In the United States, the first attempt at humane treatment of psychiatric disorders was by the Quakers, who, in 1752, used the Pennsylvania Hospital in Philadelphia to house patients in its basement; however, the environment in the hospital was damaging to patients, some of whom were shackled to walls[1]. Other early institutions for people deemed "mentally disturbed" were opened in the late 1700s in New York. In 1824, the Eastern Lunatic Asylum (now Eastern State Hospital) opened in Lexington, Kentucky. By 1890, every state had at least one publicly supported mental hospital, with populations that were rapidly expanding; by the 1950s, these institutions housed more than 500,000 patients [1]. One of the earliest practitioners of what could be called psychiatry was Dr. Benjamin Rush, who has been called the father of American psychiatry and who wrote the first American textbook on mental diseases (Medical Inquiries and Observations upon Diseases of the Mind) in 1812.

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.

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].

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].

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].

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].

Asenapine is a dibenzo-oxepino pyrrole atypical antipsychotic with mixed serotonin-dopamine antagonist activity. It is unique as the only atypical antipsychotic available in a sublingual formulation. When administered sublingually for the management of agitation, the onset of effects is seen within 15 minutes. In bipolar disorder/acute mania, initial effects are present within days, with continued improvements over one to two weeks [19]. In patients being treated for schizophrenia, the initial effects are observed within one to two weeks, and maximal effects are noted in four to six weeks.

The Clozapine REMS Program provides a centralized point of access for prescribers and pharmacies to certify before prescribing or dispensing clozapine and to enroll and manage patients on clozapine treatment [23]. The monitoring requirements are established for the general population (most patients being prescribed clozapine) and for patients with benign ethnic neutropenia (BEN). BEN is a condition observed in certain ethnic groups whose average ANCs are lower than "standard" laboratory ranges for neutrophils. It is most commonly observed in individuals of African descent (approximate prevalence of 25% to 50%), some Middle Eastern ethnic groups, and in other non-White ethnic groups with darker skin; it is also more common in men [23]. At initiation of therapy, ANC monitoring should be conducted weekly for six months. If ANC levels remain ≥1,500/mcL in the general population or ≥1,000/mcL in patients with BEN, monitoring frequency may be reduced to every two weeks from 6 to 12 months, then monthly after 12 months. If neutropenia develops, monitoring may be more frequent, from three times weekly to daily depending on the severity of the neutropenia [23]. Prescribers are required to submit patients' ANC levels to the Clozapine REMS Program for every prescription of clozapine according to the patient's monitoring frequency.

There are no absolute contraindications to the use of quetiapine, aside from hypersensitivity. Drowsiness is a common effect and may be severe enough to result in impairment, inability to safely carry out activities of daily living (increased fall risk), and nonadherence [19]. Other common adverse effects include hypertension, orthostatic hypotension (particularly among elderly patients), tachycardia, dyslipidemias, weight gain, increased appetite, xerostomia, agitation, dizziness, extrapyramidal reaction, headache, and withdrawal syndrome.

Risperidone's high 5-HT2 and dopamine-D2 receptor antagonist activity is responsible for its antipsychotic action. However, alpha1, alpha2 adrenergic, and histaminergic receptors are also antagonized with high affinity. Onset of action is within days to 2 weeks, though peak effect may be experienced after up to 12 weeks [19]. An orally disintegrating tablet may be used to manage acute agitation, with 70 minutes mean time to calm.

Onset of symptoms is generally apparent within two weeks of treatment initiation. Clinical presentation consists of rigidity/stiffness, high fever, sweating, confusion, unstable blood pressure, and agitation. Signs and symptoms usually progress to a peak after three days. Prompt recognition is necessary to avoid significant morbidity and mortality, and treatment is immediate cessation of the antipsychotic medication and implementation of supportive measures (e.g., hydration, cooling) [30]. In more severe cases, administration of bromocriptine mesylate or dantrolene sodium may be indicated.

Treatment of tardive dyskinesia can be difficult and an impediment to the clinical stabilization of the patient. The primary consideration for patients receiving typical antipsychotics should be dose reduction or switching medications. Patients should be warned that tardive dyskinesia symptoms may initially worsen transiently as medication dosages are lowered (i.e., withdrawal-emergent dyskinesias). If a new medication will be used, clozapine should be considered first, as it has the lowest risk of tardive dyskinesia. However, it is vital to ensure that control of psychosis is maintained, particularly in patients at risk for self-harm or violence.

In 2017, the FDA approved the first medications for the treatment of tardive dyskinesia: valbenazine (Ingrezza) and deutetrabenazine (Austedo). The initial dose of valbenazine is 40 mg once daily. This is increased to 80 mg once daily after one week [19]. Continuation of a daily dose of 40 mg or 60 mg may be considered based on response and tolerability. Improvement is seen in 2 to 6 weeks, with the result stabilizing between 16 to 32 weeks. Deutetrabenazine is started at a dosage of 6 mg twice daily. This is increased as needed and tolerated in increments of 6 mg/day up to a maximum of 48 mg/day [19].

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].

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].

With oral ingestion, MAOIs inhibit the catabolism of dietary amines. When foods containing tyramine are consumed, the individual may suffer from hypertensive crisis [50]. If foods containing tryptophan are consumed, hyperserotonemia may result. The amount required to cause a reaction varies greatly from individual to individual and depends on the degree of inhibition, which in turn depends on dosage and selectivity.

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].

Nearly all commercially available antidepressants are associated with sexual side effects. SSRI/SNRIs show the highest rates of sexual dysfunction, including impaired sexual motivation, desire, arousal, and orgasm affecting men and women. Prescribers greatly underestimate the prevalence and patient burden of sexual side effects from antidepressants and other medications [56]. Among antidepressants, prevalence rates of sexual side effects are highest with venlafaxine and SSRIs; moderate with TCAs and MAOIs; low with bupropion, trazodone, nefazodone, mirtazapine, agomelatine, and vilazodone; and lowest with the reversible MAOI moclobemide [57,58]. As noted, gepirone is not associated with sexual dysfunction. Compared to spontaneous patient reporting, systematic inquiry increases the rate of identifying sexual side effects by ≥60% [58].

Antidepressant discontinuation (more appropriately termed withdrawal) symptoms are described by the FINISH mnemonic (flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, hyperarousal), may be experienced by up to 40% of patients when antidepressants are stopped abruptly, and may occur with any antidepressant [62,63,64,65]. SSRI withdrawal symptoms are far more frequent with paroxetine. Common symptoms include dizziness, nausea, headache, confusion, low energy, weakness, sleep disturbance, flu-like symptoms, restlessness, agitation, anxiety, panic, anger, and irritability. Less common and more severe symptoms include electric-shock sensations, vertigo, paresthesia, intensified suicidal ideation, aggression, derealization, depersonalization, and visual/auditory hallucinations. Gradual tapering is a reasonable strategy but does not prevent the onset of SSRI withdrawal [66]. SSRI withdrawal syndrome is least likely with fluoxetine and vortioxetine [62].

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.

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].

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].

Meta-analyses suggest alprazolam, lorazepam, and diazepam are effective but comparable in generalized anxiety disorder efficacy, while clonazepam shows much greater efficacy in the treatment of panic disorder than alprazolam, lorazepam, and diazepam, which all have modest efficacy [112].

Benzodiazepine treatment of anxiety disorders is controversial. While effective in rapid anxiety reduction, the potential drawbacks with long-term use are substantial. These agents are indicated when potent, short-term anxiolytic effects are necessary to permit infrequent exposure to feared stimuli and potentially severe anxiety, such as airplane travel [103,106,113]. Clonazepam, lorazepam, and alprazolam are effective for short-term use in panic disorder, generalized anxiety disorder, and SAD, but ineffective for, and potentially worsening, comorbid depression [114]. The rapid anxiolytic effects make benzodiazepines highly appealing to patients with anxiety, but aside from this specific context, benzodiazepine prescribing for as-needed use is discouraged [106,115,116]. Benzodiazepines can reinforce pill taking, serve as a safety signal that undermines self-efficacy, and become incorporated into conditioned fear responses; these concerns are heightened with as-needed use. On-demand dosing links pill taking to rapid anxiety reduction, powerfully reinforcing avoidance in anxiety-provoking situations and encouraging longer-term reliance on the drug. This iatrogenic effect also contributes to poor response to cognitive-behavioral therapy.

The current recommended prescribing is for time-dependent use, instead of panic response-dependent use, to minimize the risks [103]. This would also seem to maximize risk of withdrawal syndrome from uninterrupted versus intermittent drug exposure.

Benzodiazepines are also useful in the initial weeks of SSRI/SNRI initiation to rapidly reduce anxiety and possible early anxiogenic medication side effects before the onset of SSRI/SNRI anxiolytic effects [103,106,113]. However, patients may discontinue the antidepressant when co-prescribed a rapidly effective benzodiazepine, believing the benzodiazepine's symptom relief makes the SSRI/SNRI unneeded. Supportive therapy with regular visits or phone contacts may also help patients remain adherent until the delayed onset of antidepressant benefits appears or early antidepressant side effects lessen [117].

Another indication for benzodiazepine use is for the short-term relief (two to four weeks only) of anxiety that is severe, disabling, or subjecting the individual to unacceptable distress. Perhaps the greatest prescribing challenge with benzodiazepines is preventing short-term use from insidiously developing into long-term use. Patients with the most severe anxiety may obtain the greatest relief and become most hesitant to discontinue use [118]. In many cases, clinicians ignore the recommended two- to four-week prescribing limit, mainly because alternative options with superior anxiolytic effects are not available [119]. Clinicians intending to prescribe alprazolam should carefully consider the likelihood that its use will remain restricted to the very short term—a few days to a couple weeks—to see the patient through a crisis [118].

Long-term benzodiazepine use can result in added symptoms during stable-dose maintenance, including increasing anxiety and withdrawal-associated symptoms such as perceptual disturbances and paresthesia. This emerging withdrawal syndrome despite ongoing benzodiazepine use is much more likely with highly potent and rapidly eliminated alprazolam or lorazepam and is temporarily alleviated by dose escalation. As craving, dysphoria, and other withdrawal symptoms develop over time between doses, the motivation to continue benzodiazepine use for anxiolysis gradually merges with the need to avoid withdrawal symptoms [124].

Despite comparable dosing, patients with panic disorder often show greater difficulty tapering than patients with generalized anxiety disorder. Problems during alprazolam tapering are most severe during the last half of the taper. Patients with panic disorder receiving diazepam or alprazolam had fewer problems during taper of the top 50% of daily dose. However, with abrupt discontinuation of the remaining dose, alprazolam caused significantly more anxiety, relapse, and rebound. This may reflect greater problems withdrawing from short half-life, high-potency benzodiazepines like alprazolam [43].