypromine (Parnate)

Phenelzine (Nardil)

Isocarboxazid (Marplan)

Selegiline (Emsam)

Dosing

initial dose: 30 mg orally per day in divided doses; if an adequate response is not obtained, the dose can be increased in 10 mg/day increments every 1 to 3 weeks; maximum dose is 60 mg/day in divided doses (30 mg BID)

initial dose: 15 mg orally TID; dose should be rapidly increased, based on patient tolerance, to at least 60 mg/day; dose may need to be increased to 90 mg/day for symptom management after maximum benefit is achieved, the dose should be decreased slowly over several weeks to 15 mg daily or every other day

initial dose: 10 mg orally BID; dose can be increased by 10 mg every 2 to 4 days to 40 mg/day during week 1; the dosage can then be increased by 20 mg/week as needed to a maximum dose of 60 mg/day divided to 2 to 4 doses/day

initial dose: 6 mg/day via a transdermal patch; if needed, increase the dose by 3 mg/day at 2-week intervals; maximum daily dose is 12 mg/day adults over 65: maximum dose 6 mg/day

Side Effects

Most likely to cause sexual dysfunction, and may cause insomnia/agitation or orthostatic hypotension

Most likely to cause sexual dysfunction and orthostatic hypotension; may cause drowsiness

Most likely to cause sexual dysfunction

May cause anticholinergic effects, insomnia, or orthostatic hypotension

Patient Education

selegiline (Emsam) use may result in a positive urine test for amphetamines apply the patch to dry, intact skin on the upper torso, thigh, or outer arm every 24 hours apply the patch at the same time every day do not cut the patch into smaller pieces avoid alcohol consumption avoid all foods containing tyramine avoid cold and flu medications

(Rush, 2022; Woods, 2023)

A systematic review and meta-analysis published by Cipriani and colleagues in 2018 reviewed 522 double-blind, randomized controlled trials involving 116,477 patients diagnosed with MDD and 21 different antidepressants. Unfortunately, this analysis only recorded outcomes at or around 8 weeks, which is a brief period, especially for long-acting medications. The authors noted that 426 of the 522 (81%) reviewed trials were of moderate- or high-risk bias. Despite these limitations, the results demonstrated that all antidepressants were more effective than placebo. Agomelatine (Valdoxan), amitriptyline (Elavil), escitalopram (Lexapro), mirtazapine (Remeron), paroxetine (Paxil), venlafaxine (Effexor), and vortioxetine (Trintellix) were among the most effective, while fluoxetine (Prozac), fluvoxamine (Luvox), reboxetine (Edronax), and trazodone (Desyrel) were among the least effective. Agomelatine (Valdoxan) is a novel antidepressant that acts as a melatonin agonist and serotonin antagonist. It has been marketed in Europe since 2009 and in Australia since 2010 but is not currently approved by the FDA for use in the US. Reboxetine (Edronax) is a norepinephrine reuptake inhibitor that is not approved for use in the US. Regarding tolerability, agomelatine (Valdoxan), citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), sertraline (Zoloft), and vortioxetine (Trintellix) had the lowest dropout rates. In contrast, amitriptyline (Elavil), duloxetine (Cymbalta), fluvoxamine (Luvox), reboxetine (Edronax), trazodone (Desyrel), and venlafaxine (Effexor) had the highest dropout rates. Overall, when evaluating effectiveness as well as tolerability, the authors determined that the best options for the treatment of depression are agomelatine (Valdoxan) and escitalopram (Lexapro), and the worst choices are fluvoxamine (Luvox), reboxetine (Edronax), and trazodone (Desyrel; Cipriani et al., 2018).

Uncategorized and Atypical Antidepressants 

There are a few uncategorized and atypical antidepressants that have varying mechanisms of action. Bupropion (Wellbutrin) is an atypical antidepressant that inhibits the reuptake of dopamine, serotonin, and norepinephrine. It is prescribed for depression, as well as SAD and smoking cessation. Initial IR dosing is 100 mg orally BID, which is increased to TID if there is no improvement after several weeks. Initial SR dosing is 150 mg once daily in the morning, increasing to a target dose of 150 mg BID after 4 days. Bupropion (Wellbutrin) is one of the few antidepressants not frequently associated with sexual dysfunction. However, it poses a seizure risk, so it should be avoided in patients with preexisting seizure disorders. It primarily affects dopamine in the brain and therefore does not carry a risk for serotonin syndrome. The most common side effects include headaches, weight loss, dry mouth, insomnia (worse with IR formula), nausea, dizziness, constipation, tachycardia, QTc prolongation, and sore throat (FDA, 2017; Rush, 2022; Woods, 2023).

Trazodone (Desyrel) is an antidepressant that inhibits serotonin transporters and serotonin type 2 receptors. It inhibits the reuptake of serotonin and blocks histamine and alpha-1-adrenergic receptors. It is usually prescribed for depression when other medications have failed. When used for MDD, the initial dosing is 150 mg daily in divided doses, increasing the dose by 50 mg every 3 to 4 days as needed to a maximum daily dose of 600 mg in an inpatient setting and 400 mg in outpatient settings. Trazodone (Desyrel) should not be used by patients being treated with MAOIs, linezolid (Zyvox), methylene blue (ProvayBlue), fentanyl (Duragesic), or any other serotonergic drugs due to its heightened risk for serotonin syndrome. APRNs must ensure that MAOIs are discontinued at least 14 days before initiating trazodone (Desyrel). Patients should be advised to take the medication before bedtime due to drowsiness and sedation. Rare adverse effects include priapism (a persistent and painful erection not associated with sexual arousal) and cardiac arrhythmias (Coryell, 2022b; Shin & Saadabadi, 2022).

Brexanolone (Zulresso) is a neuroactive steroid gamma-aminobutyric acid (GABA), a receptor-positive modulator approved by the FDA in 2019 to treat depression of postpartum onset for individuals older than 15. While the mechanism of action is not fully understood, it is thought to be related to its positive allosteric modulation of GABA-a receptors. Brexanolone (Zulresso) is administered by continuous intravenous (IV) infusion over 60 hours. Patients may experience excessive fatigue, tiredness, sedation, or a sudden loss of consciousness during the infusion. Due to the risk of alterations in consciousness, brexanolone (Zulresso) can only be administered in a facility with a provider on-site. The drug is only available through a restricted risk evaluation and mitigation strategy (REMS) drug safety program. Patients must be monitored for sedative effects every 2 hours during non-sleep periods and should be advised to report any signs of excessive tiredness. Continuous pulse oximetry should be maintained to monitor for hypoxia. The infusion should be immediately discontinued for any signs or symptoms of excessive sedation. Other common side effects include dry mouth and facial flushing. Patients should avoid alcohol, opioids, benzodiazepines, and other CNS depressants due to the heightened risk of sedation and loss of consciousness. It is also associated with an increased risk for suicidality. Brexanolone (Zulresso) carries a risk for abuse, can lead to dependence, and is classified as a Schedule IV controlled substance under the Controlled Substances Act (Sage Therapeutics, 2022; Woods, 2023).

Resistant Depression 

Up to 67% of patients being treated for depression fail to respond to first-line therapy. Resistant depression is the failure of at least two other antidepressants (administered for at least 6 weeks each) without achieving remission or at least a 50% improvement in mood. Often, the resistance is not related to the medication or treatment but to compliance with administration by the patient. Failure can also be due to an incorrect dose or inadequate time to develop a therapeutic response. When treating resistant depression, APRNs should reevaluate the diagnosis to ensure accuracy and consider comorbidities such as anxiety, substance use disorder (SUD), or psychosis. Consistency in medication administration should be confirmed and an upward titration in dosage considered, if appropriate. For some patients, a change in medication therapy may be warranted, such as switching from an SSRI to an SNRI or adding a second medication to the regimen. Psychotherapy should be added if not already a component of the treatment plan, and brain-stimulation therapies can be considered (APA, 2022; Hasin et al., 2018).

 

Esketamine (Spravato) 

Esketamine (Spravato) is an n-methyl D-aspartate (NMDA) antagonist made from ketamine, an anesthetic introduced in the 1960s to treat battle wounds during the Vietnam War. Since then, ketamine has gained attention regarding its role in treating severe depression. In 2019, esketamine (Spravato) nasal spray, a more potent version of ketamine, earned FDA approval when used in conjunction with an oral antidepressant for adults with treatment-resistant depression. Esketamine (Spravato) works by increasing levels of the neurotransmitter glutamate in the brain. It has a rapid onset, immediately impacting brain cells and relieving depressive symptoms within hours. Common side effects include dissociation (e.g., difficulty with attention, judgment, and thinking), nausea, dizziness, drowsiness, vertigo, and anxiety. It has a boxed warning related to its risk for sedation, dissociation, misuse, dependence, and suicidal thoughts and behaviors. Therefore, it is a federally controlled substance only available through a REMS program. Esketamine (Spravato) must be administered under the supervision of an HCP in a healthcare setting that is certified in the REMS program. Patients cannot take the spray home and must be monitored for signs of sedation and dissociation for at least 2 hours following each dose. The first 1 to 4 weeks of treatment administration is twice weekly, then once weekly during weeks 5 to 8. The maintenance dose is administered once weekly or every other week based on patient response (FDA, 2019; NIMH, 2022e; Woods, 2023.). For more information on Depression, see the NursingCE course on Depression.

Anxiety

Anxiety disorders are the most common mental health illness in the US, affecting more than 40 million (19.1%) adults aged 18 and older. Individuals with anxiety are 3 to 5 times more likely to visit an outpatient provider and are 6 times more likely to be hospitalized for psychiatric treatment. People with anxiety disorders generally experience persistent concern and worry associated with nonspecific physical and psychological symptoms (restlessness, sleep disturbances, irritability, fatigue, difficulty concentrating, or muscle tension) that impact their life negatively (Anxiety & Depression Association of America [ADAA], 2022; NIMH, 2022a).

Anxiety disorders are comprised of generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD), phobias (i.e., an intense fear of places or situations that causes panic-like reactions), separation anxiety disorder, and selective mutism. Many experience anxiety episodes manifested by sweating, heart palpations, and nervousness; all are considered normal responses when appropriately triggered and not maladaptive. Some degree of anxiety is adaptive and facilitates cautiousness in potentially dangerous situations or promotes practice, preparation, and rehearsal to improve functioning. Anxiety is considered an illness requiring treatment when triggered without a threat and when symptoms become debilitating or negatively impact an individual’s life (Barnhill, 2022; Boland & Verduin, 2022; NIMH, 2022a).

Both environmental and genetic influences can contribute to anxiety disorders. Risk factors include childhood shyness, stress buildup, certain personality types, exposure to stressful or traumatic life events when young, comorbid psychological conditions, drug/alcohol use, and biological relatives with anxiety disorders. Additionally, anxiety may be linked to ongoing health issues such as diabetes, heart disease, thyroid dysfunction (e.g., hyperthyroidism), respiratory disorders (e.g., asthma, chronic obstructive pulmonary disease), drug misuse, alcohol or drug withdrawal, chronic pain, irritable bowel syndrome (IBS), and rare tumors that produce hormonal imbalances (e.g., pheochromocytoma; Barnhill, 2022; NIMH, 2022a).

Nonpharmacologic Treatment 

CBT is an effective psychotherapy for individuals with anxiety disorders. CBT teaches individuals to rethink, respond, and react to situations to feel less anxious and fearful. CBT is the gold standard for psychotherapy. Exposure therapy is a form of CBT utilized to treat certain anxiety disorders. Exposure therapy enhances individuals’ ability to confront the fears underlying their anxiety disorder and re-engages in activities they have been avoiding, as seen in phobias. Virtual therapy uses computer programs to treat agoraphobia and social anxiety disorder. Patients are provided with a virtual environment, like the environment responsible for their phobia. They identify with the specific avatars during multiple sessions until they can cope with the anxiety while preparing for exposure in real life. Additional nonpharmacological treatments include lifestyle changes such as avoiding excessive caffeine, reducing or avoiding alcohol, smoking cessation, and managing stress effectively, such as meditation, exercise, and mindfulness, which can help reduce anxiety symptoms and complement the effects of psychotherapy (Boland & Verduin, 2022; NIMH, 2022a).

Pharmacologic Treatment 

It is recommended that CBT is used in combination with pharmacological interventions as treatment for anxiety. SSRIs and SNRIs are the first-line agents for GAD, panic, and social anxiety disorders. These medications are well tolerated and do not cause dependency. Commonly prescribed SSRIs and dosages are fluoxetine (Prozac) 20 to 80 mg a day, sertraline (Zoloft) 50 to 200 mg a day, citalopram (Celexa) 20 to 60 mg a day, paroxetine (Paxil) 20 to 50 mg a day, and escitalopram (Lexapro) 10 to 20 mg a day. The SNRIs venlafaxine (Effexor) 75 to 150 mg and duloxetine (Cymbalta) 30 to 90 mg are also effective for anxiety. Selection should be based on the side effect profile, patient preference, patient history, and drug interactions (Craske & Bystritsky, 2021; Gregory & Hardy, 2022). The potential side effects of SSRIs and SNRIs are listed in Table 3.

Other medications, such as benzodiazepines, are known to improve anxiety symptoms but are no longer recommended as first-line therapy due to their side effect profile and the risk of tolerance, dependence, abuse, or misuse. For patients with severe anxiety without a history of substance abuse, a benzodiazepine may be initiated to manage symptoms until the first-line treatment reaches therapeutic levels. They are also frequently used for short-term anxiety management during minor medical procedures (e.g., dental work) or as pre-sedation. Benzodiazepines enhance the effects of gamma-aminobutyric acid (GABA) in the brain. They promote relaxation and alleviate muscular tension and other physical symptoms of anxiety. The most commonly used benzodiazepines include clonazepam (Klonopin), alprazolam (Xanax), diazepam (Valium), and lorazepam (Ativan). Of these, diazepam (Valium) and clonazepam (Klonopin) are the most widely used for anxiety due to their rapid onset and long half-life, which can decrease the risk of withdrawal symptoms when discontinued. Adverse effects of benzodiazepine include drowsiness or tiredness, dizziness, nausea, blurred vision, headache, confusion, and nightmares. Benzodiazepines should be used cautiously in older adults as this population is more sensitive to these drugs and can experience cognitive impairment, delirium, and falls (American Geriatrics Society Beers Criteria Update Expert Panel, 2019; Craske & Bystritsky, 2021; Garakani et al., 2021).

Buspirone (Buspar) can be used as an adjunct treatment for individuals that do not experience a complete response to treatment with an SNRI or SSRI and CBT. Buspirone (Buspar) acts as a partial agonist of serotonin receptors. The initial dose is 10 mg/day, increasing by 10 mg every 1 to 2 weeks based on patient response up to a maximum dose of 60 mg/day. Buspirone (Buspar) must be taken daily as it is ineffective when used as needed. Treatment should be continued for at least 4 to 6 weeks before determining its effectiveness. Adverse effects of buspirone (Buspar) include dizziness, headache, nausea, nervousness, lightheadedness, excitement, and insomnia (Craske & Bystritsky, 2021; Garakani et al., 2021).

Propranolol (Inderal) is a non-cardioselective beta blocker that can help alleviate the physical symptoms of anxiety due to stage fright/performance anxiety, such as sweating, trembling, hyperventilation, and tachycardia. Typical dosing is 40 mg administered 1 hour before participating in the anxiety-causing activity. Adverse effects include hypotension, bradycardia, dizziness, weakness, fatigue, and cold hands. Since propranolol (Inderal) is a non-selective beta blocker, it is contraindicated in asthmatics (Szeleszczuk & Fraczkowski, 2022). For more information on anxiety disorders, see the NursingCE course on Anxiety.

            

Bipolar Disorder

Bipolar disorder, formerly known as manic depression, is characterized by unusual shifts in an individual's mood, activity level, and concentration. Bipolar disorder affects approximately 5.7 million (2.6%) adults in the US (Depression and Bipolar Support Alliance [DBSA], n.d.; NIMH, 2023). There are currently four classifications:

• Bipolar I disorder: characterized by the presence of at least one lifetime manic episode lasting at least 1 week (or any duration if hospitalization is required); a manic episode is a period of abnormally elevated or irritable mood, over-activity, racing thoughts, rapid speech, inflated self-esteem, and decreased need for sleep, usually interspersed with depressed periods; may also experience hypomania (like mania but less severe) or an MDE, but this is not required for diagnosis
• Bipolar II disorder: characterized by the presence of at least one lifetime MDE and hypomanic episode lasting at least 4 days without a history of mania; is no longer considered less severe than bipolar I disorder due to mood instability and effect on the individual's social and work life
• Cyclothymic disorder: characterized by at least 2 years (1 year for children) of hypomanic or depressive symptoms without meeting the criteria for an episode of hypomania, mania, or major depression
• Other specified and unspecified bipolar: bipolar disorder-like symptoms that do not match any of the above three categories, such as symptoms induced by substance abuse or caused by certain medical conditions such as Cushing’s disease, multiple sclerosis (MS), or stroke (APA, 2022)

While the exact cause of bipolar disorder is still unknown, it is hypothesized to be some combination of altered brain structure or function, genetics, and environmental factors. Patients with bipolar disorder are at higher risk for thyroid disease, migraines, heart disease, diabetes, obesity, and other physical illnesses. Individuals diagnosed with bipolar disorder are also more likely to suffer from other mental health disorders such as anxiety, ADHD, or SUD. Symptoms of a depressive episode match the symptoms of depression described above. The behavior seen in a manic episode may include the previously mentioned symptoms as well as disorganized or nonlinear patterns of thoughts or speech and risk-taking behaviors such as excessive spending, gambling, or sexual promiscuity. Hypomanic episodes may present as the individual feeling excellent, being highly productive, and functioning well. Due to this, many individuals with bipolar II disorder are diagnosed during an MDE, as some may view the symptoms of hypomania as desirable. Hypomania may develop into full mania if left untreated. Some patients with bipolar I disorder may also suffer from psychotic features, such as delusions or hallucinations when experiencing a manic episode (APA, 2022; NIMH, 2023).

Risk factors include a first-degree relative with bipolar disorder, a stressful or traumatic childhood life event, and drug or alcohol use. It is typically diagnosed in the teenage years or early 20s. If left untreated, bipolar disorder can lead to drug or alcohol abuse, legal or financial problems, damaged relationships, and poor work or school performance. It is considered the sixth leading cause of disability worldwide, resulting in an average decrease in life expectancy by 9.2 years. Suicide risk is 20 to 30 times higher in patients diagnosed with suicide than in the general population, and approximately 5% to 6% of individuals diagnosed with bipolar disorder die by suicide (APA, 2022; DBSA. n.d.).

Treatment

Bipolar disorder is a lifelong illness requiring consistent and regular treatment as symptoms will return over time. Treatment includes psychotherapy and medication management to control symptoms. Psychotherapy may consist of CBT, family-focused therapy, interpersonal and social rhythm therapy (IPSRT), or psychoeducation and, in severe cases, may require ECT or repetitive transcranial magnetic stimulation (rTMS; NIMH, 2023).

Medications for bipolar disorder may include mood stabilizers, atypical antipsychotics, and antidepressants. Lithium (Lithobid) is a commonly prescribed mood stabilizer that alters sodium transport across neurons (NIMH, 2022e). According to the International Society for Bipolar Disorders (ISBD), lithium (Lithobid) alone is recommended as the first-line treatment for acute mania and maintenance therapy of bipolar I disorder. It is considered the first-line treatment for acute depression in bipolar I disorder. It is also considered first-line maintenance treatment and second-line treatment for acute depression in bipolar II disorder. There is moderate concern about long-term safety and tolerability with lithium (Lithobid) use as it is considered possibly hazardous in breastfeeding individuals. Common side effects include tremor, polyuria/polydipsia (excessive urination/thirst), weight gain, GI disturbances (diarrhea, vomiting), drowsiness, and cognitive impairment. More serious potential reactions include seizures, ventricular arrhythmias, syncope, and coma (Yatham et al., 2018).

Alternatives for mood stabilization include antiepileptic drugs (AEDs) such as divalproex sodium (Depakote), carbamazepine (Tegretol), and lamotrigine (Lamictal). Divalproex sodium (Depakote) is first-line monotherapy for acute mania and maintenance therapy of bipolar I disorder, second-line for acute depressive episodes in bipolar I disorder, third-line for maintenance treatment in bipolar II disorder, and third-line for acute depression treatment in bipolar II disorder. Carbamazepine (Tegretol) is considered a second-line treatment in acute mania. It can be used for maintenance treatment, but it is considered a second-line treatment for bipolar I disorder and a third-line treatment for bipolar II disorder. Lamotrigine (Lamictal) is not recommended for acute mania. It is considered a first-line treatment for maintenance therapy of bipolar I disorder, first-line treatment for acute depression in bipolar I disorder, second-line for acute depression in bipolar II disorder, and first-line maintenance treatment for bipolar II disorder (Yatham et al., 2018). The dosing for lithium and other mood stabilizers/AEDs, when used to treat bipolar disorder, is as follows:

• lithium (Lithobid): initial dose of 300 mg orally BID or TID titrated to a blood level between 0.6 and 1.2 mEq/L
• divalproex sodium (Depakote): loading dose of 20 to 30 mg/kg required, then 250 to 500 mg orally TID daily titrated to a blood level between 50 and 125 mcg/mL; maximum dose is 60 mg/kg/day
• carbamazepine (Tegretol): initial dose of 200 mg orally BID, increasing gradually by 200 mg/day until blood level between 4 and 12 mcg/mL; maximum dose is 1600 mg/day
• lamotrigine (Lamictal): initial dose of 25 mg orally once daily for 2 weeks, then 50 mg once daily for 2 weeks, then 100 mg once daily for 1 week, then titrated as needed by 50 mg increments up to 200 mg once daily (Coryell, 2022a; Woods, 2023)

Regarding safety and tolerability for long-term use, divalproex sodium (Depakote) has moderate safety and minor tolerability concerns, carbamazepine (Tegretol) has minor safety and moderate tolerability concerns, and lamotrigine (Lamictal) has minimal safety or tolerability concerns. The disadvantages of most mood stabilizers include their renal toxicity and the need for initial serum drug levels to be monitored until dosing is stable and then periodically to rule out toxicity (this is true for lithium [Lithobid], divalproex sodium [Depakote], and carbamazepine [Tegretol]). Mood stabilizers are also associated with several adverse effects, including itching, rash, polydipsia, polyuria, tremors, nausea, vomiting, slurred speech, tachycardia, bradycardia, irregular heartbeat, loss of consciousness, changes in vision, seizures, hallucinations, loss of coordination, and angioedema (NIMH, 2022e; Woods, 2023).

Patients taking mood stabilizers should have specific monitoring based on the medication prescribed. Those on Lithium (Lithobid) should have serum lithium levels evaluated following one week of therapy, following all dose adjustments, in the presence of any concerning side effects, and annually. They should also have their thyroid-stimulating hormone (TSH) checked at baseline, then 2 weeks, 6 weeks, and annually after treatment initiation. Renal function should be evaluated at baseline, then 2 weeks, and annually after treatment initiation. Patients prescribed valproic acid (Depakote) should have serum levels evaluated after 1 week of therapy, following all dose adjustments, in the presence of any concerning side effects, and annually. In addition, liver function tests (LFTs) should be checked at baseline, 2 weeks after initiation, and annually, as well as if any symptoms or clinical suspicion for hepatitis develops. A complete blood count (CBC) should be evaluated at 2 weeks, 6 months, and then annually after initiating treatment unless the patient develops any signs of bruising easily or bleeding, which should prompt additional CBC monitoring. For patients taking carbamazepine (Tegretol), serum drug levels should be monitored at 1 week, 4 weeks, annually, and with any dose increases. These patients should have a CBC checked at 1 week, 1 month, 4 months, and annually. Sodium level should be checked at 1 week and then annually, and LFTs should be checked at 2 weeks and annually. With oxcarbazepine (Trileptal), patients should have their sodium level checked at baseline and 1 month following treatment initiation. Patients taking lamotrigine (Lamictal) do not require any laboratory monitoring (Woods, 2023).

             Atypical or second-generation antipsychotics (SGAs) help treat the symptoms of agitation, delusions, and hallucinations often seen in bipolar disorder. This may include quetiapine (Seroquel), asenapine (Saphris), aripiprazole (Abilify), paliperidone (Invega), risperidone (Risperdal), olanzapine (Zyprexa), ziprasidone (Geodon), cariprazine (Vraylar), clozapine (Clozaril), lumateperone (Caplyta), and lurasidone (Latuda). These drugs function mainly by antagonizing dopamine D2 and serotonin 5-HT2A receptors in the brain, except for aripiprazole (Abilify) and cariprazine (Vraylar), which function as partial dopamine and serotonin 5-HT1A agonists and 5-HT2A antagonists. As a class, adverse effects for this group of drugs may include drowsiness, dizziness, restlessness, weight gain, anticholinergic effects, nausea, vomiting, hypotension, seizures, and leukocytopenia (NIMH, 2022e; Woods, 2023). Antipsychotics will be discussed in greater depth in the section on schizophrenia.

According to the ISBD, there is evidence to support the use of quetiapine (Seroquel), asenapine (Saphris), aripiprazole (Abilify), paliperidone (Invega), risperidone (Risperdal), and cariprazine (Vraylar) for the treatment of acute mania. It is estimated that as many as 50% of patients will significantly improve with monotherapy in 3 to 4 weeks. Combination therapy increases this by about 20% and may benefit patients with a history of partial response to monotherapy, with psychotic mania, or where rapid response is desired. In those cases, there is evidence supporting the combination of lithium (Lithobid) or divalproex sodium (Depakote) with quetiapine (Seroquel) or risperidone (Risperdal). There is also evidence supporting the use of olanzapine (Zyprexa) either as monotherapy or with lithium (Lithobid), divalproex sodium (Depakote), carbamazepine (Tegretol), or ziprasidone (Geodon) as second-line treatments for acute mania. In the treatment of acute depression in bipolar disorder, first-line treatment includes the use of quetiapine (Seroquel) or a combination of lurasidone (Latuda) and lithium (Lithobid) or divalproex sodium (Depakote). Olanzapine (Zyprexa) is considered the second-line treatment for acute depression in bipolar I disorder (NIMH, 2022e; Yatham et al., 2018).

 For long-term maintenance therapy, there is evidence supporting the use of quetiapine (Seroquel), asenapine (Saphris), or aripiprazole (Abilify) either as monotherapy or combined with lithium (Lithobid) or divalproex sodium (Depakote) as first-line treatment of bipolar I disorder. Evidence also supports using olanzapine (Zyprexa) or risperidone (Risperdal) as second-line maintenance treatment options in bipolar I disorder. In bipolar II disorder, evidence supports using quetiapine (Seroquel) as a first-line treatment for acute depression or long-term maintenance therapy. Second-line treatment options for long-term maintenance treatment of bipolar II disorder include venlafaxine (Effexor), and third-line treatment options include carbamazepine (Tegretol) or risperidone (Risperdal), primarily to prevent hypomania episodes. Regarding safety and tolerability, there are more concerns with olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal) than the other SGAs discussed here, especially when combined with lithium (Lithobid) or divalproex sodium (Depakote; Yatham et al., 2018).

SSRIs, SNRIs, and bupropion (Wellbutrin) are sometimes used for acute depressive symptom management in bipolar disorder. According to the ISBD, these drugs should not be used as monotherapy in patients with bipolar I disorder acute depression. However, there is evidence supporting their use as second-line adjunctive therapy (with lithium [Lithobid], divalproex sodium [Depakote], or an SGA) for acute depression. In patients with bipolar II disorder, there is evidence suggesting bupropion (Wellbutrin), sertraline (Zoloft), or venlafaxine (Effexor) are appropriate second-line treatments when used as adjuncts for acute depression, and a third-line option includes fluoxetine (Prozac). For long-term maintenance therapy in patients with bipolar II disorder, there is evidence supporting the use of venlafaxine (Effexor) as a second-line treatment and escitalopram (Lexapro), fluoxetine (Prozac) or other antidepressants as third-line treatment options only. Antidepressants should be avoided in patients with a history of antidepressant-induced mania or hypomania, current or predominantly mixed features, or recent rapid cycling. TCAs should be avoided in patients with Bipolar I disorder due to the increased risk of mania. Small studies have shown that the MAOI tranylcypromine (Parnate) may be more effective than other antidepressants in treating bipolar depression (Coryell, 2022a; Yatham et al., 2018).

Schizophrenia

According to WHO, approximately 24 million people (0.32%) are affected by schizophrenia worldwide. The lifetime risk of schizophrenia is approximately 0.3% to 0.7%. This severe mental disorder typically begins in late adolescence or early adulthood and is characterized by psychoses or distortions in thinking, perception, emotions, language, behavior, or sense of self. Individuals diagnosed with schizophrenia have a life expectancy of 10 to 20 years lower than the general population (APA, 2022; WHO, 2022).

Multiple studies suggest that schizophrenia results from abnormalities in several neurotransmitters—including dopaminergic, serotonergic, and alpha-adrenergic hyperactivity or glutaminergic and GABA hypoactivity—due primarily to genetics. For this reason, obtaining a complete history is essential. An individual with a parent diagnosed with schizophrenia has a 40% risk of developing the disease, and environmental factors further increase the risk. Questions should be asked regarding birth weight, the presence of gestational diabetes, birth via an emergency cesarean section, maternal nutritional deficiencies, birth month, and type and location of their childhood residence. Children of African American or Caribbean migrants have a 10 times greater risk of developing schizophrenia than Americans of European descent. Cannabis use is associated with psychosis and should be addressed when obtaining a health history (Hany et al., 2023).

Symptoms of schizophrenia are categorized as positive (e.g., hallucinations, delusions, disorganized thoughts and speech, repetitive movements), negative (e.g., diminished emotional expression, avolition, alogia, anhedonia, asociality), or cognitive (poor executive functioning, decreased focus/attention, poor working memory). Negative symptoms contribute to the morbidity of schizophrenia and are not as commonly experienced with other psychotic disorders (APA, 2022). Risk factors for schizophrenia include:

• age:
  • men: peak onset of symptoms between early to mid-20s
  • women: peak onset of symptoms between the late 20s to early 30s
  • the onset of symptoms seldom occurs past 45 years and rarely before puberty
  • gender differences may be linked to the effects of estrogen on women
• gender: men exhibit more negative symptoms and experience more cognitive impairment than women; women experience more mood symptoms
• family history increases risk by 10%
• intrauterine infections, a traumatic delivery, or trauma during pregnancy increase the risk of the fetus developing schizophrenia
• season of birth: individuals born in late winter or early spring (defined as February or March in the northern hemisphere) have a higher incidence of schizophrenia
• growing up in an urban environment is associated with a higher incidence of schizophrenia
• environmental stressors
  • relationship stress
  • difficulties at school or work
  • heavy cannabis use
• people with schizophrenia abuse alcohol and drugs more frequently than the general population (APA, 2022; Boland & Verdiun, 2022)

Treatment

Treatment for schizophrenia is multifactorial and lifelong and includes pharmacological management and psychosocial support. A psychiatrist usually guides treatment, and due to the complexity of the diagnosis, treatment in a coordinated specialty care (CSC) program is recommended. CSC is a recovery-oriented team approach involving case managers, family, social workers, and educational and employment service involvement. Research has demonstrated that CSC is more effective than typical treatment alone. Patients participating in CSC experience more effective treatment management, improved quality of life, and more involvement in social settings such as work or school. Due to these documented benefits, CSC has become the standard of care per the APA practice guideline for patients diagnosed with schizophrenia. ECT is a treatment recognized as beneficial to patients with psychosis related to schizophrenia that is unresponsive to pharmacotherapy. According to the APA, utilizing ECT as an adjunct therapy to treatment with antipsychotics increases the remission rate. ECT is also beneficial when initiated for patients who require emergent treatment or those with an increased risk of suicide (APA, 2021; NIMH, 2022f).

Pharmacotherapy includes the management of the acute phase, followed by maintenance therapy, which strives to improve socialization, self-care, and mood. The rationale for maintenance treatment is to prevent relapse. Medication management aims to manage symptoms using the lowest effective dosage with the fewest side effects. In many cases, combination therapy with multiple medications is necessary to gain adequate control over the condition. Identifying the proper medication combination and dosing levels can take time to achieve the desired outcome. While it can take several weeks to notice an improvement in symptoms, prompt initiation of medication therapy is recommended. It should occur within 5 years of the first acute episode, as this is when most of the illness-related changes in the brain occur (Freudenreich & McEvoy, 2023; Tamminga, 2022).

According to the APA (2021) practice guidelines for treating patients with schizophrenia, which are currently being reviewed and will be released at the end of 2023, SGAs are considered first-line treatment. While the selection of the type of antipsychotic agent depends on various individual patient factors, SGAs are generally preferred over first-generation antipsychotics (FGAs) due to their superior side effect profile. The APA guideline also acknowledges that an evidence-based algorithm approach to antipsychotic selection is unavailable due to limitations in clinical trial designs and a lack of direct drug-to-drug comparisons. There are no benefits of utilizing one antipsychotic over another, except for clozapine (Clozaril). Clozapine (Clozaril) is the only medication within the class of SGAs that is not recommended as first-line treatment, as it carries a risk for life-threatening agranulocytosis. Clozapine (Clozaril) is reserved for patients whose symptoms are resistant to treatment with other antipsychotic drugs. It is the most effective antipsychotic drug for managing treatment-resistant schizophrenia (APA, 2021; Freudenreich & McEvoy, 2023).

The APA guideline recommends that drug selection is premised on the risks and benefits of the prescribed therapy, individual patient factors such as co-existing medical conditions, the potential for those conditions to be affected by medication side effects, the risk for drug interactions, psychosocial support, patient and family preference, as well as the feasibility of compliance with the chosen therapy. Before starting antipsychotic treatment, providers should obtain a complete and thorough medication history, reviewing current medications, any antipsychotic medications used in the past, and the patient's tolerance for treatment. Assessing drug allergies, medication interactions, or contraindications to the prescribed pharmaceutical treatment is critical. In addition, all psychotropic medications appear to cross the placenta and have been found in amniotic fluid and human breast milk. Providers must weigh the potential benefits of treatment and the potential harms of untreated illness regarding the potential for adverse fetal or neonatal effects in females of childbearing age. Untreated or inadequately treated maternal psychiatric illness can result in poor adherence to prenatal care, inadequate nutrition, increased alcohol or tobacco use, and disruptions to the family environment and mother-infant bonding (APA, 2021).

FGAs and SGAs are available in IR and ER oral formulations, short-acting IM, and long-acting injectable (LAI) agents. LAI medications are a practical option for patients who are nonadherent with oral medication therapy. However, APRNs are advised to determine the etiology of the patient's nonadherence with oral treatment before changing to LAI. If nonadherence is related to undesirable adverse effects of oral treatment, the patient should be changed to an alternative oral medication before transitioning to LAI. When starting patients on antipsychotic medications, providers are advised to start at the lowest dose possible and gradually increase it, as recommended by each drug's prescribing guidelines. Agitation and hallucinations typically resolve first (within days), but delusions may take weeks to resolve, and full effects are usually seen within 6 weeks; some antipsychotic medications require strict monitoring as outlined by the FDA REMS drug program, which is reserved for drugs with serious safety concerns to help ensure the benefits of the medication outweigh the risks. REMS is designed to mitigate the occurrence and severity of certain risks by enhancing the safe use of high-risk medication as described within the FDA-approved prescribing information through the heightened monitoring and surveillance of patients receiving these medications (APA, 2021; FDA, 2021; NIMH, 2022d).

First-Generation Antipsychotics

FGAs work by antagonizing dopamine D2 receptors. Some of the most common FGAs are chlorpromazine (Thorazine), haloperidol (Haldol), fluphenazine (Prolixin), loxapine (Loxitane), molindone (Moban), perphenazine (Trilafon), thioridazine (Mellaril), thiothixene (Navane), and trifluoperazine (Stelazine). FGAs pose the highest risk for extrapyramidal symptoms (EPS) among all antipsychotic medications. EPS are drug-induced movement disorders among the most common adverse effects of centrally-acting dopamine-receptor-blocking medications. EPS are often debilitating and interfere with communication, socialization, motor skills, and activities of daily living. These symptoms can include acute dystonia (spasms of the tongue, neck, face, and back), parkinsonism (tremor, shuffling gait, drooling, instability, stooped posture), akathisia (compulsive and repetitive motions, agitation), and tardive dyskinesia (lip-smacking, worm-like tongue movements). Other less common side effects of FGAs include orthostasis, QT prolongation, weight gain, seizures, hyperlipidemia, and glucose abnormalities (APA, 2021; D'Souza & Hooten, 2023). Refer to Table 4 for a detailed overview of the dosing and special considerations of several FGAs.

Table 4

Common Types of FGAs

• 
  

Medication	Dosage	Special Considerations
Chlorpromazine (Thorazine)	By mouth (PO): 25 to 2000 mg/day Intramuscularly (IM): 25 to 200 mg IM/day	IM injection should be administered to the upper outer quadrant of the gluteal area Requires a lower dose with IM than oral due to significant oral first-pass metabolism Use with caution in patients with hepatic or renal impairment
Haloperidol (Haldol)	PO: 5 to 100 mg/day IM: 2 to 20 mg/day administered in divided doses; 2 to 5 mg IM every 4 to 8 hours	Contraindicated in patients with severe toxic CNS depression or patients who are comatose Hypersensitivity can include anaphylaxis and angioedema
Fluphenazine (Prolixin)	PO: 2.5 to 40 mg/day IM: 10 mg/day	IM dose should be 33% to 50% of the oral dose Use is contraindicated with hepatic impairment Use with caution in renal impairment
Loxapine (Loxitane) Loxapine (Adasuve) inhaler	PO: 20 to 250 mg/day Aerosol powder inhalation: 10 mg/day	Loxapine (Adasuve) inhaler is used to treat agitation and requires participation in the REMS program due to the risk of bronchospasm
Thioridazine (Mellaril)	PO: 150 to 800 mg/day	Risk for dose-related QTc prolongation Obtaining a baseline ECG and serum potassium level is recommended, and use should be reserved for treatment failure of other antipsychotic drugs Use with caution in patients with hepatic impairment
Thiothixene (Navane)	PO: 6 to 60 mg/day	Smoking may interfere with cytochrome P450 1A2 (CYP1A2) induction, impairing drug metabolism
Trifluoperazine (Stelazine)	PO: 4 to 50 mg PO/day	Smoking may interfere with CYP1A2, impairing drug metabolism Contraindicated in patients with hepatic disease

(APA, 2021; Woods, 2023)

 

Second-Generation Antipsychotics

Examples of SGAs include quetiapine (Seroquel), asenapine (Saphris), aripiprazole (Abilify), brexpiprazole (Rexulti), paliperidone (Invega), risperidone (Risperdal), olanzapine (Zyprexa), ziprasidone (Geodon), cariprazine (Vraylar), lurasidone (Latuda), and clozapine (Clozaril). SGAs antagonize dopamine D2 and serotonin 5-HT2A receptors in the brain, except for aripiprazole (Abilify) and cariprazine (Vraylar), which function as partial dopamine and serotonin 5-HT1A agonists and 5-HT2A antagonists. Clozapine (Clozaril) also works differently, antagonizing alpha-adrenergic and cholinergic muscarinic receptors. EPS will occur less frequently with SGAs than with FGAs; however, EPS risk increases with dose escalation. As a class, SGAs pose a risk for metabolic side effects, such as weight gain, hyperlipidemia, seizures, and diabetes, contributing to the increased risk of cardiovascular mortality in patients diagnosed with schizophrenia. Less commonly, SGAs can cause orthostasis and QTc prolongation (APA, 2021; D'Souza & Hooten, 2023). According to the 2019 American Geriatrics Society Beers Criteria, antipsychotic drugs should be avoided as a first-line treatment for delirium in older patients unless they are a threat to themselves or others. This is due to the increased risk of stroke and mortality in older adults with dementia and olanzapine (Zyprexa)-induced syncope (American Geriatrics Society Beers Criteria Update Expert Panel, 2019). Refer to Table 5 for a detailed overview of the dosing and special considerations of common SGAs.

Table 5 

Common Types of SGAs

Medication	Dosage	Special Considerations
Quetiapine (Seroquel)	PO (IR): 50 to 800 mg/day PO (ER): 50 to 300 mg/day	IR forms are only marginally affected by food, whereas ER forms are significantly affected if consumed with a high-fat meal taking ER tablets on an empty stomach or with a snack of fewer than 300 calories is recommended
Lurasidone (Latuda)	PO: 40 to 160 mg/day	It must be administered with a snack or meal of at least 350 calories
Olanzapine (Zyprexa)	PO: 5 to 20 mg/day IM: 10 mg/2mL (1 mL to 4 mL/day)	IM administration is primarily utilized when the patient presents with severe agitation When used for an acute episode, the recommended dose is 2.5 to 10 mg up to a maximum dose of 30 mg/day Smokers may require a 30% greater daily dose than nonsmokers due to CYP1A2 induction, and females may need lower doses due to the increase in prolactin secretion that may occur IM administration often requires a 40% dose reduction compared to the oral dose due to first-pass metabolism
Risperidone (Risperdal)	PO: 2 to 8 mg/day	Dose adjustment is required in patients with a CrCl below 30 mL/min or severe hepatic impairment
Cariprazine (Vraylar)	PO: 1.5 to 6 mg/day	Use is not recommended in patients with severe hepatic impairment or those with renal impairment and a CrCl below 30 mL/min
Clozapine (Clozaril)	PO: 12.5 to 900 mg/day	Reserved for treatment-resistant schizophrenia Only available through a REMS program due to the risk for life-threatening agranulocytosis, which is a decline in the white blood cell count, namely the absolute neutrophil count (ANC) It requires monitoring ANC at baseline and frequent intervals (usually weekly or biweekly) Increases the risk for orthostatic hypotension and seizures
Ziprasidone (Geodon)	PO: 80-160 mg/day	This is used for the acute treatment of agitation in schizophrenia There is an increased risk of bone fractures with long-term use.

(APA, 2021; Woods, 2023)

 

Monitoring of Patients on Antipsychotics

While several important monitoring domains are required for patients on antipsychotic medications, adherence is one of the most common problems that impair effective outcomes. Monitoring for side effects is essential, as undesirable side effects are most commonly associated with treatment nonadherence and treatment discontinuation. Some side effects of treatment will improve over time, whereas others may worsen with dose escalation. Early in treatment, the most common side effects include sedation, fatigue, orthostatic hypotension, and anticholinergic effects such as dry mouth, constipation, and difficulty urinating. As treatment progresses, many of these side effects dissipate or improve. In contrast, side effects corresponding with metabolic syndrome (e.g., weight gain, hyperlipidemia, and hyperglycemia) worsen as the duration of therapy increases. Furthermore, EPS can also worsen with dose escalation of antipsychotics, particularly FGAs. All types of antipsychotics are associated with sexual dysfunction, including loss of libido, anorgasmia, erectile dysfunction, and ejaculatory disturbances such as retrograde ejaculation (APA, 2021).

When antipsychotic medications are utilized, the APRN must monitor patients for physical and laboratory changes resulting from treatment (APA, 2021). Patients taking SGAs should undergo the following monitoring parameters at baseline and follow-up visits, as specified:

• personal and family history of obesity, diabetes, hyperlipidemia, hypertension, or cardiovascular disease should be assessed before initiating treatment and then annually
• weight, height, and body mass index (BMI) should be assessed before treatment, at every follow-up visit for 6 months, and then at least every 3 months
• fasting blood glucose or hemoglobin AIC should be assessed before treatment, at 4 months after treatment initiation, and then annually
• fasting lipid profile should be assessed before treatment, at 4 months after treatment initiation, and then annually
• based on which antipsychotic is prescribed, an ECG should be performed before initiating treatment and repeated with each dose change (APA, 2021)

For more information on schizophrenia, see the NursingCE course on Psychotic Disorders.

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