Side effects and its countermeasures of antidepressant

We reviewed the side effects of antidepressants. Tricyclic antidepressants(TCAs) are associated with a higher frequency of adverse events than those of SSRIs and SNRIs, particularly with respect to anticholinergic-like effects(dry mouth, constipation, and blurred vision), delirium, and cardiovascular adverse events. On the other hand, SSRIs have some special side effects that include nausea, sexual dysfunction, and extrapyramidal symptoms. With regard to milnacipran, a member of the SNRI family, dysuria occurs at a higher frequency than with TCAs or SSRIs. When side effects occur, clinicians give patients symptomatic treatment or substitute the drugs that cause the adverse effects with other antidepressants that have different pharmacological effects.     

Antidepressants for chronic neuropathic pain

Tricyclic antidepressants have been used to manage pain for several decades, and are superior treatments for some patients suffering from neuropathic pain. Unfortunately, older antidepressants have dose-limiting side effects that can lead to drug intolerance. The most common are anticholinergic side effects, although some patients experience sexual dysfunction. Cognitive impairment, sedation, and orthostatic hypotension also are relatively common. Taking an overdose of tricyclic antidepressants can be lethal in overdose. Several weeks of therapy may be required before antinociception occurs, but tricyclic antidepressants in optimal doses appear to be the most effective treatment for neuropathic pain; this is supported by systematic reviews comparing them with other agents. Newer medications such as atypical antidepressants and anticonvulsants may be overtaking older antidepressants, but they should not be overlooked as important options for the management of pain.     

Review of pharmacological efficacies and side effects of antidepressants

We reviewed the pharmacological efficacies and side effects of antidepressants. Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs) are most popularly prescribed for anxiety disorders as well as mild or moderate depression. These drugs have less orthostatic, cognitive, cardiovascular, and anticholinergic side effects. Tricyclic antidepressants are still important for treating severe depression, and mianserin and trazodone are useful for treating delirium. Clinicians should select antidepressants considering their pharmacologic profiles and avoiding adverse effects.     

Antidepressants and antiepileptic drugs for chronic non-cancer pain

The development of newer classes of antidepressants and second-generation antiepileptic drugs has created unprecedented opportunities for the treatment of chronic pain. These drugs modulate pain transmission by interacting with specific neurotransmitters and ion channels. The actions of antidepressants and antiepileptic drugs differ in neuropathic and non-neuropathic pain, and agents within each medication class have varying degrees of efficacy. Tricyclic antidepressants (e.g., amitriptyline, nortriptyline, desipramine) and certain novel antidepressants (i.e., bupropion, venlafaxine, duloxetine) are effective in the treatment of neuropathic pain. The analgesic effect of these drugs is independent of their antidepressant effect and appears strongest in agents with mixed-receptor or predominantly noradrenergic activity, rather than serotoninergic activity. First-generation antiepileptic drugs (i.e., carbamazepine, phenytoin) and second-generation antiepileptic drugs (e.g., gabapentin, pregabalin) are effective in the treatment of neuropathic pain. The efficacy of antidepressants and antiepileptic drugs in the treatment of neuropathic pain is comparable; tolerability also is comparable, but safety and side effect profiles differ. Tricyclic antidepressants are the most cost-effective agents, but second-generation antiepileptic drugs are associated with fewer safety concerns in elderly patients. Tricyclic antidepressants have documented (although limited) efficacy in the treatment of fibromyalgia and chronic low back pain. Recent evidence suggests that duloxetine and pregabalin have modest efficacy in patients with fibromyalgia.     

Quetiapine cross-reactivity with plasma tricyclic antidepressant immunoassays

BACKGROUND: Toxicology screens obtained on patients who have overdosed on drugs frequently include tricyclic antidepressants (TCAs) as part of the evaluation. Quetiapine is an antipsychotic agent with structural similarity to the TCAs. OBJECTIVE: To determine whether quetiapine may cross-react with plasma TCA immunoassays in vitro using commonly available autoanalyzers. METHODS: Quetiapine stock solution was added to 9 separate samples of pooled drug-free human plasma to produce concentrations ranging from 1 to 640 ng/mL that were verified by gas chromatography. No quetiapine metabolites were present. Each spiked plasma sample was tested in a blinded fashion using the Abbott Tricyclic Antidepressant TDx Assay on the TDxFLx autoanalyzer in 2 separate laboratories, the Syva Emit tox Serum Tricyclic Antidepressant Assay on the AU400 autoanalyzer and the S TAD Serum Tricyclic Antidepressant Screen on the ACA-Star 300 autoanalyzer. The TDx assay is quantitative, while Emit and S TAD are qualitative screening assays with a threshold of 300 ng/mL for TCA positivity. The outcome of interest was a positive TCA result. RESULTS: The quantitative assay showed concentration-related TCA cross-reactivity beginning at quetiapine concentrations of 5 ng/mL. The 640-ng/mL spiked sample produced TCA results of 379 and 385 ng/mL in labs 1 and 2, respectively. The qualitative assays were screened as TCA positive at quetiapine concentrations of 160 and 320 ng/mL for the S TAD and Emit assays, respectively. CONCLUSIONS: Quetiapine cross-reacts with quantitative and qualitative plasma TCA immunoassays in a concentration-dependent fashion. Therapeutic use or overdose of quetiapine may result in a false-positive TCA immunoassay result.     

Inhibition of 22Na influx by tricyclic and tetracyclic antidepressants and binding of [3H]imipramine in bovine adrenal medullary cells

In bovine adrenal medullary cells we investigated the effects of antidepressants on ionic channels and secretion of catecholamines. Tricyclic (imipramine, amitriptyline and nortriptyline) and tetracyclic (maprotiline and mianserin) antidepressants inhibited carbachol-induced influx of 22Na, 45Ca and secretion of catecholamines (IC50, 14-96 microM). Influx of 22Na, 45Ca and secretion of catecholamines due to veratridine also were inhibited by these drugs (IC50, 10-17 microM). However, antidepressants did not suppress high concentration of K-induced 45Ca influx and catecholamine secretion, suggesting that antidepressants do not inhibit voltage-dependent Ca channels. [3H]Imipramine bound specifically to adrenal medullary cells. Binding was saturable, reversible and with two different equilibrium dissociation constants (13.3 and 165.0 microM). Tricyclic and tetracyclic antidepressants competed for the specific binding of [3H]imipramine at the same concentrations as they inhibited 22Na influx caused by carbachol or veratridine. Carbachol, d-tubocurarine, hexamethonium, tetrodotoxin, veratridine and scorpion venom did not inhibit the specific binding of [3H]imipramine. These results suggest that tricyclic and tetracyclic antidepressants bind to two populations of binding sites which are functionally associated with nicotinic receptor-associated ionic channels and with voltage-dependent Na channels, and inhibit Na influx. Inhibition of Na influx leads to the reduction of Ca influx and catecholamine secretion caused by carbachol or veratridine.     

Tricyclic antidepressant poisoning

Tricyclic antidepressant poisoning causes predictable electrocardiographic abnormalities and can be lethal. Cardiac arrhythmias, hypotension, seizures, and coma are common. Sodium bicarbonate is still considered the treatment of choice for severe toxicity, although a variety of supportive measures may be taken. Hypertonic saline appears to be a promising alternative. A QRS interval longer than 100 ms appears to be a better predictor of serious complications than is an elevated serum tricyclic antidepressant level. Cardiovascular toxicity is classically manifested as ventricular dysrhythmias, hypotension, heart block, bradyarrhythmias, or asystole. Activated charcoal binds tricyclic antidepressants. Give 30 to 50 g orally or by nasogastric tube with or without a cathartic (sorbitol 0.5 g/kg or 30 g of magnesium sulfate). Sodium bicarbonate is indicated if the QRS duration is more than 100 ms or the terminal right-axis deviation is more than 120 degrees. The suggested dosage is 1 to 2 mEq/kg, repeated as needed. Tricyclic antidepressants are used not only for depression but also for chronic pain syndromes, obsessive-compulsive disorder, panic and phobic disorders, eating disorders, migraine prophylaxis, and peripheral neuropathies.     

Tricyclic antidepressant overdose at Westmead and Mount Druitt Hospitals

Tricyclic antidepressants are frequently taken in overdose and may be lethal. In this study, over nearly four years, there was only one death from tricyclic antidepressant overdose at the Westmead Hospital, that patient being transferred comatose and probably brain-dead after a cardiac arrest at another hospital. The pharmacology of tricyclic antidepressants is reviewed and recommendations are made for the treatment of overdose.     

Depression and the cardiovascular system: increasing evidence of a link and therapeutic implications

This review explores the epidemiological evidence for the relationship between depression and cardiovascular disease from a mechanistic standpoint. It is important to examine the biological, behavioral and social mechanisms to improve outcomes for depressed cardiac patients. A number of plausible biobehavioral mechanisms linking depression and cardiovascular disease have been identified. Tricyclic antidepressants have various effects on the cardiovascular system, while selective serotonin reuptake inhibitors are not associated with adverse cardiac effects and should, therefore, be the preferred choice for the treatment of most patients with comorbid depression and cardiovascular disease.     

Bupropion does not antagonize cardiovascular actions of clonidine in normal subjects and spontaneously hypertensive rats

Tricyclic antidepressants (TADs) are known to antagonize the hypotensive and sedative actions of clonidine. We compared the effects of bupropion and imipramine pretreatment on the acute hypotensive and sedative actions of clonidine in eight normotensive male subjects in a randomized, double-blind crossover study. Pretreatment with bupropion, 100 mg by mouth three times a day for 9 days, had no effect on baseline supine blood pressure (BP) and heart rate (HR) and did not modify the hypotensive, bradycardic, and sedative actions of clonidine. Imipramine, 25 mg by mouth three times a day for 9 days, increased supine and standing HR and decreased standing systolic BP. In half the subjects the hypotensive action of clonidine was reduced 40% to 50% by imipramine. The specific binding of 3H-yohimbine to alpha 2-receptors of platelet membranes was not affected by pretreatment with either antidepressant. In spontaneously hypertensive rats, 16 days of bupropion, 25 mg/kg subcutaneously, had no effect on baseline BP and HR and did not antagonize the hypotensive and bradycardic effects of clonidine, 5 mg/kg iv. Pretreatment with desipramine, 5 mg/kg subcutaneously for 16 days, accelerated baseline HR and reduced cardiovascular actions of clonidine. These observations suggest that not all antidepressants antagonize the effects of clonidine. If the negative interaction between TADs and clonidine is a result of sensitivity of alpha 2-receptors, these receptor changes are not the common denominator of antidepressant activity and may only be seen with TADs.     

Sodium Channel Blockade May Contribute to the Analgesic Efficacy of Antidepressants

Sodium channel blockers such as lidocaine, lamotrigine, and carbamazepine can be effective in the treatment of neuropathic pain. Though not approved for neuropathic pain indications, tricyclic antidepressants are often considered first-line treatment for conditions such as post-herpetic neuralgia and diabetic neuropathy. Several tricyclic antidepressants have been shown to block peripheral nerve sodium channels, which may contribute to their antihyperalgesic efficacy. In this study, we compared the sodium channel–blocking potency of a number of antidepressants, including tricyclic antidepressants and selective serotonin reuptake inhibitors. All compounds tested inhibited Na_V1.7 in a state- and use-dependent manner, with affinities for the inactivated state ranging from 0.24 μmol/L for amitriptyline to 11.6 μmol/L for zimelidine. The tricyclic antidepressants were more potent blockers of Na_V1.7. Moreover, IC₅₀s for block of the inactivated state for amitriptyline, nortriptyline, imipramine, desipramine, and maprotiline were in the range of therapeutic plasma concentrations for both the treatment of depression as well as neuropathic pain. By contrast, fluoxetine, paroxetine, mianserine, and zimelidine had IC₅₀s for Na_V1.7 outside their therapeutic concentration ranges and generally were not efficacious against post-herpetic neuralgia or diabetic neuropathy. These results suggest that block of peripheral nerve sodium channels may contribute to the antihyperalgesic efficacy of certain antidepressants.PerspectiveTricyclic antidepressants are often considered first-line treatment for neuropathic pain. Some tricyclic antidepressants block sodium channels, which may contribute to their antihyperalgesic efficacy. In the current study, we compared the potency of peripheral sodium channel blockade for several tricyclic antidepressants and selective serotonin reuptake inhibitors with their therapeutic efficacy.     

Chronic facial pain from psychiatric point of view - differential diagnosis and therapeutic strategies

Chronic facial pain may cause diagnostic and therapeutic difficulties, thus demanding a complete interdisciplinary consultation. As in 20 to 25% of patients with a nociceptive or primary neuropathic pain a psychiatric comorbidity is expected, it is necessary to include psychiatric and psychosomatic examinations. Every 8th male and every 4th female pain patient has the statistical risk of having a depression at the same time. Depression may develop as a consequence of pain, but may also be the primary basis for a pain syndrome. An independent coincidence is possible as well.Besides affective disorders, persistent somatoform pain syndromes, syndromes of conversion, hypochondriac or artificial disorders and pain in psychosis have to be excluded in patients presenting with chronic facial pain.In depression, persistent somatoform pain syndromes, atypical facial pain but also when dysfunctional illness beliefs and coping mechanisms are present, cognitive-behavioral therapy should be offered to the patient. Motivation to psychotherapy may be difficult, especially in patients relying exclusively on physical illness beliefs. The physician should develop and extend the physical illness beliefs together with the patient to a model that includes biological as well as psychosocial factors.Tricyclic antidepressants may be indicated not only in depression, but also in chronic pain due to the analgetic effects of these drugs. The choice of drug therapy should conform to the main complaints of depression and accompanying illnesses.Indication of antidepressants or neuroleptic drugs in somatoform pain syndromes is still unclear. Their potential slight effect may simply be due to the high comorbidity between somatoform pain syndromes and depression.     

Advances in pharmacotherapy: depression in the elderly– issues and advances in treatment

Depression continues to be a major cause of morbidity and mortality in the elderly. It is estimated that 1–5% of elderly persons who live in the community and 5–43% of nursing–home patients have major depression. Symptoms of depression in the elderly do not differ substantially from younger patients. Tricyclic antidepressants continue to be the drugs of choice in the elderly because of their long record of use with proven efficacy, known adverse effect profile and availability of less expensive generic formulations. The newer secondgeneration antidepressants, including serotonin reuptake inhibitors, appear to offer a major advantage of fewer serious adverse effects in the elderly. This review will highlight recent developments regarding the prevalence and treatment of depression in the elderly.     

The treatment of depression in an ambulatory care setting

Nurse practitioners in a primary care setting often see patients suffering from depression. Many of these patients can be treated in the primary care setting by the nurse practitioner, in collaboration with a psychiatric clinical nurse specialist. Treatment modalities that can be effectively used for depressed patients in this setting include brief individual or group psychotherapy using short-term therapy models such as cognitive or interpersonal therapy, and/or antidepressant medications. Basic concepts and intervention techniques for the cognitive and interpersonal therapy models are described. Tricyclic antidepressants are highlighted including tables and content on action, target symptom side effects, drug-drug interactions, dosage schedules and patient education. In addition, other medications for depression such as lithium, monoamine oxidase inhibitors and psychostimulants are briefly reviewed.     

Tricyclic antidepressants and children

Tricyclic antidepressants have been used in the treatment of certain childhood disorders for more than 20 years, and indications for their use in the pediatric population are increasing. Research supports the use of tricyclics for preadolescent children as adjunctive therapy for major depression, attention deficit hyperactivity disorder, enuresis, tic disorders, anxiety disorders and eating disorders. The range of indications and effects of tricyclics in the treatment of children, and issues related to management by health care providers are discussed in this article.     

Cardiotoxic side effects associated with tricyclic antidepressant overdose.

Tricyclic antidepressants (TCAs) are a popular, effective medication prescribed for patients with depression. The patient with severe depression may exhibit suicidal tendencies; thus, overdose of a prescribed TCA may occur, resulting in a potentially fatal outcome. The cardiotoxic effect of TCA overdose is the most pronounced complication. Multiple rhythm disturbances may occur in the presence of a TCA overdose. The greatest number of adverse cardiac symptoms and electrocardiographic changes are likely to occur within the first 24 hours after overdose. Nursing care of the patient with a TCA overdose is based upon ongoing patient assessment, identification of problems and potential problems, establishment of expected patient outcomes, and specific nursing interventions.     

Tricyclic antidepressants and histamine H1 receptors.

Tricyclic antidepressants and some structurally related compounds were tested for their ability to antagonize histamine H1 and muscarinic acetylcholine receptors of cultured mouse neuroblastoma cells. As a group, tertiary amine tricyclic antidepressants tended to be more potent than secondary amine drugs at both receptors. The most potent antihistamine, doxepin hydrocholoride, was about 4 times more potent than amitriptyline hydrochloride, about 800 times more potent than diphenhydramine hydrochloride, and about 8,000 times more potent than desipramine hydrochloride, the least potent tricyclic antidepressant at both the histamine H1 and the muscarinic acetylcholine receptors. All tricyclic drugs except desipramine hydrochloride were more potent as antihistamines than as anticholinergics. Doxepin hydrochloride and amitriptyline hydrochloride may be the most potent antihistamines known, and the antihistaminic potencies of these and the other tricyclic antidepressant drugs may relate directly to their ability to cause sedation and drowsiness in patients.     

Appropriate use of psychotropic drugs in nursing homes

The Omnibus Budget Reconciliation Act (OBRA) of 1987 limited the use of psychotropic medications in residents of long-term care facilities. Updates of OBRA guidelines have liberalized some dosing restrictions, but documentation of necessity and periodic trials of medication withdrawal are still emphasized. Antidepressant drugs are typically underutilized in nursing homes. Tricyclic antidepressants have many side effects and thus are not preferred medications in elderly patients. Anxiety and insomnia are common problems in the institutionalized elderly. If behavioral measures are not successful, antidepressant medications with shorter half-lives may avoid drug accumulation, which can lead to excessive sedation, cognitive impairment and an increased risk for falls. In the elderly, antipsychotic medications can cause serious side effects, such as extrapyramidal symptoms and tardive dyskinesia. Newer antipsychotic drugs are less often associated with these side effects, but they should be used only for specific diagnoses and when behavioral and environmental measures are unsuccessful.     

Phenytoin prophylaxis of cardiotoxicity in experimental amitriptyline poisoning

Tricyclic antidepressants (TCA) are drugs with Type IA antiarrhythmic properties that cause severe cardiac conduction blocks, hypotension, and ventricular dysrhythmias at toxic levels. Phenytoin has been proposed as a prophylaxis and treatment of these dysrhythmias, since it is thought to improve conduction in this setting. Anesthetized dogs were given a loading dose of phenytoin, followed by constant amitriptyline infusion until death. Variables known to affect TCA toxicity, such as arterial pH, were carefully controlled. There were no significant differences between the phenytoin and control group in any physiologic parameter, including toxicity, drug levels, or dose to death. However, duration and frequency of episodes of ventricular tachycardia were dramatically increased in the phenytoin group. It is concluded that prophylactic phenytoin in this animal model provides no benefits and may in fact increase the severity of ventricular tachycardia and hypotension. In addition, it is speculated that similar adverse effects of phenytoin might be seen in other Type IA antiarrhythmics if the extremely toxic levels seen in this study with TCA were reached.     

Antidepressant use and risk of out-of-hospital cardiac arrest: a nationwide case-time-control study

Treatment with some types of antidepressants has been associated with sudden cardiac death. It is unknown whether the increased risk is due to a class effect or related to specific antidepressants within drug classes. All patients in Denmark with an out-of-hospital cardiac arrest (OHCA) were identified (2001-2007). Association between treatment with specific antidepressants and OHCA was examined by conditional logistic regression in case-time-control models. We identified 19,110 patients with an OHCA; 2,913 (15.2%) were receiving antidepressant treatment at the time of OHCA, with citalopram being the most frequently used type of antidepressant (50.8%). Tricyclic antidepressants (TCAs; odds ratio (OR) = 1.69, confidence interval (CI): 1.14-2.50) and selective serotonin reuptake inhibitors (SSRIs; OR = 1.21, CI: 1.00-1.47) were both associated with comparable increases in risk of OHCA, whereas no association was found for serotonin-norepinephrine reuptake inhibitors/noradrenergic and specific serotonergic antidepressants (SNRIs/NaSSAs; OR = 1.06, CI: 0.81-1.39). The increased risks were primarily driven by: citalopram (OR = 1.29, CI: 1.02-1.63) and nortriptyline (OR = 5.14, CI: 2.17-12.2). An association between cardiac arrest and antidepressant use could be documented in both the SSRI and TCA classes of drugs.