Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine have been regarded as less toxic in overdose than tricyclic antidepressants (TCAs). Within the TCAs, dothiepin has greater toxicity. Venlafaxine may be more toxic than SSRIs. AIM: To assess the toxicity in overdose of venlafaxine and SSRIs compared to TCAs, and of dothiepin compared to other TCAs. DESIGN: Cohort study of prospectively collected data from the Hunter area, NSW, Australia. METHODS: First admissions with antidepressant deliberate self-poisoning (DSP) (November 1994 to April 2000) were identified; the presence of seizures, life-threatening arrhythmias, coma, serotonin toxicity or ICU admission, and QRS duration were noted. RESULTS: There were 538 admissions, with no deaths. The odds ratio (OR) for seizures with dothiepin vs. other TCAs was 3.4 (95%CI 1.2-9.9). Seizures occurred in 7/51 (14%) venlafaxine overdoses; all patients with seizures consumed > or =900 mg. The OR for seizures vs. TCAs was 4.4 (95%CI 1.4-13.8). Coma was less likely with venlafaxine and SSRIs. SSRIs, but not venlafaxine, were less likely to prolong the QRS to > or =100 ms. ICU admission was less likely for SSRIs. Serotonin toxicity was much more common with venlafaxine and SSRIs. DISCUSSION: Venlafaxine and dothiepin are pro-convulsant in overdose. Venlafaxine is more likely to cause serotonin toxicity, but less likely to cause coma than TCAs. SSRIs are less likely to cause coma, require ICU admission, or prolong the QRS, but are more likely to cause serotonin toxicity. Antidepressants other than TCAs or venlafaxine should be considered in patients at risk of seizure or suicide.     

Panic disorder and antidepressants

Anxiety disorders, specifically, panic disorder, are the most common mental health disorders. Unless the clinician has a high index of suspicion, panic disorder or social anxiety disorder may remain undetected. Although quality of life(QOL) issues have long been recognized in severe psychiatric disorders, they have only recently come to be considered for the anxiety disorders. While the older tricyclic antidepressants(TCAs) are efficacious in the treatment of theses anxiety disorders, recent studies with paroxetine and other selective serotonin reuptake inhibitors(SSRIs) have emphasized the role of serotonin in the aetiology of these conditions. Both the TCA and SSRI antidepressants are effective in treating a wide variety of anxiety disorders. SSRIs, due to their greater safety and tolerability, should be the preferred choices in treating anxiety disorders in those instances.     

Serotonergic thrombocytopathy and its effects on platelets during orthopaedic surgery

The serotonergic effects on platelet dysfunction (thrombocytopathy) can cause deficient hemostasis during orthopaedic surgery. Peripheral serotonin located within the granules of platelets assists in initial platelet aggregation. Selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) are drugs used to treat a myriad psychological-related, mental-related, and psychosocial-related disorders. A correlation exists between low levels of peripheral serotonin and a bleeding diathesis during orthopaedic surgery. The relationship of excessive bleeding during orthopaedic surgery secondary to thrombocytopathy and low levels of serotonin caused by drugs that inhibit the reuptake of serotonin is presented.     

Suicidal bupropion ingestions in adolescents: increased morbidity compared with other antidepressants

Objective: Bupropion is often categorized as a newer generation antidepressant and assessed with serotonin reuptake inhibitors as a lower risk than older tricyclic antidepressants (TCAs). The objective of this study was to compare outcomes in adolescent suicide from ingestions between bupropion and TCA medications.

Study design: An analysis of the National Poison Data System for exposures coded “suspected suicide” in adolescents (age: 13–19) was undertaken for the years 2013–2016 and included TCAs or bupropion. We compared clinical effects, therapies and medical outcomes.

Results: Over the four-year period there were 2253 bupropion and 1496 TCA adolescent suspected suicide calls. There was a significant linear increase in bupropion ingestions over the four years. Across all years, there were on average 189.2 (95% CI: 58.1–320.4; p?=?.01) more ingestions of bupropion than TCA. When comparing bupropion to a TCA, ingestions of bupropion were significantly more likely to be accompanied by seizure (30.7% vs 3.9%; p?p?p?p?p?Conclusions: Adolescents who overdose on a single medication in a suicide attempt with bupropion have a statistically significant higher incidence of major outcomes and seizures. The risks of bupropion as a potential means of suicidal gesture by overdose must be considered, and weighed against its benefits and side effect profile when choosing an appropriate agent for the treatment of depression in adolescents.     

The symptoms, neurobiology, and current pharmacological treatment of depression.

Depression as a medical disorder increasingly is being recognized and treated. The mood of an individual with major depression is often described as sad, hopeless, or discouraged, and there are many physical symptoms associated with depression. Pharmacologic treatments for depression have advanced greatly since the development of the first therapies, monoamine oxidase inhibitors (MAOIs). Many medications, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs), currently are available to help combat this health problem. Newer medications have eliminated many of the side effects associated with older therapies, and treatments in development are designed with the goal of further improving on efficacy while eliminating side effects.     

Psychopharmacology and oral psychosomatic disorder

It is uncommon to encounter patients presenting with medically and psychiatry unexplained oral symptoms like pain or discomfort. These symptoms have been called "oral psychosomatic disorders (OPSD)" in general. From a clinical point of view, OPSD may be due to several biochemical disorders involving neurotransmitters in the brain, incomplete connections between oral region and undefined complaints due to cognitive processes in higher centers of the brain. The main psychosomatic treatment is psychopharmacological therapy with antidepressants, including tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors(SNRIs), selective serotonin reuptake inhibitors(SSRIs), and other antidepressants (e.g., mirtazapine)". The proper use of these antidepressants is extremely important for the successful treatment of OPSD.     

Use of antidepressant medications: are there differences in psychiatric visits among patient treatments in the Veterans Administration?

BACKGROUND: Information on the effectiveness of newer antidepressants like serotonin-norepinephrine reuptake inhibitors in terms of healthcare utilization is limited. Treatment guidelines affect evaluation. Second-line medications are usually prescribed to patients with higher utilization. OBJECTIVES: The objective of this study was to compare antidepressants within the Veterans Affairs (VA) healthcare system on the basis of the number of outpatient psychiatric visits for each class of antidepressants. RESEARCH DESIGN AND SUBJECTS: We conducted a retrospective cohort design using precollected information from VA national databases from 1999 and 2000. The study identified 92,537 patients on serotonin specific reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs). MEASURES: We stratified individual patients by the number of visits in the baseline year for each medication class. For each stratum, we created a dichotomized variable YK: Yk = 1 if there is a reduction of K visits or more and 0 if there is no reduction. We calculated the odds of reduction of psychiatric visits among the 3 classes of antidepressants. RESULTS: TCAs and SSRIs were associated with greater odds of reduction compared with SNRIs at the level of 1 through 10 or 11 visits, respectively. SNRIs were associated with greater odds of reduction in visits at the level of 14, 16, or more visits compared with SSRIs and TCAs, respectively (P <0.05). SSRIs were associated with greater odds of reduction compared with TCAs at the level of 1 to 11 visits (P <0.05); there were no significant differences between the 2 classes above 11 visits. CONCLUSION: Effectiveness research using databases should consider how medications are prescribed within systems. Treatment guidelines result in differences in severity and utilization among users of different medications.     

ANTIDEPRESSANTS IN THE ELDERLY

Antidepressants are effective in the treatment of depression but their use in the elderly merits special attention. In general, the tertiary amine tricyclic antidepressants (TCAs) tend to produce significant side-effects in the elderly. In contrast, nortriptyline, desipramine and lofepramine are better tolerated than other TCAs. The newer antidepressants including the selective serotonin reuptake inhibitors are useful alternatives in the treatment of depression in the elderly. As pharmacokinetic studies show that higher steady-state plasma levels of tertiary amine antidepressants may be found in the elderly than in the younger population, a lower dosage is recommended. However, the need for a lower dose in the elderly is less certain for the secondary amine TCAs. The optimum duration of continuation and maintenance antidepressant therapy requires further study. For delusional depression, there is evidence to support the superiority of ECT and combination antipsychotic/antidepressant treatment over antidepressant alone. The ultimate choice of antidepressant will be a balance of efficacy, safety, acceptability and cost.     

Relative Toxicity of Selective Serotonin Reuptake Inhibitors (SSRIs) in Overdose

Background: Selective serotonin reuptake inhibitors (SSRIs) have increasingly replaced tricyclic antidepressants (TCAs) in the treatment of depression. They appear to be safer in overdose, but there is little information on their spectrum of toxicity in overdose, or relative toxicity of each agent. Objective: To determine the effect of SSRIs in overdose, as a group, and the relative toxicity of five different SSRIs. Methods: A review of consecutive SSRI poisoning admissions to a single toxicology unit. Outcomes examined were length of stay [LOS], intensive care [ICU] admission rate, coma, seizures, electrocardiographic [ECG] abnormalities, and presence of serotonin syndrome [SS]. Logistic regression was used to model the outcome QTc > 440 msec. Results: There were 469 SSRI poisoning admissions analyzed after exclusions. The median LOS for all SSRI overdose admissions was 15.3 h (IQR: 10.5–21.3) and 30 of 469 (6.4%; 95% CI 4.3–9.0%) cases were admitted to ICU. The incidence of seizures was 1.9% and coma was 2.4%. Serotonin syndrome occurred in 14% of overdoses. Comparison of median QTc intervals of the five SSRIs was significantly different (p = 0.0002); citalopram (450 IQR: 436–484) was individually different to fluoxetine (p = 0.045), fluvoxamine (p = 0.022), paroxetine (p = 0.0002), and sertraline (p = 0.001). The proportion of citalopram overdoses with a QTc > 440 msec was 68%, differing significantly from sertraline (adjusted OR: 5.11 95% CI 2.32–11.27). Comparison of median QT intervals of the five SSRIs was statistically different (p = 0.026); citalopram (400 IQR: 380–440) was individually different from sertraline (p = 0.023). Conclusions: This study shows SSRIs are relatively safe in overdose despite serotonin syndrome being common. The exception was citalopram, which was significantly associated with QTc prolongation. We believe that cardiac monitoring should be considered in citalopram overdose, particularly with large ingestions and patients with associated cardiac disease.     

The management challenges of chronic pain: the role of antidepressants

Chronic pain is both difficult for patients to tolerate and for clinicians to treat effectively. It differs from other types of pain in etiology and impact, which in turn affects the duration and modalities of treatment options. Forty years of research have confirmed the efficacy of antidepressant agents in the management of chronic pain, yet these agents are used inadequately. A significant amount of evidence supports the use of the traditional tricyclic antidepressants (TCAs) in the management of chronic pain, but because of their acute synaptic effects on multiple, nontherapeutic receptor systems, they are associated with numerous undesirable side effects. The newer selective serotonin reuptake inhibitors (SSRIs) have, comparatively, only serotonin-receptor-mediated side effects. These agents have not been thoroughly studied in the treatment of chronic pain. Moreover, because SSRIs impact reuptake of only one monoamine system, it is plausible that they may be less efficacious than the TCAs in treating chronic pain. Venlafaxine, the first agent in the new class of serotonin (5-HT)-norepinephrine (NE) reuptake inhibitors, is unique because it inhibits reuptake of both 5-HT and NE (and to a lesser extent dopamine), as do some of the TCAs; however, it accomplishes this without affecting other nontherapeutic receptors. Venlafaxine is at least as effective as the TCAs, but is more tolerable, because it lacks the receptor-mediated side effects common to the TCAs. The unique characteristics of venlafaxine, including minimal cytochrome P-450 drug interaction, may make it a particularly useful antidepressant in the adjunctive treatment of chronic pain.     

New drugs in the treatment of depression and schizophrenia

Pharmacological agents are important in the treatment of many patients with major depression or psychotic illness. Antidepressant drugs such as the tricyclic antidepressants and non-selective monoamine oxidase inhibitors are associated with significant adverse effects, especially in overdose. Newer antidepressants include selective serotonin reuptake inhibitors and reversible, selective monoamine oxidase inhibitors. These new drugs are clinically effective and have greatly improved side effect profiles, being considerably safer in overdose than older agents. In the treatment of psychosis, risperidone and clozapine represent clinical advances and are less likely to induce adverse neurological effects than existing neuroleptic agents.     

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.     

Tolerability and safety of fluvoxamine and other antidepressants

Selective serotonin [5-hydroxytryptamine (5-HT)] reuptake inhibitors (SSRIs) and the 5-HT noradrenaline reuptake inhibitor, venlafaxine, are mainstays in treatment for depression. The highly specific actions of SSRIs of enhancing serotonergic neurotransmission appears to explain their benefit, while lack of direct actions on other neurotransmitter systems is responsible for their superior safety profile compared with tricyclic antidepressants. Although SSRIs (and venlafaxine) have similar adverse effects, certain differences are emerging. Fluvoxamine may have fewer effects on sexual dysfunction and sleep pattern. SSRIs have a cardiovascular safety profile superior to that of tricyclic antidepressants for patients with cardiovascular disease; fluvoxamine is safe in patients with cardiovascular disease and in the elderly. A discontinuation syndrome may develop upon abrupt SSRI cessation. SSRIs are more tolerable than tricyclic antidepressants in overdose, and there is no conclusive evidence to suggest that they are associated with an increased risk of suicide. Although the literature suggests that there are no clinically significant differences in efficacy amongst SSRIs, treatment decisions need to be based on considerations such as patient acceptability, response history and toxicity.     

Rational use of antidepressants

The key to the proper treatment of affective illness is a correct diagnosis of the subtype of depressive illness. Thus, primary treatment recommendations include the tricyclic antidepressants for a major depressive episode, electroconvulsive therapy for a major depressive episode with psychotic features, and monoamine oxidase inhibitors for dysthymic disorder and atypical depressive episodes. Nonresponding patients are treated with either lithium augmentation of TCA therapy or ECT. Second-generation antidepressants are recommended in situations where their adverse effect profiles offer significant advantages over TCAs in an individual patient. Maintenance antidepressant treatment may be necessary to prevent recurrent depressive episodes.     

Serotonin syndrome caused by overdose with paroxetine and moclobemide.

Well known clinical syndromes can be produced by overdose with more commonly ingested substances such as opiates or tricyclic antidepressants. A case of a much more unusual syndrome presenting to the accident and emergency department resulting from overdose with a combination of tablets is reported. The clinical presentation of serotonin syndrome and its management are described. This resulted from acute ingestion of paroxetine, a selective serotonin reuptake inhibitor, and moclobemide, a monoamine oxidase inhibitor.     

Serotonin syndrome caused by overdose with paroxetine and moclobemide.

Well known clinical syndromes can be produced by overdose with more commonly ingested substances such as opiates or tricyclic antidepressants. A case of a much more unusual syndrome presenting to the accident and emergency department resulting from overdose with a combination of tablets is reported. The clinical presentation of serotonin syndrome and its management are described. This resulted from acute ingestion of paroxetine, a selective serotonin reuptake inhibitor, and moclobemide, a monoamine oxidase inhibitor.     

The efficacy and tolerability of dothiepin and three selective serotonin reuptake inhibitors in the treatment of major depression: A review of six double-blind studies

The introduction of the selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression has highlighted some of the limitations of the more established tricyclic antidepressants (TCAs). There are six recently published studies that compare the efficacy and tolerability of the SSRIs fluvoxamine, fluoxetine, and paroxetine with the TCA dothiepin. The results of these studies indicate that SSRIs do not have more potent antidepressant properties than dothiepin, nor exhibit a faster onset of antidepressant effect; indeed, premature withdrawal from treatment due to adverse events was more frequent with SSRIs than with dothiepin. Although the frequency of side effects not resulting in withdrawal was similar with SSRIs and dothiepin, the spectrum of such events was different. Dothiepin was associated with more anticholinergic effects, notably dry mouth, drowsiness, and blurred vision, whereas SSRIs were associated with a greater incidence of nausea, rash, and sweating. The present review shows that certain perceived advantages of SSRIs over TCAs may not be borne out in clinical practice, particularly in comparisons with dothiepin.     

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.     

Pharmacokinetics and drug interactions of antidepressive agents

Tricyclic antidepressive agents(TCAs) are conventional antidepressant. Cytochrome P450(CYP) 2D6 is involved in the hydroxylation of TCAs, while N-demethylation of TCAs is mediated by other such as CYP2C19, 3A4 and 1A2. The elimination of TCAs is impaired by CYP2D6 inhibitors such as quinidine. Newer antidepressants, selective serotonin uptake inhibitors(SSRIs), are also metabolized in the liver. Fluvoxamine, an SSRI, is a potent inhibitors for CYP1A2 and CYP2C19, moderate for CYP3A4 and weak for CYP 2D6. Paroxetine, another SSRI, causes substantial inhibition of CYP2D6 activity. Milnacipran, a serotonin and noradrenaline reuptake inhibitor, is mainly excreted unchanged in urine and some part as its glucronide conjugate. In contrast to many SSRIs, milnacipran is devoid of metabolic inhibition.