There are individual and environmental risk factors for QTc prolongation including age over 65 years, female sex (longer QTc interval than men and twice the risk of drug-induced TdP), preexisting cardiovascular disease, congenital long QT syndrome (Jervell and Lange-Nielsen syndrome ), bradycardia (sinus bradycardia, second and third -degree atrioventricular block) and electrolyte disturbances (hypokalemia, hypomagnesemia). High plasma concentrations of the offending drug from overdose, rapid infusion of the drug, inhibition of drug metabolism by concomitantly administered drugs, and/or reduced drug clearance due to renal or hepatic insufficiency can also increase the risk for QTc prolongation (Wenzel-Seifert et al. 2011).
TdP typically presents as dizziness, seizures, and syncope. It can lead to ventricular fibrillation and sudden cardiac death. Prolonged QTc interval at baseline has been shown to be a risk factor for drug induced QT prolongation and life threatening arrhythmia (Shouten et al. 1991). Drugs that prolong the QT interval bind to cardiac potassium channels (IKr, also known as HERG channels). The resulting blockade of potassium efflux from cardiomyocytes prolongs the repolarization phase. In the congenital long-QT syndrome a mutation of the IKr gene causes prolongation of the QT interval.
There is considerable intra-individual variability of QTc. In a given individual QTc can vary from 76 to 102 millisecond (ms) over the course of 24 h (Wenzel-Seifert et al. 2011). In normal persons, the mean QTc length is roughly 400 ms. The upper limit of normal is defined as 460 ms for women, and 450 ms for men. A QTc interval >500 ms is considered to be a major risk factor for the development of TdP.
Among psychotropic medications thioridazine and ziprasidone have the highest risk of QTc prolongation (Wenzel-Seifert et al. 2011; Beach et al. 2013). Clinically significant risk is associated with haloperidol given intravenously in high doses. QTc prolongation has been reported with newer antipsychotic drugs (mainly quetiapine, risperidone, olanzapine, clozapine), most of the tricyclic and tetracyclic antidepressants, selective monoamine reuptake inhibitors—citalopram, fluoxetine, paroxetine, venlafaxine, and lithium. The risk of pathological QTc prolongation increases with the dose. Thioridazine, pimozide, sertindole, droperidol, and IV haloperidol have been documented to cause torsade de pointes and sudden death. There is no documented association with olanzapine, quetiapine, or risperidone and sudden death (Glassman and Bigger 2001). There are case reports of ziprasidone causing Tdp especially in overdose (Heinrich et al. 2006; Manini et al. 2007).
Individual risk in each patient should be carefully considered. Factors that can help to reduce the risk includes checking EKG for QTc before treatment in high risk patients, slow dose escalation in cases of altered elimination or inhibited metabolism, regular EKG monitoring of patients at high risk and those taking additional medications that can prolong the QTc interval, monitoring serum potassium and potential electrolyte loss in patients with vomiting, diarrhea, diuretic therapy, and eating disorders, and administration of magnesium sulfate if the QTc is markedly prolonged (Wenzel-Seifert et al. 2011). Discontinue psychotropic medication if the QTc is longer than 500 ms, Use alternate medication for agitation like benzodiazepines or anticonvulsants until QTc returns to normal.
8.7.5 Neurological Conditions
8.7.5.1 Cerebrovascular Disease
Patients with cerebrovascular disease are sensitive to the CNS side effects of psychotropic medications. Psychotropic drugs causing postural hypotension like TCAs and low potency typical antipsychotics should be avoided in patients with syncopal episodes. SSRIs are preferred in post-stroke depression. Studies on use of SSRIs on post stroke patients have shown improvement in global cognitive functioning, specifically in verbal and visual memory functions (Jorge et al 2010) and decrease in dependence, disability, neurological impairment, anxiety, and depression (Mead et al. 2012).
SSRI exposure is associated with an increased risk of intracerebral and intracranial hemorrhage especially in combination with anticoagulants (Hackam and Mrkobrada 2012).
8.7.5.2 Epilepsy
The prevalence of depression in patients with epilepsy ranges from 20 to 30 % in community samples to 50 to 55 % in epilepsy clinics (Jackson and Turkington 2005) with a 4–5 times increased risk of suicide in this population (Matthews and Barabas 1981).
All antidepressants and antipsychotics are known to lower seizure threshold. Seizure incidence rate ranges from approximately 0.1–1.5 % in patients treated with a therapeutic dose of these medications compared to the general population rate of 0.07–0.09 %. In overdose, the seizure risk increases to 4–30 % (Pisani et al. 2002). It is a dose-dependent adverse effect.
Risk factors for seizures include individual factors like inherited seizure threshold, history of seizures, brain injury, older age, and reduced drug clearance. Medication risk factors include higher dose, rate of upward titration of medication and sudden drug withdrawal. To reduce risk for seizures it is important to evaluate for these factors and start medication at a low dose with a slow escalation avoiding complex drug combinations (Pisani et al. 2002).
Psychotropic drugs with the highest seizure risk include bupropion, maprotiline, and clomipramine among antidepressants, and chlorpromazine and clozapine among antipsychotics. Antidepressants with lower seizure risk include phenelzine, tranylcypromine, fluoxetine, paroxetine, sertraline, trazadone, and venlafaxine. Fluphenazine, haloperidol, pimozide, and risperidone are among antipsychotics with the lowest seizure risk (Pisani et al. 2002).
8.7.5.3 Parkinson’s Disease (PD)
Neuropsychiatric symptoms are common in PD including depression, anxiety, apathy, fatigue, and cognitive impairment. Medications used for the treatment of PD can cause psychiatric symptoms including delusions, hallucinations, manic symptoms, impulsive behaviors, and agitation. These symptoms can affect the quality of life and daily functioning and place the patient at increased risk for nursing home placement. Depressive symptoms are present in 30–40 % of PD patients and 40 % of patients have anxiety symptoms (Aarsland et al. 2009).
Most antidepressants have been reported to be effective and well tolerated when used to treat depression and anxiety symptoms in PD. SSRIs can potentially have interaction with monoamine oxidase inhibitors used to treat PD like selegiline, with increased risk for serotonin syndrome. Benzodiazepines should be used with caution as they can increase the risk for falls and worsen cognitive, autonomic, and sleep related problems (Aarsland et al. 2009).
Apathy and fatigue are common symptoms in patients with Parkinson’s disease and can contribute significantly to disability. Apathy is seen in 17–70 % of patients with PD. Prevalence of fatigue is about 32–58 % which may predate the onset of motor symptoms and increase over time. Medications used to treat these symptoms have limited evidence of efficacy, including dopamine agonists, psychostimulants, and modafinil (Aarsland et al. 2009).
Psychotic symptoms occur frequently in patients with PD and may be accompanied by affective and behavioral symptoms. Conventional antipsychotics are not recommended for use in patients with PD, as they have been reported to significantly worsen the motor symptoms of PD. Clozapine has been shown to be effective for the treatment of psychosis in PD without aggravation of parkinsonian symptoms (Eng and Welty 2010). Even a low dose of clozapine, 50 mg or less, can significantly improve drug induced psychosis without worsening parkinsonism (The Parkinson study group 1999). Quetiapine has been frequently used to treat psychosis in PD and has shown some efficacy in open label trials, even though placebo controlled studies have shown conflicting results. One comparative study with clozapine showed no statistically significant difference in effectiveness compared to quetiapine (Shotbolt et al. 2010). Olanzapine has worsened parkinsonian symptoms in three trials (Weintraub and Hurtig 2007).
8.7.6 Diabetes Mellitus
Serotonin norepinephrine reuptake inhibitors (duloxetine, venlafaxine) provide benefit both for depression and diabetic neuropathic pain (Goldstein et al. 2005; Sindrup et al. 2005; Zin et al. 2008). TCAs can also help with the neuropathic pain but patients may be more vulnerable to the anticholinergic side effects, postural hypotension, and sexual dysfunction.
Use of atypical antipsychotics in diabetes should be weighed against the risk of metabolic syndrome with these drugs including weight gain, glucose intolerance, new onset type 2 diabetes mellitus, diabetic ketoacidosis, and hyperlipidemia. Clozapine and olanzapine have the highest risk and should be avoided in diabetics (Jin et al. 2004).
8.7.7 Psychotropics and the Syndrome of Inappropriate Release of Antidiuretic Hormone (SIADH)
Antidiuretic hormone (ADH) induces water retention in the distal tubule and collecting duct of the nephron. SIADH involves sustained release of ADH from the posterior pituitary or enhanced action of ADH on the kidneys. Increased ADH activity impairs kidney’s ability to dilute urine resulting in decreased excretion of ingested water and concentrated urine. If fluid intake is not reduced serum hypotonicity and hyponatremia will occur. Patient will present with normal volume status (euvolemia) because the excess water distributes evenly throughout the body’s fluid compartments. Common symptoms of SIADH include weakness, lethargy, headache, anorexia, and weight gain. Severe cases present with confusion, convulsions, coma, and death. The early symptoms are vague and nonspecific, and may mimic symptoms of psychiatric disorder (Spigset and Hedenmalm 1995).
SIADH is reported with all class of psychotropics except lithium, which was used in the past to treat SIADH. Risk factors for SIADH and hyponatremia with psychotropics include concomitant use of thiazide diuretics, female gender, older age, low BMI, first few weeks of treatment, polypharmacy, CYP3A4 interactions, basal low levels of sodium (hyponatremia), and hyperkalemia (Wilkinson et al. 1999; Madhusoodanan et al. 2002; Spigset and Hedenmalm 1997). There are a large number of reports of SIADH and hyponatremia associated with SSRI use, with the incidence varying from 0.5 to 32 % (Jacob and Spinler 2006). In a review of reported cases of hyponatremia and SIADH associated with SSRIs, fluoxetine was involved in about 75 % of the cases, paroxetine in about 12 %, sertraline and fluvoxamine in about 11 % of the cases. The median time to onset of hyponatremia was 13 days (range 3 to 120 days). Most (83 %) of the published cases involved patients 65 years of age or more (Liu et al. 1996). Elderly patients should be monitored closely in the first 4 weeks of SSRI therapy for clinical signs suggestive of hyponatremia.
Treatment of SIADH includes discontinuation of the offending drug, restriction of fluid intake, and in severe cases may require infusion of sodium chloride. If continued treatment with an antidepressant or antipsychotic is indicated, a drug with a different pharmacological profile should be chosen, and the serum sodium levels should be monitored closely. If treatment with the drug that caused SIADH must be continued, concomitant treatment with demeclocycline may reduce the tendency to hyponatremia.
8.7.8 Respiratory Illness
The prevalence of clinical anxiety ranges from 10 to 55 % among patients with COPD (Willgoss and Yohannes 2013). Prevalence of depressive symptoms is 2.5 times greater for patients with severe COPD than controls (van Manen et al. 2002).
Antidepressants (SSRIs and SNRIs) are indicated as first line agents for treating depression and anxiety in COPD patients. Benzodiazepines can significantly reduce the ventilatory response to hypoxia. This may precipitate respiratory failure in a patient with marginal respiratory reserve. Patients with severe bronchitis (“blue bloaters”), severe restrictive lung disease, and sleep apnea are most vulnerable to the adverse effects of benzodiazepines. Antipsychotics in small doses are safer alternatives to benzodiazepines for treating acute anxiety in COPD but their potential neurological and cardiovascular side effects should be considered before use in medically ill patients. Non-pharmacological interventions like cognitive behavior therapy, pulmonary rehabilitation, relaxation therapy, and palliative care have shown to reduce depression and anxiety and improve quality of life in patients with COPD (Cafarella et al. 2012; Mikkelsen et al. 2004).
8.8 Psychotropic Drug Induced Medical Emergencies
8.8.1 Neuroleptic Malignant Syndrome (NMS)
NMS is a rare, idiosyncratic, life threatening complication of treatment with antipsychotic drugs. It is characterized by fever, severe muscle rigidity, autonomic dysfunction, and mental status changes. Recent data suggest an incidence of 0.01–0.02 % (Stubner et al. 2004). NMS remains a significant source of morbidity and mortality (10 %) in patients on antipsychotics if unrecognized and untreated.
Risk factors associated with increased incidence of NMS include agitation, dehydration, restraint, preexisting brain pathology, malnutrition, and iron deficiency (Rosebush et al. 1991). In 15–20 % of cases a prior episode of NMS is described (Caroff and Mann 1993). Pharmacologic variables that increase the risk include exposure to drugs that block dopamine D2 receptors. NMS has been reported in non-psychiatric patients treated with dopamine antagonists like prochlorperazine and metoclopramide. Withdrawal of dopaminergic agents like l-dopa can precipitate NMS like reaction. High potency conventional antipsychotics are associated with the greatest risk compared to low potency and atypical antipsychotics. Higher dosage and rapid dose escalation, depot neuroleptics, and more than one antipsychotic (33 % increased risk) are other factors found to increase the risk for NMS (Keck et al. 1989).
8.8.1.1 Clinical Features
The signs and symptoms useful to make the diagnosis of NMS include recent exposure to dopamine antagonists, or dopamine agonist withdrawal; hyperthermia >100.4 °F or >38.0 °C on at least two occasions; rigidity; mental status alteration; creatine kinase elevation at least four times the upper limit of normal; sympathetic nervous system lability; tachycardia plus tachypnea; and a negative workup for other causes (Gurrera et al. 2011).
Clinical Course: Onset is related to the initiation of neuroleptic treatment. Progression of symptoms is usually insidious over days. There are occasional cases of fulminant onset within hours of drug administration. Alteration in mental status and other neurological signs precede systemic signs in more than 80 % of cases of NMS (Velamoor et al. 1994).
Laboratory investigations are essential to rule out other disorders or complications. Abnormal laboratory findings seen in NMS, although not specific for the diagnosis, include elevated creatine phosphokinase (CPK), leukocytosis, elevated transaminases, and low serum iron.
Complications include metabolic acidosis, respiratory failure, irreversible brain damage, pulmonary embolus, electrolyte disturbances, coagulopathy, rhabdomyolysis, and renal failure.
Once NMS is diagnosed and oral antipsychotic drugs are discontinued, it is self-limited in most cases. The mean recovery time after drug discontinuation is about 7–10 days. The duration of NMS episode may be prolonged when long acting depot antipsychotics are implicated.
Risk factors for increased mortality include older age, higher temperatures, depot neuroleptics, preexisting brain pathology, and development of renal failure.
8.8.1.2 Management of NMS
Early diagnosis and discontinuation of the offending agent including antipsychotics, lithium, and all dopamine blocking agents including antiemetics, and initiating supportive medical therapy is the mainstay in the management of NMS. Supportive measures include serial monitoring of CPK and electrolytes, aggressive volume resuscitation, physical cooling measures for extreme hyperthermia, and antihypertensives or pressors for autonomic instability. Intensive medical care should include careful monitoring for complications including cardiorespiratory failure, renal failure, aspiration pneumonia, and coagulopathies. Benzodiazepines do not have a preventive effect but they may ameliorate symptoms and hasten recovery in milder cases. In patients with more severe symptoms not responding to supportive measures, dantrolene (1–10 mg/kg/day in divided doses), bromocriptine (2.5–15 mg tid), or amantadine (200–400 mg/day) have been reported to reduce time to recovery and decrease mortality. ECT may be effective if symptoms are refractory to supportive care and pharmacotherapy, even late in the course of NMS, and in patients with severe rigidity and catatonia (Strawn et al 2007)
8.8.1.2.1 Guidelines for Treatment (Strawn et al. 2007)
Mild or early NMS: Discontinue antipsychotics, use supportive measures and benzodiazepines
Moderate NMS (rigidity and temperatures 38–40 °C, HR 100–120 bpm): Discontinue antipsychotics, use supportive measures, and use benzodiazepines or amantadine or bromocriptine.
Severe NMS: (severe rigidity, catatonia, temp >40, HR > 120 bpm) Discontinue antipsychotics, use supportive measures and use dantrolene or bromocriptine or amantadine. Consider ECT.
8.8.1.2.2 Guidelines for Rechallenge
There is a 30 % risk of recurrence following subsequent rechallenge with antipsychotics (Pope et al. 1991). At least 2 weeks after recovery from NMS should be allowed before rechallenge with antipsychotics. Reduce potential risk factors and consider alternate medications. Low doses of low potency typical antipsychotics or atypical antipsychotics should be titrated gradually after a test dose. Patients should be carefully monitored for early signs of NMS. Ideally, rechallenge should occur in a hospital.
8.8.2 Serotonin Syndrome (SS)
Serotonin syndrome is a potentially life threatening adverse reaction resulting from therapeutic drug use, intentional or accidental overdose of drug or from interactions between drugs that result in excess of serotonergic agonism of the central and peripheral serotonergic receptors. The serotonin syndrome can range from mild to moderate to lethal. Differentiating serotonin syndrome from neuroleptic malignant syndrome can be difficult in a patient receiving both serotonergic and antipsychotic medications.
Overstimulation of serotonin receptors can be caused by precursors of serotonin or by serotonin agonists like buspirone, l-dopa, lithium, LSD, l-tryptophan, and trazodone, from decreased serotonin metabolism from MAOIs, from increased serotonin release from amphetamines, cocaine, MDMA (“ecstasy”), fenfluramine, or from inhibition of serotonin reuptake from antidepressants, meperidine, and tramadol.
8.8.2.1 Clinical Features
The symptoms and signs of serotonin syndrome include (Boyer and Shannon 2005):
1.
Neuromuscular symptoms: Delirium, agitation, anxiety, irritability, affective instability, restlessness, ataxia/incoordination, muscle rigidity, myoclonus, tremor, hypereflexia, clonus, trismus, teeth chattering, seizures.
2.
Gastrointestinal symptoms: Nausea, vomiting, diarrhea, incontinence.
3.
Autonomic symptoms: Hypertension, hypotension, tachycardia, diaphoresis, shivering, sialorrhea, mydriasis, tachypnea.
4.
Hyperthermia.
Differential diagnosis for serotonin syndrome includes infections, toxic-metabolic delirium, alcohol withdrawal delirium, extrapyramidal side-effects, adrenergic or anticholinergic toxicity, neuroleptic malignant syndrome, malignant hyperthermia, pheochromocytoma, and carcinoid tumor.
Clinical course and outcome: Symptom onset is rapid, usually developing within 6 h of an increase or addition of a serotonergic agent and typically resolves within 24 h (Iqbal et al. 2012). Patients with mild SS may present with chronic or subacute symptoms. Serotonin syndrome is usually self-limited, with an uneventful resolution, once the offending agent has been discontinued.
Nonspecific laboratory findings may include elevated total white blood cell count, CPK levels, transaminases, and decreased serum bicarbonate level. Severe cases can result in complications like disseminated intravascular coagulation, rhabdomyolysis, metabolic acidosis, renal failure, myoglobinuria, and adult respiratory distress syndrome.
8.8.2.2 Management of SS
Discontinuation of serotonergic agents, supportive measures including intravenous fluids, cooling blankets, treating autonomic dysfunction usually reverses the symptoms in mild cases. Benzodiazepines can be used to treat tremors and agitation. In more severe cases, serotonin antagonists—cyproheptadine and chlorpromazine, have shown to reverse the symptoms (Gillman 1999; Graudins et al. 1998). Cyproheptadine, 4–8 mg orally or through the nasogastric tube, repeated every 6 h up to a maximum of 32 mg/day has produced rapid resolution of symptoms. Antipsychotic agents with 5-HT2A antagonist activity such as chlorpromazine may reverse the symptoms in severe cases of SS. Chlorpromazine should not be routinely used to manage SS, especially if the patient is hypotensive and/or NMS cannot be excluded (Iqbal et al 2012).
Related posts:
The Why and How of Psychiatric Consultation
Interviewing in Consultation-Liaison Psychiatry
Anxiety and Anxiety Disorders
Dissociative Disorders
The Renal Dialysis and Kidney Transplant Patient
Obstetrics and Gynecology Patients: Menstrual Cycle, Pregnancy, and Postpartum-Related Psychiatric Disorders
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
