75: Serotonin Reuptake Inhibitors and Atypical Antidepressants

In the United States, major depressive disorder is a leading cause of disability and affects 14.8 million American adults; it is also the largest cause of disability for adolescents and those 15 to 44 years of age.^1,93 Although major depressive disorder can develop at any age, the median age at onset is 32 years and it is more prevalent in women.^94,95 The exact etiology of depression and the mechanism by which increased serotonergic and norepinephrine neurotransmission modulates mood remains unclear. Antidepressants modulate the activity of serotonin and norepinephrine and dopamine to achieve their effect. The class of selective serotonin reuptake inhibitors (SSRIs) includes citalopram, escitalopram (active enantiomer of citalopram), fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone (Fig. 75–1). Atypical antidepressants extend the pharmacologic principles of SSRIs to achieve beneficial effects for patients with depression. The SSRIs and atypical antidepressants comprise the current standard for the treatment of depression.⁸⁰ SSRIs also are used to treat obsessive–compulsive disorders, panic disorders, alcoholism, obesity, and various nonpsychiatric disorders such as migraine headaches and chronic pain syndromes.^11,125,131 They have excellent safety profiles when compared with monoamine oxidase inhibitors (MAOIs) and the cyclic antidepressants. Like many xenobiotics, the appropriateness of their use and the associated morbidity and mortality is questioned as the patient population has aged and the comorbidity profiles of those using the SSRIs have changed.

Serotonin (5-hydroxytryptamine) got its name after its initial discovery as a vasoconstrictor. Synonyms for 5-hydroxytryptamine include thrombotin, enteramin, substance DS, and 3-(β-aminoethyl)-5-hydroxyindole. SSRIs initially were marketed in the United States in the early 1980s and still are considered a first-line therapy for treatment of depressive disorders in the United States and Europe.⁶³ SSRIs are as effective as the cyclic antidepressants and MAOIs for the treatment of major depression and have fewer significant adverse events associated with their therapeutic use and are less problematic in overdose (Chaps. 71 and 73). An increased risk of suicidal behavior is reported with the use of many antidepressants compared with herbals or counseling alone.¹⁰⁸ This is particularly true in children and adolescents, and may be related to delayed onset of therapeutic efficacy coupled with increased energy associated with the initiation of therapy.

Table 75–1 lists the pharmacology, therapeutic doses, and metabolism of available SSRIs and atypical antidepressants. Modulation of serotonin and norepinephrine neurotransmission has a significant role in the treatment of depression.¹⁴⁶ There are seven widely known classes of serotonin receptors, with many exhibiting subtype classifications (Chap. 14). SSRIs selectively inhibit serotonin reuptake via the serotonin transporter due to the p-trifluoromethyl or p-fluoro substitution, present in many of these xenobiotics.¹⁸² Serotonin neurons are located almost exclusively in the median raphe nucleus of the brainstem, where they extend into and are in close proximity to norepinephrine neurons that are located primarily in the locus ceruleus (Fig. 75–2).¹⁰ The interplay between norepinephrine and serotonin likely explains the effectiveness of antidepressants that do not directly modulate serotonin neurotransmission.

The SSRIs display diverse elimination patterns and have numerous active metabolites, which substantially increase both the duration of therapeutic effectiveness and the duration during which drug interactions and adverse drug effects can occur after the medication is discontinued (Table 75–1). Important pharmacokinetic and pharmacodynamic drug interactions are reported with therapeutic dosing (see Serotonin Toxicity). The SSRIs and their active metabolites are substrates for—and potent inhibitors of—CYP2D6 and other CYP isoenzymes.^73,147 For example, fluoxetine, fluvoxamine, citalopram, venlafaxine, mirtazapine, paroxetine, and sertraline are substrates for CYP2D6, whereas paroxetine, norfluoxetine, and fluoxetine inhibit the same enzyme (Table 75–1). Alternatively, mirtazapine induces CPY3A4 enzymes, while trazodone and vilazodone metabolism may be decreased after this same enzyme is inhibited.^160,163 The consequences of these interactions manifest when the metabolism of medications that rely on these enzymes for metabolic transformation is altered (Chap. 13). Genetic polymorphism typing holds promise in identifying patients at highest risk for both adverse drug events and antidepressant efficacy with therapeutic dosing.^90,91

The causes of depression and mechanism by which antidepressants ameliorate depressive symptoms are not well understood. Some postulated causes of depression include decreased neuronal serotonin storage, decreased synaptic serotonin, increased serotonin receptor sensitivity, and serotonin over activity resulting in depressed dopamine neurotransmission.^{146,162,176,181} Others postulate that physiologic stress and associated atrophy of dendritic processes with a loss of neurons and glial elements occur.¹⁶ These changes were most pronounced in the prefrontal cortex and the hippocampus on autopsy of depressed patients. It is unclear how these changes occur, although it is likely that complex signaling pathways including disruptions in synaptic proteins and synaptic activity are contributory. In addition to the direct pharmacologic effect of increasing synaptic concentrations of serotonin, antidepressants increase neurogenesis in the prefrontal cortex and glia in oligodendrocytes and activate complementary factors such as brain derived neurotrophic factor and mitogen-activated protein kinase. The requirement for these endogenous mediators may explain previous research finding no difference in the concentration of serotonin-binding sites or serotonin receptor activity between depressed patients who respond to SSRIs and those who do not respond.^31,151 Although the causes of depression are diverse and not well understood, genetic polymorphisms of the serotonin transporter may also be involved with individual responses to SSRI therapy.¹⁴² Unlike cyclic antidepressants and other atypical antidepressants, SSRIs have little direct interaction with cholinergic receptors, γ-aminobutyric acid receptors, sodium channels, or adrenergic reuptake (Table 75–2).

Most effects that occur following overdose are direct extensions of the pharmacologic activity of SSRIs in therapeutic doses. Excess serotonergic stimulation is prominent and nonselective. Acute signs and symptoms include nausea, vomiting, dizziness, blurred vision, and, less commonly, central nervous system (CNS) depression and sinus tachycardia.^26,28 Seizures and changes on electrocardiography (ECG), including prolongation of the QRS complex and QT interval duration, have been reported, but they rarely occur with most SSRIs, even after large overdoses (Table 75–3).^88,143 Infrequently, SSRI overdose results in life-threatening effects. In two fatalities, the patient reportedly ingested 40 to 75 times the maximum daily dose of fluoxetine. Serum fluoxetine concentrations were 4500 and 6000 ng/mL, with the latter including a measured norfluoxetine concentration of 5000 ng/mL, which was more than 10 times higher than the therapeutic steady state serum.^38,97

Citalopram

Citalopram and its S(+) enantiomer escitalopram cause QT interval prolongation and seizures in a dose-related manner.¹⁷³ These effects are reported at doses as low as 400 mg for citalopram and 190 mg for escitalopram.^35,185 In large case series, these effects typically occur after ingestions exceeding 600 mg citalopram or in patients with serum concentrations more than 40 times the expected therapeutic concentrations.^74,138,139 In two of these series, seizures were an early finding, occurring within 2 hours, whereas the development of abnormalities on ECG were delayed for as long as 24 hours following ingestion.^86,139 One case report, with concentrations at least 10 times the maximum therapeutic serum concentrations, documented prolongation of the QT interval and torsade de pointes occurring 32.5 hours after ingestion. Concentrations of citalopram and desmethylcitalopram were 477 mg/mL and 123.2 mg/mL, respectively.¹⁷¹

Although the mechanisms are unclear, experimental models suggest that the didesmethylcitalopram metabolite of citalopram prolongs the QT interval by blocking I_Kr, whereas high concentrations of both the parent drug and this metabolite result in seizures (Chaps. 16 and 64).^25,32 The elimination half-life of the R-enantiomer of citalopram exceeds that of the S-enantomer.¹⁷⁷ The implications of this difference on the formation and effects of racemic forms of didesmethylcitalopram are unclear.

Vilazodone

Vilazodone is a relatively new SSRI that is also a 5-HT_1a agonist. Although little data exist regarding vilazodone in overdose, the drug is expected to have similar effects to other SSRIs.²

Treatment of patients with acute SSRI overdose is largely supportive. Dextrose and thiamine should always be considered for patients who present with altered mental status. Although cardiac manifestations after SSRI overdose are rare, a 12-lead ECG should be obtained to identify other cardiotoxic drugs, such as cyclic antidepressants, to which the patient may have access (Chaps. 16, 70, and 71). If overdose of citalopram or escitalopram is suspected, then 24 hours of cardiac monitoring is recommended to exclude the possibility of delayed QT interval prolongation and subsequent risk for ventricular dysrhythmias. After the patient is stabilized, oral activated charcoal (1 g/kg) may be useful to adsorb drug remaining in the gastrointestinal tract. In fact, lowering of blood concentrations and reduction in risk for QT interval prolongation is demonstrated when activated charcoal is given shortly after escitalopram and citalopram ingestion.^58,59,174 Patients with small unintentional overdoses of SSRIs other than citalopram and escital­opram are not expected to develop significant signs and symptoms of poisoning. Patients with well defined unintentional ingestions of up to 100 mg of citalopram and 50 mg of escitalopram can usually be managed safely at home with close observation.¹²⁷ Fatalities resulting from SSRIs are rare and most commonly occur after multiple drug ingestions and manifestations of drug interactions resulting from excess serotonergic effects (see Serotonin Toxicity).⁶⁸ Forensic analysis of individual cases of intentional ingestions suggests the minimum lethal concentrations of fluoxetine, paroxetine, and sertraline after isolated overdose are 0.63, 0.4, and 1.5 mg/L, respectively. Postmortem concentrations in case reports include a citalopram heart blood concentration of 3.35 mg/L, a whole blood concentration of 11.6 mg/L, and urine concentrations of 32.43 to 149.67 mg/L.^84,114 When mono-N-desmethylcitalopram was measured, concentrations of 1.02 mg/L were found in the blood and 12.1 mg/L in the urine. An infant survived with citalopram plasma mono-N-desmethylcitalpram concentrations of 1.4 mg/L.¹¹⁷

Adverse events commonly associated with therapeutic doses of SSRIs as well as with overdose include gastrointestinal symptoms such as anorexia, nausea, vomiting, diarrhea, sexual dysfunction—in both men and women—headache, insomnia, jitteriness, dizziness, and fatigue.¹⁸³ Less common adverse events include sedation, particularly following citalopram and paroxetine, which result from their weak anticholinergic activity, and anxiety following fluoxetine treatment.¹¹⁰ Serotonin activity inhibits platelet secretory response, platelet aggregation, and platelet plug formation.²¹ Although the effect increases in SSRIs with increased potency, clinical bleeding is rare, and significant only in patients concurrently on other antiplatelet medications, most notably aspirin.^34,36 This effect may be of potential benefit in patients at risk for cardiovascular events.¹¹⁸ Other rarely reported adverse events include new-onset panic disorder, priapism, bradycardia, hepatotoxicity, and urinary incontinence.^{4,20,29,48,100,122,164} Movement disorders, most commonly akathisia, parkinsonism, myoclonus, and dystonia, also occur after SSRI use.^7,154 These extrapyramidal adverse events may be related to the complex interplay between serotonergic and dopaminergic activity. Predisposing factors for the development of movement disorders include concomitant use of dopamine antagonists such as the antipsychotics.¹⁰⁴

The syndrome of inappropriate antidiuretic hormone (SIADH; Chap. 19) in which severe hyponatremia may occur rapidly is associated with SSRI use. In an animal model, the effect appears to be serotonin mediated, with increased concentrations of serum cortisol, adrenocorticotropin, and vasopressin reported.⁶¹ Rat studies demonstrated that stimulation of 5-HT_1C receptors increases antidiuretic hormone secretion.¹³⁷ However, human case control studies have not confirmed defects in osmoregulated release of vasopressin using water loading tests and measurement of vasopressin concentrations after 3 to 11 months of paroxetine use.¹¹⁶ A review of the literature identified women older than 70 years concomitantly receiving diuretic therapy and with low baseline serum sodium concentrations were at greatest risk for developing SIADH.^22,98 Although reported to occur from 3 days to 4 months after initiation of therapy, a case-matched control study of 203 patients identified that SIADH occurs most frequently within the first 2 weeks of therapy.¹²¹ Hyponatremia may occur when switching from one SSRI to another.⁹ Efforts to predict risk through poor CYP2D6 genotype metabolizer status or high serum concentrations have not been successful.¹⁶⁷ Patients older than 50 years of age using SSRIs may be at increased risk for bone fracture presumably due to a serotonergic effect on osteoblasts and osteoclasts.¹⁴⁵ However, depression itself is also implicated in decreasing bone density in adults and children and the implications of these findings are unknown.¹⁷⁹

Serotonin Toxicity

The most common severe adverse event associated with SSRIs is the development of the serotonin toxicity. This is also referred to in life-threatening cases as serotonin syndrome and serotonin behavioral or hyperactivity syndrome. It was first described in patients treated with MAOIs who were given other xenobiotics that enhance serotonergic activity.^{37,72,130,161} However, ingestion of an MAOI is not required for serotonin toxicity to develop, and its occurrence is unpredictable (Table 75–4).

Pathophysiology.

The pathophysiologic mechanism of serotonin toxicity is not completely understood but involves excessive selective stimulation of serotonin 5-HT_2A and perhaps 5-HT_1A receptors.²⁷ Animal models demonstrate that specific stimulation of 5-HT_1A receptors results in signs and symptoms of serotonin toxicity even when 5-HT_2A receptors were inactivated using a specific antagonist.⁴¹ However, a subsequent animal study and a human retrospective case series showed that the potency of 5-HT_2A antagonist therapy was directly related to resolution of the findings attributed to serotonin toxicity.⁶⁵ 5-HT_1D receptors are not implicated in cases of serotonin toxicity.

Serotonin toxicity occurs most frequently following use of combinations of serotonergic xenobiotics (Table 75–4), but may occur following high therapeutic dosing or overdoses of single serotonergic xenobiotocs.^40,77,92,133 Interactions resulting in serotonin toxicity can occur while switching serotonergic xenobiotics, particularly when an insufficient time lag occurs before initiating the alternative therapy.¹¹² Residual pharmacologic effects, receptor downregulation or upregulation, and the presence of active metabolites may be causative in these circumstances. For example, fluoxetine metabolism results in the active metabolite norfluoxetine, which has comparable pharmacologic effects and a half-life substantially longer than fluoxetine. The clearance of norfluoxetine takes approximately 2 weeks.

Although sporadic reports occur, selective MAO subtype B (MAO-B) inhibitor drug combinations and triptans (5-HT_1B/1D receptor agonists) are rarely reported to result in serotonin toxicity at therapeutic doses.^53,56

Manifestations.

Signs of serotonin toxicity include altered mental status, agitation, tachycardia, myoclonus, hyperreflexia, diaphoresis, tremor, diarrhea, incoordination, muscle rigidity, and hyperthermia (Table 75–5). The clinical manifestations of serotonin toxicity are diverse, and minor manifestations are common after initiation of SSRI and atypical antidepressant therapy. In fact, a prospective study of depressed inpatients given clomipramine demonstrated that 16 of the 38 patients experienced manifestations consistent with the serotonin toxicity, with 14 having spontaneously resolution within one week without discontinuation of therapy.¹⁰⁷ Life-threatening effects invariably result from hyperthermia caused by excessive muscle activity that may be more prominent in the lower extremities. Sustained severe hyperthermia can lead to death through denaturation of essential protein and enzymatic function that ultimately results in elevated lactate and metabolic acidosis, rhabdomyolysis, renal and hepatic dysfunction, disseminated intravascular coagulation, or acute respiratory distress syndrome (Chap. 30).^120,169

Diagnosis.

Although fulminant life-threatening cases are easy to recognize, mild cases of serotonin toxicity are more difficult to distinguish from similar appearing disorders due to other causes. In an effort to determine diagnostic criteria, a study that included 38 cases of presumed serotonin toxicity suggested diagnostic criteria to include three of the following signs and symptoms—altered level of consciousness, agitation, myoclonus, hyperreflexia, diaphoresis, tremor, diarrhea, and incoordination—when other etiologies were excluded.¹⁶⁹ A modification, the Hunter Serotonin Toxicity Criteria, which included the variables myoclonus, agitation, diaphoresis, hyperreflexia, hypertonicity, and fever, was validated in 473 patients and found to correlate best with a clinical toxicologic diagnosis of serotonin toxicity (Table 75–5).⁵² Currently, no diagnostic test capable of determining whether a patient is experiencing serotonin toxicity is available. A single case report demonstrated increased urinary serotonin concentrations after serotonin toxicity.³⁹

Management.

Treatment of patients with serotonin toxicity begins with supportive care and focuses on decreasing core body temperature and muscle activity. Because muscular rigidity is thought to be greatly responsible for hyperthermia and death, rapid external cooling in conjunction with aggressive use of sedative hypnotics such as benzodiazepines should limit complications and mortality (Chap. 30). In severe cases, neuromuscular blockade should be considered to achieve rapid muscle relaxation. The time course of the serotonin toxicity is variable and related to the time required to eliminate the offending xenobiotics. In most patients, the manifestations of serotonin toxicity resolve within 24 hours after the offending xenobiotic is removed. However, serotonin toxicity can be prolonged when it is caused by xenobiotics with long half-lives, protracted duration of effects, or active metabolites.

Animal models indicate that pretreatment with serotonin antagonists can prevent development of serotonin toxicity.^64,83,165 Several case reports indicate the successful use of 4 mg oral cyproheptadine, an antihistamine with nonspecific serotonin antagonist effects at 5-HT_1A and 5-HT_2A receptors.^72,105 Patients who typically responded had no hyperthermia and mild to moderate manifestations of serotonin toxicity. Evidence supports the use of cyproheptadine in this patient group. Current recommendation suggests doses of 8 to 16 mg orally repeated as needed. Further research is warranted to determine the success of higher doses given to gain sufficient 5-HT_2A antagonistic effects in more severely affected patients.⁶⁵ Other xenobiotics anecdotally reported to be successful for the treatment of symptoms caused by serotonin toxicity include methysergide, chlorpromazine, atypical antipsychotics, and propranolol.^{65,66,69,75,150} However, these therapies cannot be recommended at this time.

Differentiating Serotonin Toxicity from Neuroleptic Malignant Syndrome

Many features overlap between serotonin toxicity and the neuroleptic malignant syndrome (NMS; Chap. 70). Some authors call these “spectrum disorders” caused by drugs with antidopaminergic effects, proserotonergic effects, or both.¹⁶⁸ This position is supported by the finding that 5-HT_2A agonism results in an overall decrease in neuronal dopamine release. Some authors also report NMS after use of serotonin-enhancing xenobiotics. However, low concentrations of measured dopamine and normal concentrations of serotonin metabolites in NMS patients support the hypothesis of central dopaminergic hypoactivity in NMS.^12,128 Although altered mental status, autonomic instability, and changes in neuromuscular tone that may result in hyperthermia are common to both disorders, many differences are apparent. It is now clear that the implicated xenobiotics, time course, pathophysiology, and manifestations are distinct (Table 75–6).⁶⁵ Signs and symptoms of serotonin toxicity develop within minutes to hours after exposure to the offending xenobiotics, whereas NMS typically develops days to weeks after daily exposure.⁷¹ In addition, after symptoms develop and offending xenobiotics are discontinued, NMS can last for as long as 2 weeks, whereas serotonin toxicity usually resolves quickly, and is directly correlated with the pharmacokinetic metabolic profile of the offending xenobiotic. A review of the literature indicates that patients presenting with serotonin toxicity are more likely to exhibit agitation, hyperactivity, clonus and myoclonus, ocular oscillations (opsoclonus), shivering, tremors, and lower limb hyperreflexia, whereas patients presenting with NMS were more likely to exhibit bradykinesia and lead pipe rigidity.⁶⁵

Atypical antidepressants are defined as not belonging strictly to a set classification of antidepressants. They are not SSRIs, cyclic antidepressants, or MAOIs. Most are derivatives of SSRIs and have additional pharmacologic effects that were selected in an attempt to decrease the undesirable side effects of traditional antidepressants.

Serotonin/Norepinephrine Reuptake Inhibitors

Venlafaxine.

In addition to inhibiting serotonin reuptake, venlafaxine inhibits norepinephrine reuptake. Venlafaxine produces rapid downregulation of central β-adrenergic receptors, which may result in a faster onset of antidepressant effect.¹⁵⁶ Patients with acute venlafaxine overdose may present with nausea, vomiting, dizziness, tachycardia, CNS depression, hypotension, hypoglycemia, hyperthermia, hepatic toxicity, including zone 3 necrosis, rhabdomyolysis, and seizures^{57,134,158,180,186} (Chap. 23). Sodium and potassium channel blocking effects are rarely clinically apparent; however, QRS prolongation and QT prolongation may lead to ventricular tachycardia and result in death.^17,24,149 One report indicated a positive incremental association of clinical toxicity with a maximum measured venlafaxine serum concentration of 25.8 μmol/L.¹¹⁹ Although no clinical data regarding efficacy are available, sodium bicarbonate may be helpful in attenuating the sodium channel blocking effects that leads to QRS prolongation (Antidotes in Depth: A5). In addition, gastrointestinal decontamination with activated charcoal with or without whole-bowel irrigation may decrease serum concentrations and decrease the incidence of seizures in select patients, particularly following the ingestion of extended-release formulations.^102,103 Adverse events associated with chronic therapeutic doses of venlafaxine include alopecia, yawning, focal myositis facial flushing, and dose-related increases in blood pressure.^{46,49,54,87,136}

Desvenlafaxine, duloxetine, and milnacipran—similar drugs to venlafaxine—should be expected to have similar effects.^51,101,109

Other Atypical Antidepressants with Reuptake Inhibition as Part of Their Mechanism

Bupropion.

The use of bupropion, especially extended-release formulations, is common for the treatment of depression. Bupropion is also frequently used as in the treatment of smoking cessation therapy, attention deficit hyperactivity disorder, and, occasionally, in compulsive eating disorders.^5,115 The pharmacologic mechanism of action of bupropion, a substituted cathinone (β-keto amphetamine) and its active metabolite, hydroxybupropion, include inhibition of the release and reuptake of dopamine and, to a lesser extent, serotonin and norepinephrine.⁸ Chronic doses above 450 to 500 mg/day place patients at risk for seizure.^43,89 Frequent effects that occur following overdose include tachycardia, hypertension, gastrointestinal symptoms, and agitation.^15,18 Large acute overdoses may result in seizures, QRS prolongation, or both.^{67,79,132,159} In some cases, effects were delayed for up 10 hours, and seizures up to 24 hours, particularly following the ingestion of sustained-release preparations.^78,159,166 Symptoms can continue for up to 48 hours.

Studies are conflicting as to whether seizures are caused by bupropion or its metabolite hydroxybupropion.^60,140 Elevated bupropion and hydroxybupropion concentrations are documented after seizures. The exact mechanism for seizures caused by hydroxybupropion is unclear at this time.^43,60,89,148 Treatment, when required for seizures, should be supportive and includes judicious use of benzodiazepines. QRS prolongation is likely due to gap junction dysfunction and therefore may not be uniformly responsive to sodium bicarbonate (Antidotes in Depth: A5). Bupropion is a lipophilic drug with a logP of 3.47 and a logD at pH 7 of 3.08. These physiochemical characteristics and the ability of bupropion to effect myocardial conduction have led to the proposed use of intravenous fat emulsion after overdose. Intravenous fat emulsion therapy was used to successfully resuscitate a 17 year-old woman who ingested multiple drugs including bupropion even after sodium bicarbonate and advanced life support failed and should be considered in similar cases (Antidotes in Depth: A20).¹⁵⁹ Early after an overdose of sustained-release bupropion, activated charcoal should be considered, with use of multiple doses of activated charcoal or possibly whole-bowel irrigation after large, potentially life-threatening ingestions.

Other serious adverse events reported following chronic bupropion use include cholestatic and hepatocellular dysfunction and rhabdomyolysis, with isolated reports of chest pain, dystonia, trigeminal nerve dysfunction, mania, generalized erythrodermic psoriasis, erythema multiforme, dyskinesia, altered vestibular and sensory function, and serum sickness.^{6,39,42,45,50,70,96,111,172,184}

Trazodone.

Trazodone is an antagonist at 5-HT₂ receptors, a partial agonist at 5-HT₁, and a weak serotonin reuptake inhibitor. In addition, trazodone has peripheral α-adrenergic antagonist activity. CNS depression and orthostatic hypotension are the most common complications after acute overdose of trazodone.⁶² Trazodone is rarely reported to cause SIADH. This effect may be responsible for seizures, which rarely occur after acute overdose.^13,175 Rarely, cardiac conduction delays are also reported following overdose.¹⁵⁷ Priapism, reported with trazodone, may occur occasionally after overdose.⁶² Management of hypotension includes supportive care and administration of fluids and vasopressors, if necessary.

Mirtazapine.

The mechanism of action of mirtazapine is unique. In addition to serotonin reuptake inhibition, mirtazapine increases neuronal norepinephrine and serotonin through α₂-adrenergic antagonism.⁴⁴ Mirtazapine also blocks some subtypes of 5-HT receptors, including 5-HT₂ and 5-HT₃, which may have antidepressive effects.¹²⁹ The main effects that occur after acute mirtazapine overdoses include altered mental status, tachycardia, and hypothermia.^113,178 Large overdoses may cause respiratory depression and prolongation of the QT interval.^30,144 Rare adverse reactions associated with the therapeutic use of mirtazapine causing serotonin toxicity, hepatitis, hypertension, and reversible agranulocytosis is reported.^3,81,85,126

The term “drug discontinuation syndrome” is used to describe the physiologic manifestations that occur after abrupt antidepressant cessation. The choice of terminology between withdrawal syndromes and drug discontinuation syndromes is unclear, but they may relate to the manifestations occurring after therapeutic use versus misuse, that is, alcohol or heroin withdrawal and SSRI discontinuation syndrome. Drug discontinuation syndromes are commonly reported after abrupt discontinuation of conventional antidepressants, including cyclic antidepressants and MAOIs (Chaps. 71 and 73).¹⁰⁶ SSRIs cause a discontinuation syndrome that typically begins within 5 days after drug discontinuation and may last up to 3 weeks.⁷⁶ The most frequently reported symptoms include dizziness, lethargy, paresthesias, nausea, vivid dreams, irritability, and depressed mood.¹⁵³ The risk factors associated with development of a discontinuation syndrome are not fully clarified; however, in a given individual, a genetic polymorphism of the 5-HT_1A receptor may play a role.¹²⁴ The syndrome is more common with SSRIs with shorter elimination half-lives (paroxetine > fluvoxamine > sertraline > fluoxetine). In addition, SSRIs with high-potency serotonin reuptake inhibition are more frequently implicated (paroxetine > sertraline > clomipramine > fluoxetine > venlafaxine >trazodone). Of the SSRIs, paroxetine most often results in a discontinuation syndrome, which is mild to moderate in 20% to 40% of patients receiving 20 mg daily.¹⁴ Several studies demonstrate that the vast majority of cases are attributed to paroxetine with an approximately 20% risk with sertraline, venlafaxine, and escitalopram and 10% risk with fluvoxamine.^14,23 Fluoxetine discontinuation syndrome occurs less frequently, at only two cases per 1 million prescriptions.¹⁴¹ The long elimination half-life of fluoxetine and its active metabolite norfluoxetine probably decrease the incidence of discontinuation syndrome by providing a tapered effect following cessation.

Because of difficulty in distinguishing symptoms of discontinuation syndrome from underlying disease, many authors have proposed diagnostic criteria for the SSRI discontinuation syndrome.²³ All proposed criteria include discontinuation of the SSRI in concordance with CNS effects, gastrointestinal distress, or anxiety.¹⁷⁰ The prominent CNS findings include dizziness, ataxia, vertigo, sensory abnormalities, including electric shocklike sensations and paresthesia, and behavior abnormalities, including aggression and impulsivity.

The biochemical basis of the discontinuation syndrome appears to be similar to tryptophan depletion, which results in an acute decrease in synaptic serotonin.⁴⁷ In fact, abrupt discontinuation versus drug taper was a noted risk factor in paroxetine cases when compared with those who did not experience discontinuation symptoms.⁸² Although postulated, antimuscarinic withdrawal seems an unlikely cause because the antimuscarinic effects of desipramine failed to protect against paroxetine withdrawal in a human model.⁵⁵

Treatment of patients exhibiting the discontinuation syndrome should include supportive care and resumption of the discontinued drug or administration of another SSRI if the implicated drug is contraindicated.¹⁵² The drug then should be tapered at a rate that allows for improved patient tolerance. Many of the other antidepressants discussed in this chapter also result in discontinuation reactions. Symptoms appear similar to those reported following discontinuation of SSRIs and are treated in a similar manner.¹⁹

• In acute overdose SSRIs or atypical antidepressants usually are not life threatening, although some produce seizures or cardiac toxicity. The management of these patients frequently is complicated because these patients likely have access to more life-threatening antidepressants such as tricyclic antidepressants and MAOIs.

• Monitoring for 24 hours is recommended for the delayed cardiotoxicity with citalopram or escitalopram as well as for delayed seizures following extended release bupropion ingestion.

• Drug interactions and adverse drug events are associated with serotonin reuptake inhibitors and may lead to acute life-threatening events, including serotonin toxicity.

• Serotonin toxicity can produce life-threatening hyperthermia and should be treated with aggressive cooling and sedation. Cyproheptadine may be useful in early cases, and neuromuscular blockade may be necessary in refractory cases.

References