Psychiatric disease, substance use disorders, and drug overdose

SSRIs.

Serotonin is produced by hydroxylation and decarboxylation of l-tryptophan in presynaptic neurons, then stored in vesicles that are released and bound to postsynaptic receptors when needed for neurotransmission. A reuptake mechanism allows for return of serotonin to the presynaptic vesicles. Metabolism is by MAO type A. Serotonin-specific reuptake inhibitors, as their name implies, inhibit reuptake of serotonin from the neuronal synapse without having significant effects on reuptake of norepinephrine and/or dopamine.

SSRIs comprise the most widely prescribed class of antidepressants and are the drugs of choice to treat mild to moderate depression. These drugs are also effective for treating panic disorders, posttraumatic stress disorder, bulimia, dysthymia, obsessive-compulsive disorder, and irritable bowel syndrome. Common side effects include insomnia, agitation, headache, nausea, diarrhea, dry mouth, and sexual dysfunction. Appetite suppression is associated with fluoxetine therapy, though this effect is usually transient. Abrupt cessation of SSRI use, especially use of paroxetine and fluvoxamine, which have short half-lives and no active metabolites, can result in a discontinuation syndrome that can mimic serious illness and can be distressing and uncomfortable. Discontinuation symptoms typically begin 1 to 3 days after abrupt cessation of SSRI use and may include dizziness, irritability, mood swings, headache, nausea and vomiting, dystonia, tremor, lethargy, myalgias, and fatigue. Symptoms are relieved within 24 hours of restarting SSRI therapy.

Among SSRIs, fluoxetine is a potent inhibitor of certain hepatic cytochrome P450 enzymes. As a result, this drug may increase plasma concentrations of drugs that depend on hepatic metabolism for clearance. For example, addition of fluoxetine to treatment with tricyclic antidepressant drugs may result in twofold to fivefold increases in plasma concentrations of tricyclic drugs. Some cardiac antidysrhythmic drugs and some β-adrenergic antagonists are also metabolized by this enzyme system, and fluoxetine inhibition of enzyme activity may result in potentiation of their effects.

Serotonin syndrome.

Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur with therapeutic drug use, overdose, or interactions between serotoninergic drugs. A large number of drugs have been associated with serotonin syndrome. These include SSRIs, atypical and cyclic antidepressants, MAOIs, opiates, cough medicine, antibiotics, antiemetic drugs, antimigraine drugs, drugs of abuse (especially Ecstasy), and herbal products ( Table 29.3 ).

Typical symptoms of serotonin syndrome include agitation, delirium, autonomic hyperactivity, hyperreflexia, clonus, and hyperthermia ( Fig. 29.2 ). Additional syndromes to consider in the differential diagnosis of serotonin syndrome are listed in Table 29.4 . Treatment includes supportive measures and control of autonomic instability, excess muscle activity, and hyperthermia. Cyproheptadine, a 5-hydroxytriptamine (serotonin) type 2A (5-HT _2A ) antagonist, can be used to compete for and bind to serotonin receptors. It is available only for oral use.

Monoamine oxidase inhibitors.

Patients whose depression does not respond to other antidepressant drugs may benefit from treatment with MAOIs. MAOIs inhibit norepinephrine and serotonin and tyramine breakdown, so there is more norepinephrine and serotonin available for release. Selegiline is a subtype A MAOI that is reversible and specifically catabolizes serotonin, norepinephrine, and tyramine, the substances most directly linked to MAOI antidepressant activity. It is used in a transdermal preparation that limits enterohepatic MAO inhibition and may help eliminate the need for dietary tyramine restriction.

The principal clinical problems associated with use of MAOIs, especially the nonselective irreversible forms, include the need for dietary restrictions, the potential for drug interactions, and adverse side effects. Probably the most dreaded occurrence is very significant systemic hypertension if patients ingest foods containing tyramine (cheeses, wines) or receive sympathomimetic drugs. Both tyramine and sympathomimetic drugs are potent stimuli for norepinephrine release. Interestingly, however, orthostatic hypotension is the most common adverse effect observed in patients being treated with MAOIs ( Table 29.5 ). The mechanism for this hypotension is unknown, but it may involve accumulation of false neurotransmitters such as octopamine that are less potent than norepinephrine. This mechanism may also explain the antihypertensive effects observed with long-term use of MAOIs.

Adverse interactions between MAOIs and serotoninergic drugs have been observed. In the anesthetic environment the interaction between MAOIs and the opioid meperidine has been the most notable.

Management of anesthesia.

Anesthesia can be safely conducted in patients being treated with MAOIs despite earlier recommendations that these drugs be discontinued 14 days before elective surgery to permit time for regeneration of new enzyme. Proceeding with anesthesia and surgery in patients being treated with MAOIs influences selection and doses of drugs to be administered. Benzodiazepines are acceptable for pharmacologic treatment of preoperative anxiety. Induction of anesthesia can be safely accomplished with most intravenous (IV) induction agents, but it should be kept in mind that CNS effects and depression of ventilation may be exaggerated. Ketamine, a sympathetic stimulant, should be avoided. Serum cholinesterase activity may decrease in patients treated with phenelzine, so the dose of succinylcholine may need to be reduced. A volatile anesthetic with or without nitrous oxide is acceptable for maintenance of anesthesia. Anesthetic requirements may be increased because of increased concentrations of norepinephrine in the CNS. Fentanyl has been administered intraoperatively to patients being treated with MAOIs without apparent adverse effects. The choice of nondepolarizing muscle relaxants is not influenced by treatment with MAOIs. Spinal or epidural anesthesia is acceptable, although the potential of these anesthetic techniques to produce hypotension and the consequent need for vasopressors may argue in favor of general anesthesia. Addition of epinephrine to local anesthetic solutions should probably be avoided.

During anesthesia and surgery, it is important to avoid stimulating the sympathetic nervous system as, for example, by light anesthesia, topical application of cocaine spray, or injection of indirect-acting vasopressors to decrease the incidence of systemic hypertension. If hypotension occurs and vasopressors are needed, use of a direct-acting drug such as phenylephrine is recommended. The dose should probably be decreased to minimize the likelihood of an exaggerated hypertensive response.

Postoperative care.

Provision of analgesia during the postoperative period is influenced by the potential adverse interactions between opioids, especially meperidine and MAOIs, which can result in serotonin syndrome. If opioids are needed for postoperative pain management, morphine is a preferred drug. Alternatives to opioid analgesics such as nonopioid analgesics, nonsteroidal antiinflammatory drugs (NSAIDs), and peripheral nerve blocks should be considered. Neuraxial opioids provide effective analgesia, but experience is too limited to permit recommendations regarding use of this approach in patients being treated with MAOIs.

Nonpharmacologic treatments of depression.

For patients who do not respond well to antidepressant drug therapy, there are several forms of treatment for severe depression that do not include antidepressant medications but rather rely on various forms of brain stimulation. At the present time these alternatives include transcranial magnetic stimulation and ECT. Magnetic seizure therapy (MST) is in investigational trials.

Repetitive transcranial magnetic stimulation (rTMS) uses a magnet instead of electric current to activate the brain. An electromagnetic coil is placed against the forehead near the region of the brain thought to be involved in regulation of mood ( Fig. 29.3 ). Then short electromagnetic impulses are administered through the coil. These cause small electric currents that stimulate cells in the targeted region. The impulses can apparently not travel farther than about 2 inches from the point of origin, so the treatment is localized to the area of interest, which is typically the left or right prefrontal cortex. The impulses have about the same strength as those in use during an magnetic resonance imaging (MRI) exam. A major advantage of this treatment is that anesthesia is not needed. Most complications consist of headaches and scalp discomfort. In 2008, the US Food and Drug Administration (FDA) approved rTMS for treatment of depression in patients who have failed treatment with at least one antidepressant medication.

MST uses elements of both rTMS and ECT. It uses a magnetic pulse instead of electricity to stimulate a target area in the brain, but it uses a higher frequency of electromagnetic stimulation, with the aim of inducing a seizure. Because of this, an anesthetic is required in a manner similar to that needed for ECT. There is some evidence that MST may reduce the incidence and severity of cognitive side effects compared to traditional ECT.

Despite many decades of use of ECT, the exact mechanism for its therapeutic effect remains unknown. Alterations in neurophysiologic, neuroendocrine, and neurochemical systems are thought to be involved but have not been clearly elucidated. What is evident is that electrically induced seizures of at least 25 sec duration are necessary for a therapeutic effect. ECT is indicated for treatment of severe depression in patients who show no response to drug therapy, cannot tolerate the adverse effects of psychotropic drug therapy, or are suicidal. The electric current may be administered to both hemispheres or only to the nondominant hemisphere (which may reduce memory impairment). The electrical stimulus produces a grand mal seizure consisting of a brief tonic phase followed by a more prolonged clonic phase. The electroencephalogram shows changes similar to those present during spontaneous grand mal seizures. Typically patients undergo 6 to 12 induction treatments during hospitalization and then may continue weekly, biweekly, or monthly maintenance therapy. More than two-thirds of patients receiving ECT show significant improvement in their depressive symptoms.

In addition to the seizure and its neuropsychiatric effects, ECT produces significant cardiovascular and CNS effects ( Table 29.6 ). The typical cardiovascular response to the ECT stimulus consists of 10 to 15 sec of parasympathetic stimulation producing bradycardia with a reduction in blood pressure, followed by sympathetic nervous system activation resulting in tachycardia and hypertension lasting several minutes. These changes may be undesirable in patients with ischemic heart disease. Indeed, the most common causes of death associated with ECT are myocardial infarction and cardiac dysrhythmias, although overall mortality rates are extremely low, approximately 1 in 5000 treatments. Transient myocardial ischemia, however, is not an uncommon event. Other cardiovascular changes in response to ECT include decreased venous return caused by the increased intrathoracic pressure that accompanies the seizure and/or positive pressure ventilation and ventricular premature beats that presumably reflect excess sympathetic nervous system activity. Patients with acute coronary syndromes, decompensated congestive heart failure, significant dysrhythmias, and severe valvular heart disease require cardiologic consultation prior to initiation of ECT.

Cerebrovascular responses to ECT include marked increases in cerebral blood flow (up to sevenfold) and cerebral blood flow velocity (more than double) compared with pretreatment values. Cerebral oxygen consumption increases as well. The rapid increase in systemic blood pressure may transiently overwhelm cerebral autoregulation and result in a dramatic increase in intracranial pressure. Thus the use of ECT is prohibited in patients with known space-occupying lesions or head injury. The cerebral hemodynamic changes are also associated with increased wall stress on cerebral aneurysms, and intracranial aneurysm disease is another contraindication to ECT.

Increased intraocular pressure is an inevitable side effect of electrically induced seizures. Increased intragastric pressure also occurs during seizure activity. Transient apnea, postictal confusion or agitation, nausea and vomiting, and headache may follow the seizure. The most common long-term effect of ECT is memory impairment.

Management of anesthesia.

Anesthesia for ECT must be brief, provide the ability to monitor and limit the physiologic effects of the seizure, and minimize any interference with seizure activity or duration. Patients must fast before the procedure. IV administration of glycopyrrolate 1 to 2 min before induction of anesthesia and delivery of the electric current may be useful in decreasing excessive salivation and bradycardia. The magnitude of treatment-induced hypertension can be ameliorated with use of nitroglycerin intravenously, sublingually, or transdermally. Likewise, esmolol 1 mg/kg IV administered just before induction of anesthesia can attenuate the tachycardia and hypertension associated with ECT, and it does so better than labetalol. Many other drugs, including calcium channel blockers, ganglionic blockers, α ₂ -agonists and antagonists, and direct-acting vasodilators, have been used to treat the sympathetic overactivity during ECT, but they do not appear to offer any specific advantages over esmolol or nitroglycerin therapy.

Methohexital (0.5–1 mg/kg IV) is the traditional drug used for induction of anesthesia for ECT. It has a rapid onset, short duration of action, minimal anticonvulsant effects, and rapid recovery. Because of shortages of barbiturates in the United States, other induction drugs are now commonly used for ECT. Propofol is an alternative to methohexital and is associated with a lower blood pressure and heart rate response to ECT. Recovery time is similar after administration of methohexital and propofol, but the anticonvulsant effect of propofol can be manifested as a shortened seizure duration. Ketamine and etomidate improve the quality and duration of the electrically induced seizure, but ketamine is associated with a prolonged reorientation time after the procedure, and etomidate is associated with more hypertension after the seizure and the possibility of spontaneous seizures before the electrical stimulus is delivered.

IV injection of succinylcholine promptly after induction is intended to attenuate the potentially dangerous skeletal muscle contractions and bone fractures that can result from seizure activity. Doses of 0.3 to 0.5 mg/kg IV are sufficient to attenuate skeletal muscle contractions and still permit visual confirmation of seizure activity. The most reliable method to confirm electrically induced seizure activity is the electroencephalogram. Alternatively, tonic and clonic movements in an extremity that has been isolated from the circulation by applying a tourniquet before administration of succinylcholine are evidence that a seizure has occurred. Succinylcholine-induced myalgias are remarkably uncommon, occurring in only about 2% of patients undergoing ECT. There is no evidence that succinylcholine-induced release of potassium is increased by ECT. Ventilatory support and oxygen supplementation are continued as necessary until there is complete recovery to pretreatment cardiopulmonary status. Because repeated administration of anesthetics is necessary, it is possible to establish the exact doses of the anesthetic induction drug and succinylcholine that produce the most predictable and desirable effects in each patient.

Occasionally ECT is necessary in a patient with a permanent cardiac pacemaker or cardioverter-defibrillator. Fortunately most of these devices are shielded and not adversely affected by the electric currents necessary to produce seizures, but it is prudent to have a magnet available to ensure the pacemaker can be converted to an asynchronous mode should malfunction occur in response to the delivered electric current or to myopotentials from the succinylcholine or the seizure. Monitoring the electrocardiogram (ECG) and the plethysmographic waveform of the pulse oximeter and palpation of peripheral arterial pulses will document uninterrupted function of a cardiac pacemaker. Implantable cardioverter-defibrillators should be turned off before ECT and reactivated when the treatment is finished.

Safe and successful use of ECT has been described in patients following cardiac transplantation. In such patients, lack of vagal innervation to the heart eliminates the risk of bradydysrhythmias. However, the sympathetic responses still occur.

Lithium.

Lithium is an alkali metal, a monovalent cation, and is minimally protein bound. It does not undergo biotransformation and is excreted by the kidneys. Lithium is efficiently absorbed after oral administration. Its therapeutic serum concentration for acute mania and for prophylaxis is approximately 0.8 to 1.2 mEq/L. Because of this narrow therapeutic window, the serum lithium concentration must be monitored to prevent toxicity. The therapeutic effects of lithium are most likely related to actions on second-messenger systems based on phosphatidylinositol turnover. Lithium also affects transmembrane ion pumps and has inhibitory effects on adenylate cyclase.

Common adverse effects of lithium therapy include cognitive dysfunction, weight gain, and tremor. Lithium inhibits release of thyroid hormone and results in hypothyroidism in about 5% of patients. Long-term administration of lithium may also result in polyuria due to a form of vasopressin-resistant diabetes insipidus. Cardiac problems may include sinus bradycardia, sinus node dysfunction, atrioventricular block, T-wave changes, and ventricular irritability. Leukocytosis in the range of 10,000 to 14,000 cells/mm ³ is common.

Toxicity occurs when the serum lithium concentration exceeds 2 mEq/L, with signs of skeletal muscle weakness, ataxia, sedation, and widening of the QRS complex. Atrioventricular heart block, hypotension, and seizures may accompany severe lithium toxicity. Hemodialysis may be necessary in this medical emergency.

Lithium is excreted entirely by the kidneys. Reabsorption of lithium occurs in the proximal tubule in exchange for sodium, so diuretic use can affect the serum lithium concentration. Thiazide diuretics trigger an increase in lithium reabsorption in the proximal tubule, whereas loop diuretics do not promote lithium reabsorption. Administration of sodium-containing solutions or osmotic diuretics enhances renal excretion of lithium and results in lower lithium levels. Concomitant administration of NSAIDs and/or angiotensin-converting enzyme (ACE) inhibitors increases the risk of lithium toxicity.