#95231: Psychopharmacology

The Association of Medical Superintendents of American Institutions for the Insane was founded in 1844; in 1921, the name changed to the American Psychiatric Association (APA) [2]. In the 1800s, there was no real psychopharmacology or even a true appreciation of the biologic nature of mental illness. However, it is important to acknowledge Rush's decision to refer to "diseases of the mind," rather than more judgmental terminology common to the time, such as spiritual disease or weakness. In fact, Rush hypothesized that psychiatric disorders were caused by irritation of the blood vessels in the brain. This led to treatments such as bleeding and purging and to what could be called the first attempt at the development of a psychoactive medication—the use of mercury as a treatment for mental illness. While it is easy to dismiss such early attempts, this theory of a vascular cause of psychiatric symptoms is consistent with some current knowledge of vascular dementia, and while the theories seem ill-informed today, it is important to note that other popular theories of psychiatric etiology of the time attributed mental illness to demons, witchcraft, or moral turpitude.

During this early period, institutional care of the mentally ill was often a means to persecute women and others whom society wished to confine, which led to what some call the "coercive era" of psychiatric care. One of the most important of these cases was that of Elizabeth Packard in 1860. Elizabeth Packard was married to a clergyman who forcibly placed her in an Illinois asylum. In 1860, Illinois law allowed for involuntary hospitalization of a spouse (generally a wife) by request without any evidence. Ms. Packard was eventually able to obtain release from the hospital, but due to her husband's continuing campaign, she was forced to petition the court and was released in 1863 with a habeas corpus hearing. After gaining her freedom, Ms. Packard began a campaign for the protection of women's rights. As a result of her efforts and the efforts of others at the time, laws were passed requiring a jury trial prior to involuntary hospitalization. It is notable that the Association of Medical Superintendents of American Institutions for the Insane (now the APA) opposed these laws at the time. The damage done by these forcible hospitalizations was huge, and the association of psychiatry with coercion persists to this day. These beliefs influence both the public's acceptance of psychopharmacology as a valid and effective treatment and the acceptance of psychiatric diagnoses as true medical diagnoses, as opposed to an excuse to prescribe medications or force hospitalization.

Another leader in the development of humane custodial care of the psychiatric patients was Dorothea Dix, who, in addition to her other accomplishments, is credited with opening more than 30 state mental hospitals throughout the United States. Dix advocated for humane institutions, particularly for the poor and unhoused, and reformation of mental health treatment.

The landmark court case O'Connor v. Donaldson ruled that the government cannot confine an individual who is not dangerous and is capable of living outside the institution. This ruling was based on the case of Kenneth Donaldson, who in his youth had undergone a course of brief psychiatric care, but had recovered, married, and moved from Florida to Pennsylvania. In 1956, he travelled to Florida to visit his parents, where he made a remark (possibly a joke) that he believed someone in Pennsylvania may have been trying to poison his food. In response, his father hired a lawyer, and at a hearing (where he had no legal representation), Donaldson was civilly committed. He was then placed in a housing unit with dangerous and violent criminals. He received no treatment and, as a Christian Scientist, refused all medications and did not agree that he was experiencing mental illness, which was against the typical routine of admitting illness, accepting treatment, and being released. Donaldson spent more than 15 years in this asylum, despite friends petitioning the administrator for his release and guaranteeing that they would care for him. He eventually won his release by petitioning the courts directly and then proceeded to file suit against the administrator (O'Connor) who had blocked his release, on the constitutional ground of illegal confinement denying him his right to liberty.

The court found that mental illness alone cannot justify custodial confinement against the will of the individual. Further cases (e.g., Lake v. Cameron) introduced the concept of care in the least restrictive setting, and in 1999, the Supreme Court ruled in Olmstead v. L.C. that mental illness is a disability covered under the Americans with Disabilities Act.

At the same time that the courts were acknowledging the rights of persons with mental illness, pharmacologists were making breakthroughs; therapeutic use of chlorpromazine (Thorazine) had been discovered, and the world of psychiatry would never be the same.

The history of psychopharmacology is intertwined with the history of neurology and psychiatry. During the 19th century, psychiatry and neurology were chiefly concerned with the treatment of psychosis and deviant behaviors. The treatment of less severe conditions (e.g., depression, neurosis) was considered outside the province of psychiatry or neurology.

At the beginning of the 20th century, Sigmund Freud published his famous theories on the unconscious roots of what he termed psychoneurosis [3]. He was especially interested in conversion disorders, whereby patients displayed paralysis or other somatic symptoms that could not be explained in a medical context. Freud developed psychoanalysis (talk therapy) and thus began the outpatient treatment of patients with psychiatric concerns.

By the mid-20th century, psychoanalysis became overwhelmingly popular and was employed not only in the treatment of patients with anxiety or neurosis but also in the treatment of patients with more severe psychiatric disorders, such as psychosis, for which talk therapy had little to offer. Some postulate that the development of psychoanalysis stunted the development of psychopharmacology by promoting the notion that talk therapy could effectively treat all mental health issues.

One of the first treatments of psychosis—electroconvulsive therapy or ECT—was developed in the 1930s. Its development arose from the observation that patients with both psychosis and epilepsy seemed to experience improvements in psychotic symptoms following a seizure. While this apparent improvement may have actually been a postictal phase of the seizure disorder, it spurred a search for ways to induce seizures in patients with severe psychiatric disorders. Initial attempts used high doses of stimulant drugs to produce seizures, and the term convulsive therapy was coined. Due to drawbacks evident with the use of stimulant drugs, Italian neurologist Ugo Cerletti experimented with inducing seizures using electrical shocks delivered to the head [4].

Despite its roots in somewhat dubious observations of the effects of electric shocks on livestock, ECT remains in use today as a valid psychiatric treatment. In fact, it was one of the only truly effective psychiatric treatments in the 1930s and 1940s. It was also arguably one of the first treatments to address mental illness as a biologic disorder. Some consider the advent of convulsive therapy as the true beginning of psychopharmacology, as it relied on alteration of brain chemistry to produce improvements in patients.

Building on these advances, psychopharmacology exploded in the 1950s with the development of chlorpromazine, early antidepressants, and early mood stabilizers.

The term psychopharmacology traces its roots to 1920, appearing first in the title of a paper by David Macht describing the use of quinine and antipyretics in tests on neuromuscular coordination. However, most experts date the true birth of psychopharmacology to 1951, when chlorpromazine was first synthesized [5].

Chlorpromazine was developed in the lab of Rhône-Poulenc (an early French pharmaceutical company) for use in general anesthesia to induce calmness. It was not long before French surgeons saw the potential for the use of chlorpromazine in the treatment of psychiatric illness. The first paper on chlorpromazine (titled "A new stabilizer") was published in February 1952 in La Presse Medicale [5].

The first documented clinical psychiatric use of chlorpromazine was on January 19, 1952, when 50 mg intravenous (IV) chlorpromazine was given to a patient, 24 years of age, with severe agitation, psychosis, and possibly mania. The effects were noted as calming but also were transient in nature. After 20 days of treatment with a cumulative total of 900 mg of chlorpromazine along with concomitant barbiturates and ECT, the patient was able to be discharged home [5]. By 1957, chlorpromazine had become internationally recognized, and the American Public Health Association presented Albert Lasker Awards for Medical Research to several scientists and physicians associated with the development of chlorpromazine and introduction of the drug into clinical practice.

Perhaps the greatest contribution of chlorpromazine was not in its clinical effects but rather in its ability to distinguish the biologic basis of schizophrenia. During the course of the 1950s, studies of chlorpromazine use led to an understanding of synaptic transmission and development of the theory that synaptic transmission was not a merely electrical event but rather a chemically mediated event. By the end of the 1950s, six neurotransmitters had been identified in the central nervous system, including dopamine, norepinephrine, and serotonin [5].

The success of chlorpromazine led to the development of more antipsychotics, including thioridazine (Mellaril), haloperidol (Haldol, decanoate), trifluoperazine (Stelazine), and fluphenazine (Prolixin). However, all of these early antipsychotics were noted to have neurologic side effects, most notably extrapyramidal symptoms with parkinsonian features.

Some consider the 1950s to be a "golden age" of psychopharmacology. Beginning in 1958, tricyclic compounds based on the structure of imipramine were synthesized; these are referred to as second-generation (atypical) antipsychotics. One of these compounds was clozapine (Clozaril, Versacloz), an antipsychotic still in use today. Interestingly, clozapine did not initially attract much attention. Small trials showed mixed results, and unlike chlorpromazine, there was no consensus as to its effectiveness. The lack of extrapyramidal side effects led many researchers to erroneously believe that it was not a true antipsychotic, as the dopamine blockade theory of schizophrenia was still widely held.

The development of medications to treat psychiatric illnesses has greatly informed our understanding of the biologic nature of these illnesses—most notably the link between antipsychotics and schizophrenia. This translational research also led to the understanding of neurotransmitters and further informed the development of large classes of psychoactive medications.

The dopamine receptor D2 is a common target of the antipsychotics. Assessment of medications' ability to target receptors was made possible by the introduction of the spectrophotofluorimeter in 1955. This instrument allows for analysis of chemicals in the brain, including monoamines, which allowed for the further advancement of the field of psychopharmacology [5].

With their introduction in the 1950s, monoamine oxidase inhibitors (MAOIs) became the first class of medications used to treat depression. The incorporation of these agents into clinical practice further moved psychiatry away from inpatient care in institutions toward effective outpatient care.

Another historical breakthrough in psychopharmacology was the discovery of the use of lithium for the treatment of mania. While there is some evidence of usage in the 1800s, the seminal research reintroducing lithium for the treatment of mania was published in 1949 by John Cade [6]. Despite its ready availability and widespread use worldwide, lithium was not approved by the U.S. Food and Drug Administration (FDA) until 1970; the United States was the 50th country to approve the use of lithium for the management of mania [6].

The discovery of medications effective in the treatment of affective disorders induced a shift away from the talk therapy-only approach originally developed by Freud. Further, the ability of lithium to improve symptoms of depression supported the burgeoning biologic theory of mental illness. This change in understanding of mental illness had extensive and widespread influence on the practice of psychiatry. It extended beyond schizophrenia and bipolar disorder and helped transform etiologic theories of diseases such as autism from a focus on environmental influence (e.g., poor mothering in the case of autism) to a biologic understanding of psychiatric disorders prevalent today.

In the later part of the 20th century, psychopharmaceutical advancements continued at record pace. The development of benzodiazepines, lithium, barbiturates, and MAOIs led to an era of deinstitutionalization and the mainstream diagnosis and management of psychiatric disorders without a reliance on talk therapy. This seismic change was not without controversy, and proponents of talk therapy and psychoanalysis resisted the use of psychopharmacology to treat mental illness.

This philosophical conflict was clearly evident in the revision process for the APA's Diagnostic and Statistical Manual of Mental Disorders (DSM). In 1980, the DSM was extensively revised (creating the DSM-III), and psychoanalytic language was abandoned. In contrast to the DSM-II, the DSM-III focused on symptom-based descriptions of mental disorders for diagnostic criteria.

Psychiatry continued to evolve to accept the biologic basis of mental illness and embrace the use of pharmacologic treatment. The introduction of selective serotonin reuptake inhibitors (SSRIs), which were both well-tolerated and had better safety profiles than previous medications, revolutionized the treatment of depression. The first SSRI, fluoxetine (Prozac), was approved by the FDA in 1987. While there has been controversy regarding the possible overdiagnosing of depression or overprescribing of antidepressants, no one disputes the enormous impact fluoxetine has had on psychopharmacology [3].

At virtually the same time as the introduction of fluoxetine, a group of second-generation (atypical) antipsychotics were being approved in the United States. These medications, including risperidone (Perseris, Risperdal) and olanzapine (Zyprexa), challenged the traditional belief that only the D2 receptor/dopamine was involved in psychosis. This renewed interest in the forgotten medication clozapine and novel treatment approaches for schizophrenia.

While clozapine had been originally introduced in the 1950s and approved by the FDA in 1971, small studies had been unable to show efficacy. Use of the drug effectively ended in 1975, when the Finnish National Board of Health reported 18 individuals prescribed clozapine who developed severe blood disorders (most commonly agranulocytosis, a severe decrease or an absence of white blood cells increasing the risk of potentially fatal infection); 9 of these patients died [7]. Research since that time indicates that agranulocytosis occurs in about 1% of patients taking clozapine and neutropenia is seen in about 3% [8].

These early roadblocks to the use of clozapine were overcome, first by a system of monitoring white blood cell counts and secondly by longer studies that showed that the effects of clozapine continue to increase after four weeks of therapy, unlike chlorpromazine, which had a peak effect after two to three weeks [7]. As a result of these findings, clozapine was approved for the treatment of psychosis in the United States in 1990 [7]. The price of this drug when it was first approved, approximately $9,000 per patient per year for the medication and monitoring, was initially controversial, but it was more cost-effective than inpatient care or institutionalization [3,7].

The risk for leukopenia remains a barrier to wider use of clozapine; however, it has become a mainstay for treatment-resistant schizophrenia and is also acknowledged to reduce the risk of suicide in patients with schizophrenia. It is also used off-label in the management of treatment-resistant bipolar disorder and dementia- or Parkinson-related psychosis or agitation. With the availability of a generic version, the price of clozapine is now less than many other newer antipsychotics. Knowledge that the risk of agranulocytosis is highest in the first three months has also led to a reduction in the frequency of long-term monitoring.

Substance use disorder is a significant issue in the United States, affecting approximately 48.5 million individuals annually, or 17.1% of the population [9]. Historically, addiction was considered a moral failing—a symptom of criminality or weak character. A variety of non-effective treatments were used until the 1900s, ranging from cocaine-based therapy, hydrotherapy, and institutionalization. In the 1930s, 12-step and self-help models were established for alcohol dependence treatment. In 1949, disulfiram (Antabuse) became the first drug approved to treat alcoholism [10]. The drug works by increasing the concentration of acetaldehyde, a toxic byproduct that occurs when alcohol is broken down in the body. Excess amounts of this byproduct (as when alcohol is consumed along with the medication) cause unpleasant symptoms, such as nausea and flushing of the skin. The anticipation of these effects can assist with cessation and abstinence. For more than 40 years, disulfiram was the only medication approved for the treatment of alcohol use disorder [10]. Since then, two additional medications—naltrexone (ReVia, Vivitrol) and acamprosate (Campral)—have been approved. The conceptualization of addiction and substance use disorder has also evolved and is now recognized to be a primary, chronic disease of brain reward, motivation, memory, and related circuitry. Dysfunction in these circuits leads to characteristic biologic, psychological, social, and spiritual manifestations [11]. As a primarily biologic illness, addiction is now recognized as a valid target for pharmacotherapy.

In the early 21st century, the United States experienced an unprecedented increase in opioid prescribing, use disorder, and fatal overdose [12]. In addition to the highly beneficial therapeutic effects, the toxic side effects and addictive potential of opioids have been known for centuries. These undesired effects have prompted a search for a potent synthetic opioid analgesic free of addictive potential and other complications. However, all synthetic opioids introduced into medical use share the same abuse liabilities of the classical opioids. The search for new opioid therapeutics has resulted in the synthesis of opioid antagonists and compounds with mixed agonist-antagonist properties, such as buprenorphine, which has expanded therapeutic options and provided the basis of expanded knowledge of opioid mechanisms [13].

Nonmedical use of prescription opioids was reported in literature as early as 1880. A report in 1928 documented that injection of opioids contributed to the development of nonmedical use and misuses of prescription opioids. Before 1930, the prevalence of nonmedical opioid injecting in the United States was low. But by the mid-1940s, more than one-half the admissions to the National Institute of Mental Health's Lexington Hospital were for the misuse of prescription opioids [14]. As of 2018, there were an estimated 2.1 million individuals with opioid use disorder in the United States [15]. In addition, more than 81,000 drug overdose deaths occurred in the United States in the 12 months ending in May 2020, the highest number of overdose deaths ever recorded in a 12-month period, and the rise was mainly attributed to synthetic opioids [16].

While methadone has long been in use in specialized clinics with strict licensing, the development of alternative treatments for opioid use disorder, including buprenorphine/naloxone (Suboxone), has revolutionized the approach to managing and treating this disorder.

Typical antipsychotics (Table 1) have a primary site of action at the D2 receptor and are potent D2 receptor blockers. They also have noradrenergic, cholinergic, and histaminergic blocking action. These agents can also be described as high, intermediate, or low potency. High-potency antipsychotics are prescribed in lower doses, with the most widely prescribed of these being haloperidol (Haldol). Haloperidol is available in oral, intramuscular (IM), and long-acting IM decanoate formulations. Low-potency antipsychotics are prescribed in higher doses; the most widely used of these is chlorpromazine [17,18].

Adverse Effects

The adverse and side effect profiles of typical antipsychotics are generally poorer than the atypical antipsychotics. The prevention, detection, and treatment of extrapyramidal symptoms, most notably tardive dyskinesia, is the main challenge when prescribing typical antipsychotics.

Neurologic Effects

Patients who are prescribed typical antipsychotics should be monitored for neurologic side effects using the standardized Abnormal Involuntary Movement Scale (AIMS) (Figure 1). The AIMS consists of 12 items and can usually be completed within 10 minutes. It was developed specifically to detect and record the occurrence of tardive dyskinesia in any patient taking neuroleptic medication. Tardive dyskinesia is a syndrome characterized by abnormal involuntary movements of the patient's face, mouth, trunk, or limbs, and it affects 20% to 30% of patients who have been treated for months or years with neuroleptic medications. Patients who are older, are heavy smokers, or have diabetes are at increased risk of developing tardive dyskinesia. For most patients, this side effect develops three months after the initiation of neuroleptic therapy; in elderly patients, however, tardive dyskinesia can develop after as little as one month [20].

ABNORMAL INVOLUNTARY MOVEMENT SCALE (AIMS)

Figure 1

Source: [20]

Regular use of the AIMS allows the severity of symptoms to be followed over time. Initial AIMS testing should be done prior to the initiation of treatment and every three to six months during therapy. Either before or after completing the examination procedure, the patient should be observed unobtrusively at rest (e.g., in the waiting area). The chair used in the examination should be firm and without arms. The patient should remove his or her shoes and socks and any gum, candy, or food from his/her mouth prior to the examination. In addition to the examination and observation, the patient should be asked about:

• Dental/oral health (e.g., use of dentures, problems with teeth)

• Unintended movements in the extremities, mouth, or face and whether these movements are a bother or interfere with activities

Patients should be instructed to sit in a chair with their feet flat on the ground; a general observation of the patient's body may be made at this point. Patients should also be asked to drape their arms over their legs, with their hands hanging over their knees. Several additional tasks should be done, including:

• Opening the mouth to observe whether the tongue is moving or at rest

• Sticking the tongue out to observe for any abnormal movements

• Tapping the thumb with each finger as rapidly as possible to observe the flexibility of fingers as well as any other body movements that occur while the patient is concentrating on this manual task

• Flexing and extending the arms and wrists one at a time to monitor for rigidity and cogwheeling

• Walking around the room to observe for any parkinsonian-type movements

All findings during the examination should be recorded. It is important to note that repetitive, regular, rhythmic tremors are not recorded on the AIMS, as the tool is specific to tardive dyskinesia. However, these tremors may in fact be an adverse effect of neuroleptic treatment. If present, these movements should be monitored and considered when making treatment and pharmacotherapy decisions.

Metabolic Effects

Meta-analyses have shown that all antipsychotics are associated with an increased risk for weight gain, with the greatest gain seen with atypical agents (clozapine and olanzapine) and the least with typical agents (haloperidol). Numerous studies have concluded that H1 receptor antagonism action is most correlated with weight gain, although other receptor sites (including 5HT receptors) were also significantly associated with weight gain [21].

A reasonable approach to monitoring metabolic side effects involves measuring vital signs and weight prior to prescribing an antipsychotic agent and at every follow-up visit. Baseline blood work including a lipid profile, hemoglobin A1C, and a basic metabolic panel is also advised. Variances from baseline values and the presence or absence of weight gain can help guide the frequency of monitoring. However, obtaining laboratory studies at least yearly should be considered.

Cardiovascular Effects

Monitoring for QTc prolongation should be a consideration for all patients prescribed an antipsychotic. Obtaining a baseline electrocardiogram (EKG) prior to prescribing is good practice. Values greater than 500 msec should prompt referral to cardiology and a consideration to avoid medications that can prolong the QTc interval. Values of 450–500 msec require close follow-up EKG monitoring both after initiation of treatment and during any dosage adjustments.

Antipsychotics remain a consistently popular option for the management of psychosis and schizophrenia. Since the reintroduction of clozapine in the 1990s, there has been a steady increase in the proportion of atypical antipsychotics prescribed compared with typical antipsychotics. By 2014, atypical antipsychotics accounted for almost 80% of total antipsychotics prescribed [22]. This has been partially attributed to treatment failure with typical antipsychotics (e.g., up to 30% of patients with schizophrenia fail to respond to typical antipsychotics), a desire to avoid extrapyramidal symptoms, and expansion of FDA-approved indications for atypical agents [17]. It should be noted that some of the lesser-used, low-potency typical antipsychotics may also avoid extrapyramidal effects.

As of 2024, there were 14 atypical antipsychotics approved for use in the United States (Table 2). Like the typical agents, these drugs are used primarily for the treatment of psychoses, although several are adjunctive treatments for major depressive disorder. Novel antipsychotics with various mechanisms of actions continue to be studied and approved; clinicians should consult the latest prescribing literature when selecting a medication for their patient.

When choosing an atypical antipsychotic, it is important that the clinician fully understand the mechanism of action of the drug being considered, as they have a wide variety of actions. There are also significant pharmacokinetic differences.

A subset of antipsychotics (both typical and atypical) are available as long-acting injectable forms (Table 3). When prescribing a long-acting injectable antipsychotic, clinicians first initiate treatment with the oral form for a long enough period to demonstrate tolerance. The oral formulation should be continued until the long-acting therapy has been established. Both fluphenazine and haloperidol use sesame oil in their suspension, which may cause allergic reactions in patients sensitive to sesame.

There are no randomized controlled trials showing superiority of decanoate injections over other formulations; however, some small studies have shown at least similar efficacy of long-acting injected and oral haloperidol [24]. Plasma serum concentrations with steady-state decanoate yield lower plasma drug concentrations than with oral administration. This suggests that decanoate forms are at least as effective as oral agents and that lower doses may be effectively used with this formulation [24].

The efficacy of long-acting injectable antipsychotics other than haloperidol is not clear [25]. Studies have found varying results for different antipsychotics, both in terms of efficacy and side effect profile [24,25]. The ultimate decision to select a long-acting injectable antipsychotic is complicated and typically driven by a need to improve compliance.

There are a variety of adverse effects and special population warnings that apply across the class of antipsychotic medications. These should be taken into account when selecting an agent, structuring the treatment plan, and conducting follow-up assessments.

As discussed, risk mitigation strategies should be initiated when prescribing any antipsychotics. Although only clozapine has a formal REMS program, there are steps that should be taken with any antipsychotic prescription to minimize the potential for adverse effects and manage associated risks (Table 4).

Patients prescribed antipsychotics should receive education on the effects of the drugs, possible risks and benefits, and any recommended monitoring. However, this can be difficult if the patient has active psychosis or delusional paranoia. In these cases, caregivers and/or surrogate decision makers should be sought. All discussions should be fully documented. Patient education is an ongoing process (not a single event), and efficacy and adverse effects should be discussed regularly with patients as well as steps taken to treat or ameliorate adverse effects.

While Table 4 presents an example of risk mitigation strategies for all antipsychotics, the actual strategies used should be specific to the patient and agent(s); abnormalities should generate a consult to appropriate medical team members. Aside from prevention and early detection of adverse effects, risk mitigation strategies should include a treatment plan for any possible adverse reactions. As discussed, there are several class-wide potential adverse effects, and these known risks should be reviewed and planned for.

Patient A is 34 years of age with a history of schizoaffective bipolar disorder, first diagnosed at 18 years of age during his first year at college. His childhood was notable for several episodes of brief counseling for behavioral issues in school and at home, with a brief trial of methylphenidate (Ritalin) at 11 years of age. Patient A graduated from high school with his peers, but once at college, he developed delirious mania, paranoia, and psychosis. Treatment with olanzapine and valproic acid (Depakote) was initiated, but compliance has been an ongoing issue. During the past 16 years, the patient has had numerous episodes requiring hospitalization, one suicide attempt, and three arrests for breach of peace. He is now on probation and has been unable to maintain employment. He is living with his mother, who has communicated that he will have to leave the house if he does not take his medication. Patient A presents for medication management, stating that he does not like the weight gain he has experienced with many of the medications he has used in the past.

The nurse takes and documents a full history. On mental status exam, Patient A is alert and oriented. He scores 27 on a Mini-Mental State Exam (MMSE) and is mildly grandiose. His speech is slightly pressured but interruptible. At the time of presentation, Patient A is not taking any medications, having disagreed with his last provider's prescription of olanzapine, a drug that had been effective in the past.

Patient A is 6 feet 1 inch tall and weighs 235 pounds. His blood pressure is 124/86 mm Hg. Laboratory studies are requested, and all return normal. An EKG reveals a normal QTc and sinus rhythm.

The nurse asks Patient A what he wants to gain in his medication management, and his stated goals are to continue to live with his mother, to avoid future arrest, and to be able to maintain a job. The nurse discusses available typical and atypical oral and decanoate antipsychotics. After a long discussion, Patient A decides to try long-acting injection risperidone (Risperdal Consta). Patient education includes the risks of extrapyramidal reactions (e.g., movement disorders), weight gain, and prolactin elevation, which can lead to gynecomastia, as well as risk mitigation strategies if any of these develop.

A baseline AIMS test is conducted and is negative for any existing issues. The oral trial of risperidone is initiated, as required before using any long-acting injectable to demonstrate tolerance. The patient is titrated up to an oral dosage of 3 mg twice daily, which appears to resolve the patient's paranoia, pressured speech, and hypomania. Patient A reports that he is functioning better, but he reiterates that he does not think he will be able to comply with daily oral medication. The decision is made to progress to long-acting injected risperidone, which requires a three-week overlap with the oral medication.

While there is no exact dosage equivalency, the manufacturer recommends that a 6-mg total oral daily dose of risperidone should be converted to a bimonthly injectable dose of 37.5–50 mg long-acting risperidone. The patient is started at 37.5 mg IM every two weeks. After three weeks, the patient is stable and able to wean off the oral risperidone, decreasing to 4 mg in two divided doses for three days, then 2 mg in divided doses for three days, before total cessation. During this time, the nurse maintains frequent contact with Patient A to verify stability and compliance.

After six weeks, laboratory studies are ordered, including blood glucose level, lipids, and prolactin level, and a repeat EKG is done. All findings are normal. The nurse continues to administer the AIMS test every three months and to check weight and vital signs at every visit. While Patient A continues with this therapy, laboratory values are rechecked every three to six months.

Patient A responds well to treatment and is able to remain living with his mother. After six months, he has gained employment at a fast-food restaurant and has avoided any contact with law enforcement.

SSRIs are thought to act by inhibiting serotonin transporters (SERT) that reuptake serotonin (5-HT) into the presynaptic cell, increasing 5-HT in the synaptic cleft. SSRIs have advantages of low overdose lethality and better tolerability than first-generation antidepressants, which can improve adherence. SSRIs are particularly effective in patients with obsessive-compulsive symptoms, but may initially worsen anxiety or panic symptoms [35,43,44]. This class includes the agents fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa), escitalopram (Lexapro), and vortioxetine (Brintellix). Escitalopram may have fewer drug-drug interactions than other SSRIs, and fluoxetine may be a better choice in patients with poorer adherence due to its long half-life [35,43,44].

SNRIs act by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in an increase in the extracellular concentrations of serotonin and norepinephrine and therefore an increase in neurotransmission [35,43,44]. Most SNRIs, including venlafaxine (Effexor), desvenlafaxine (Pristiq), levomilnacipran (Fetzima), and duloxetine (Cymbalta), are several-fold more selective for serotonin than norepinephrine.

Safety, tolerability, and side effect profiles of SNRIs resemble SSRIs, with the exception that the SNRIs have been associated (rarely) with sustained elevated blood pressure. SNRIs can be used as first-line agents, particularly in patients with significant fatigue or comorbid chronic pain, and have an important role as second-line agents in patients who have not responded to SSRIs [35,43,44].

Venlafaxine is especially beneficial in treating anxiety and panic attacks in patients with depression, and acts like an SSRI at lower doses (75 mg/day) but more like an SNRI at doses ≥150 mg/day [35,43,44].

TCAs are predominantly serotonin and/or norepinephrine reuptake inhibitors that act by blocking the serotonin transporter and the norepinephrine transporter, respectively, which results in an elevation of the extracellular concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission. TCAs also have varying but typically high affinity for the H1 and H2 histamine receptors and muscarinic acetylcholine receptors. As a result, they also act as potent antihistamines and anticholinergics. These properties are generally undesirable in antidepressants, however, and likely contribute to their large side effect profiles [48].

TCAs are classified by the nature of the final amine group on the side chain, with the tertiary amines amitriptyline (Elavil), clomipramine (Anafranil), doxepin (Sinequan), trimipramine (Surmontil), imipramine (Tofranil), and lofepramine (Lomont); the secondary amines nortriptyline (Pamelor), desipramine (Norpramin), and protriptyline (Vivactil); and the tetracyclic antidepressants amoxapine (Asendin) and maprotiline (Ludiomil).

TCAs are comparable in efficacy to SSRIs/SNRIs, but their side effect profile makes them seldom used as first-line therapy [35,43,44]. TCAs may initially worsen anxiety or panic symptoms. Due to side effect potential of cardiac arrhythmia, TCAs should be used very cautiously, if at all, in patients with heart problems. Secondary amine TCAs cause less orthostatic hypotension and sedation than tertiary amines, which should be avoided in elderly patients due to the risk for orthostatic hypotension, sedation, cognitive problems, and cardiac effects. The secondary amine nortriptyline is especially effective for elderly patients with moderate-to-severe depression. Clomipramine is particularly effective in patients with obsessive-compulsive symptoms [35,43,44].

MAOIs inhibit monoamine oxidase (MAO), an enzyme that degrades and inactivates 5-HT, norepinephrine, and dopamine. This increases monoamine levels and activity. Earlier MAOIs were irreversible MAO inhibitors, deactivating the enzyme until slowly replenished over a two-week period [50,51]. MAOIs includes phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), linezolid (Zyvox, Zyvoxam, Zyvoxid), moclobemide (Aurorix, Manerix), pirlindole (Pirazidol) (approved for use in parts of Europe), and selegiline (Deprenyl, Eldepryl, Emsam).

Most MAOIs appear broadly effective in a range of depressive and anxiety disorders, and may be more effective than other antidepressant classes in major depressive disorder with pronounced anxiety or panic symptoms [35,43,44]. Major depressive disorder with atypical features may preferentially respond to MAOIs over other antidepressant classes. Although effective, MAOIs are rarely the first- or second-line treatment choice due to serious side effect potential from medication interactions and dietary restriction. The selegiline transdermal patch (Emsam) used at the lowest strength (6 mg delivered over 24 hours) may lack the dietary restrictions required of oral MAOIs [52].

The atypical antidepressants are diverse in monoamine activity and do not fit the profile of other classes. They include bupropion (Wellbutrin), nefazodone (Serzone), mirtazapine (Remeron), and trazodone (Desyrel). Nefazodone and trazodone block postsynaptic serotonin type-2 receptors and inhibit presynaptic serotonin reuptake. Bupropion inhibits activity of norepinephrine and dopamine transporters, and the active metabolite hydroxybupropion contributes to the drug's effects. Mirtazapine is a potent antagonist at 5-HT2, 5-HT3, alpha2, and H1 histamine receptors. As a group, these agents show low toxicity in overdose and may have an advantage over the SSRIs by causing less sexual dysfunction and gastrointestinal distress [35,43,44].

Each agent has apparent benefits and drawbacks, with some better suited for specific patient populations. Bupropion is associated with a risk of seizure at higher doses, especially in patients with a history of seizure or eating disorders, and should be used cautiously in anxious patients [35,43,44]. It may be more effective for atypical major depressive disorder than other antidepressants.

Mirtazapine can be very sedating and promotes appetite and weight increase, which in some patients may be desirable. It has a faster onset of action than fluoxetine, paroxetine, or sertraline, and may be superior to SSRIs in depression associated with severe insomnia and anxiety. Trazodone is also very sedating and is usually used as a sleep aid rather than as an antidepressant [35,43,44].

Gepirone is the first and only selective 5-HT1A receptor partial agonist approved by the FDA for the treatment of major depressive disorder [19]. Gepirone is in the azapirone group of compounds related to buspirone (which is approved for generalized anxiety disorder). It is noted for its absence of sexual side effects and weight gain and is being studied as a treatment for hypoactive sexual desire disorder in men and women [131,132]. It is hypothesized that the libido improvement seen in studies was independent of its antidepressant or antianxiety effects. The most common side effects are nausea and dizziness, but, according to the manufacturer, these are usually mild, transient, and associated with dosage increases [133].

Vilazodone and vortioxetine are multimodal antidepressants that combine SSRI properties with other pharmacologic actions affecting monoamine and non-monoaminergic targets. Evidence does not suggest greater efficacy than SSRI/SNRIs, but these agents may improve tolerability or efficacy on specific clinical domains [53].

Vilazodone, approved in 2011, primarily acts as a SERT inhibitor and 5-HT1A receptor partial agonist, and modestly inhibits dopamine and norepinephrine transporters. This antidepressant may be most helpful in patients lacking response to initial SSRIs. Vilazodone must be taken with food, which increases its absorption and bioavailability by 72% [54,55].

Vortioxetine, approved in 2013, acts through various serotonin receptors as an antagonist (5-HT3/7/1D), partial agonist (5-HT1B), or agonist (5-HT1A), and inhibits SERT. It also activates the glutamate system in the frontal cortex. Vortioxetine displays a specific clinical efficacy in the treatment of cognitive deficits associated with major depressive disorder. The most common side effects are nausea, vomiting, and constipation [53].

Among the antidepressants, only fluoxetine is approved for use in treating major depressive disorder in pediatric patients. In addition, fluoxetine, sertraline, fluvoxamine, and clomipramine are approved for obsessive-compulsive disorder (OCD) in pediatric patients. Other than these indications, all other use of antidepressants in children is off-label [71]. However, these off-label uses are relatively common, particularly among adolescents and pediatric patients with more severe disease.

Beginning in 2003, data have suggested an increase in attempted and completed suicides in children treated with antidepressants [72]. There is also compelling research indicating that the decrease in prescribing of antidepressant medications to adolescents in the period after 2003, both in the United States and the Netherlands, led to an increase in suicide rate [72]. In the Netherlands, the rate increased by 49% between 2003 and 2005, during which time there was a significant decrease in pediatric SSRI prescriptions.

Data for pediatric efficacy (defined as improvements in depressive symptoms) are strongest for fluoxetine, which is approved for children older than 8 years of age [72]. The best results are achieved with a combination of pharmacotherapy and cognitive-behavioral therapy. Due to the risks and complexities involved in the treatment of children with depression, it is recommended that a multidisciplinary team approach be utilized in the treatment of these patients.

Pediatric patients being treated with antidepressants for any indication should be closely observed for clinical worsening, as well as agitation, irritability, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. This monitoring should include daily observation by families and caregivers and frequent contact with the physician. It is also recommended that prescriptions for antidepressants be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose [71].

The American Psychiatric Association recommends optimizing the medication dose as a reasonable first step for patients treated with an antidepressant who have not responded fully to treatment if the side effect burden is tolerable and the upper limit of a medication dose has not been reached.

(https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf Last Accessed: September 26, 2024)

Strength of Recommendation: II (Recommended with moderate clinical confidence)

Standard antidepressants fail to produce adequate response in 30% to 50% and remission in up to 70% of patients with major depressive disorder [73,74,75]. Partial response, instead of full remission, leaves patients with impairing residual symptoms and high risk of relapse. Each relapse increases symptom severity, decreases treatment response, and heightens risk of treatment-resistant depression [76].

Treatment-resistant depression is a problem increasingly encountered by primary care and mental health providers. Contributors to treatment-resistant depression include illness severity, medical and psychiatric comorbidity, and the limitations of FDA-approved drug options. The definition of treatment resistance lacks consensus, but the most common definition is an inadequate response to two or more antidepressants. This does not consider adjunctive strategies or distinguish patients with partial versus non-response [62,77].

In addition to augmentation strategies, a diverse and growing range of interventions are available as options for treatment-resistant depression [78,79,80]. Most engage novel therapeutic targets.

Patient B, 46 years of age, presents with a history of mild-to-moderate depression for the past six months. He has been undergoing cognitive-behavioral therapy, and while he has made some gains, he continues to experience depressive symptoms, as documented by a mood map and reports from his therapist. In addition, he is overweight and complains of insomnia.

The nurse does a complete psychiatric history and orders baseline laboratory studies and EKG. The patient reports no history of suicidal ideation and has never been hospitalized. He states that he is functioning well in his job but has been unable to maintain a steady relationship, despite a desire to have a long-term partner.

Patient B's main complaints are depressed mood and insomnia. He does not endorse anxiety or panic attacks and denies any drug or tobacco use. The patient is relatively healthy, has received regular medical care, and does not take any other medications. He has no history of seizure disorder. After a long discussion with the patient, the nurse decides to start a trial of sertraline 50 mg/day and trazodone 25 mg at night.

Patient B returns in two weeks and reports that his sleep has improved and the medications are well tolerated. He agrees to return in four more weeks to determine if the medications are helping his mood, which currently has not improved. During that period, he will continue working with his therapist weekly. The nurse and therapist are in good communication, with an understanding that any changes in symptoms or tolerability should be shared immediately.

After four weeks, Patient B comes back to the office. His mood is still described as depressed by both him and his therapist, so the sertraline dosage is increased to 100 mg/day, with a plan for the patient to return in one month.

When Patient B returns in four weeks, he reports that he is feeling better and has been going out and socializing. However, he is experiencing sexual side effects (erectile dysfunction). Several options are discussed, including transitioning from sertraline to a trial of bupropion or adding a trial of sildenafil. The patient decides that he would like to switch to bupropion, because he does not like the idea of having to take another medication.

After decreasing the dose of sertraline to 50 mg for two weeks, the patient is stable and plans are made to discontinue the sertraline and start bupropion (Wellbutrin XR) 150 mg every morning. When Patient B presents in two weeks, he is happy with the new medication, reporting full resolution of the sexual side effects, but reports some residual depressed mood. The dose of bupropion is increased to 300 mg every morning.

In another four weeks, Patient B's depression is in remission and his sleep quality is significantly improved. The medications remain well-tolerated. The patient also notes that he has lost about 5 pounds, which he attributes to decreased appetite. The patient continues to work with his therapist and agrees to return monthly for at least the next three months for continued monitoring.

Patient C, 23 years of age, presents with a history of increasing mood instability, with periods of depression lasting three to four months followed by periods of increasing disorganization, lack of need for sleep, and risky behaviors (e.g., gambling, shoplifting). After her third shoplifting arrest, Patient C agreed to a plea deal that requires her to seek and comply with psychiatric care.

The clinician conducts a full psychiatric history that is significant for school and employment problems. She attempted outpatient treatment at 16 and 21 years of age, both of which were ended by the patient due to her dislike for medications and their side effects and a perceived "loss of energy" when treatment was initiated with olanzapine during a manic episode at 19 years of age.

The workup reveals a healthy woman, normal laboratory studies, normal EKG, and no medical problems. She is gravida 0 para 0 and has a progestin intrauterine device for birth control. She describes her current mood as depressed, rated 3 on a Likert scale. She describes hypersomnia, sleeping about 10 hours per day. She is currently unemployed and living with her parents. She denies any psychotic symptoms and has never attempted suicide. The patient feels her parents are supportive but firm in stating that she must engage in treatment to continue living with them. She is a nonsmoker and has no known drug use, other than occasional cannabis (less than once per week), which she does not view as problematic. She has genetic loading, with an uncle and a sister who have been diagnosed with bipolar disorder.

Patient C is currently not seeing a therapist or receiving psychotherapy. In discussing goals of care, her main goal is compliance with her probation stipulations. She also indicates that she would like to be employed and to eventually move out of her parents' house. Weight gain is identified as an intolerable side effect of pharmacotherapy; the patient states she would like to lose weight. After much discussion, Patient C agrees to see a social worker for cognitive support and to assist with employment goals.

Given the patient's goals and concerns, antipsychotics are determined to be undesirable. The clinician and patient discuss the risks and benefits of valproic acid and lithium. Patient C states that her uncle did well on lithium and that she would like to try it. In preparation for lithium prescription, the patient's thyroid hormone and calcium levels are reviewed along with kidney function; all are normal. Patient C expresses a strong desire to take pills only once per day and does not think she can remember to take a morning dose. The clinician reviews literature, which indicates that once daily dosing of lithium results in similar efficacy, with lower total doses, decreased renal toxicity, and decreased urinary frequency [91]. The patient is started on controlled-release lithium 450 mg taken at night. Eventually, she is titrated to 900 mg daily, with an average serum lithium level of 0.7 mEq/L.

As part of the patient education process, the clinician emphasizes the need for reliable birth control, as lithium crosses the placenta and is associated with serious fetal malformations following exposure in the first trimester [92]. This conversation is documented fully, including a recommendation that the patient use dual birth control (e.g., add condoms). The need to use a different medication during any planned pregnancy is reviewed.

After 12 months of therapy, Patient C has not experienced any episodes of mania. However, she describes her mood as depressed and complains of amotivation, sadness, hypersomnia, and a 10-pound weight gain. Her lithium level is stable and within the therapeutic range, and the clinician is concerned that raising the lithium dose could increase the risk of toxicity.

To address these issues, bupropion (Wellbutrin XL) 150 mg/day is added to the patient's regimen. Augmentation with low-dose bupropion appears to have the lowest risk of inducing mania among available antidepressants [93]. In six weeks, Patient C reports a gradual improvement in mood, a slight weight loss (2 to 3 pounds), and no signs or symptoms of mania. She continues to meet with her social worker and has attained employment as a front desk clerk at a hotel. She is pursuing her goal of living independently and has had no further contact with law enforcement.

The National Collaborating Centre for Mental Health asserts that all patients prescribed antidepressants for the management of anxiety should be informed that, although the drugs are not associated with tolerance and craving, discontinuation/withdrawal symptoms may occur on stopping or missing doses or, occasionally, on reducing the dose of the drug.

(https://www.nice.org.uk/guidance/cg113 Last Accessed: September 27, 2024)

Level of Evidence: Expert Opinion/Consensus Statement

SSRIs are considered first-line therapy for generalized anxiety disorder and panic disorder [101,103]. TCAs have comparable efficacy to SSRIs in panic disorder and generalized anxiety disorder [104,105]. TCAs are lethal in overdose and, compared with SSRIs, have a markedly broader, more problematic, and less tolerable side effect profile [101]. Nonetheless, TCAs may work when first-line agents do not [106]. Also, some patients with panic disorder are sensitive to both beneficial and adverse effects of TCAs, so cannot tolerate imipramine doses >10 mg/day but still experience panic blockade [101].

MAOIs are effective for panic disorder and social anxiety disorder and are thought by some to be superior options for severe, treatment-resistant anxiety disorders. As noted, MAOIs have a substantial side effect profile and impose the greatest safety burden of all antidepressants. Therefore, they are usually reserved as the last treatment option after other drug therapies have failed to achieve remission [107]. Clinicians do not routinely prescribe MAOIs for anxiety disorders, although they are probably not considered often enough in treatment-resistant patients [106].

Since their introduction in the early 1960s, benzodiazepines have been the most prescribed drugs for anxiety over the majority of the past half-century. Although SSRI/SNRI agents have replaced benzodiazepines as the top-prescribed anxiolytics, benzodiazepine prescribing remains common. In 2020, alprazolam, clonazepam, lorazepam, and diazepam were among the top 25 most frequently prescribed psychotropic medications in the United States; alprazolam ranked 9th, clonazepam ranked 12th, lorazepam ranked 16th, and diazepam ranked 23rd [108,109].

Patient D, 33 years of age, presents with a chief complaint of anxiety. He describes increasing anxiety symptoms for the last eight months, including persistent worrying that he finds challenging to control, overthinking plans, inability to let go of a worry, difficulty concentrating, fatigue, difficulty falling asleep, irritability, and nervousness. He is employed as a corrections officer with two young children. A medical workup is normal. He has engaged with a therapist for the past three months, and while he has made some gains with cognitive-behavioral therapy, his therapist has suggested a medication consultation to help with his ongoing symptoms.

Upon review of symptoms and consultation with the patient's therapist, a diagnosis of generalized anxiety disorder is confirmed. The clinician discusses goals of care with the patient; he states that he wants to avoid the medication side effects of daytime sedation or impaired concentration due to his job. Available medications are reviewed, and the decision is made to start escitalopram to address the continued symptoms of generalized anxiety. Treatment is initiated at a daily dose of 10 mg. Patient D asks about alprazolam (Xanax), as a friend told him that this medication worked for him. The clinician spends time on patient education explaining that alprazolam has a known risk of addiction and a potential for sedation. The patient agrees to the trial of escitalopram.

When Patient D returns for follow-up in four weeks, he reports improvement in his anxiety symptoms and is continuing his cognitive-behavioral therapy. After three months, the patient indicates that his symptoms are manageable and he has not experienced any adverse effects of the pharmacotherapy.

Patient E, 54 years of age, presents with active opioid use disorder. He began using prescription opioids for back pain after having served in the infantry. His usage eventually resulted in his leaving military service prior to retirement, and he currently works in construction. The patient reports having relied on prescription opioids until three years ago, when he started using heroin. He buys 10 bundles per day of what is described as heroin but is most likely synthetic fentanyl. He has accidentally overdosed on two occasions, and emergency medical services used naloxone nasal spray to revive him. He is seeking care at an intensive outpatient program for treatment.

After reviewing goals of care with the patient, the clinician identifies that he has residual chronic back pain in addition to cravings for opioids when not using. The patient is diagnosed with opioid use disorder.

Patient E states that he recently sought care for his back pain and was referred to physical therapy and advised to take nonsteroidal anti-inflammatory drugs (NSAIDs) as needed for pain management. The possibility of methadone maintenance is discussed, but the patient does not want to have to go daily for dosing and is afraid that it will impair his ability to work around heavy machinery. Safety issues are also reviewed, and nasal naloxone is prescribed for emergency use. The patient's partner receives education on use as well.

The patient states he does not wish to take a medication, but he starts attending daily 12-step meetings and working with a drug counselor. Within five days, Patient E is able to successfully complete detoxification. However, after about six weeks he experiences a relapse. His partner administers nasal naloxone after finding him unconscious.

When Patient E returns for follow-up, various options for medication-assisted therapy are discussed, and he decides to enroll in buprenorphine/naloxone therapy, with a goal of eventually being maintained on monthly buprenorphine injection. The clinician emphasizes the need for continued counseling and the need to understand that, like all chronic diseases, patients with opioid use disorder are subject to relapse. The patient is advised of the importance of seeking help early in the event of a relapse. The biologic basis of substance use disorder is stressed; there is no judgement or shame.

Patient E does well on buprenorphine/naloxone therapy and is attending physical therapy for his back pain. He has continued with regular 12-step meetings and individual psychotherapy. At each follow-up appointment, the need to keep naloxone nasal spray available for emergency use is emphasized.