Clinical Aspects of Tricyclic Antidepressant Poisoning

ABSTRACT Self-poisoning with antidepressant drugs was studied retrospectively in 225 patients admitted to an intensive care unit. Amitriptyline accounted for the overwhelming majority of cases (70%); 106 patients (47%) had taken two or more drugs, in 81 patients (36%) ethanol was found in the blood. Four patients (2%) died. On admission, 111 patients (49%) were unconscious (grade III). A further 30 patients (13%) were in grade IV coma, and of these 27 had taken amitriptyline. Twenty-four hours after admission, 22 patients (10%) remained in coma. Thirty-six patients (16%) required assisted ventilation. Nineteen patients (8%) had convulsions and 6 (3%) aspired stomach contents. Sixty-one patients (27%) had a widened QRS interval exceeding 100 msec, 18 (30%) of them required assisted ventilation, 21 (34%) were in stage IV coma and 15 (25%) had convulsions. This relationship between a widened QRS interval and the severity of intoxication should be considered in the initial assessment of patients with tricyclic antidepressant poisoning.     

Recognition of psychostimulants, antidepressants, and other inhibitors of synaptic neurotransmitter uptake by the plasma membrane monoamine transporters

The plasma membrane monoamine transporters terminate neurotransmission by removing dopamine, norepinephrine, or serotonin from the synaptic cleft between neurons. Specific inhibitors for these transporters, including the abused psychostimulants cocaine and amphetamine and the tricyclic and SSRI classes of antidepressants, exert their physiological effects by interfering with synaptic uptake and thus prolonging the actions of the monoamine. Pharmacological, biochemical, and immunological characterization of the many site-directed, chimeric, and deletion mutants generated for the plasma membrane monoamine transporters have revealed much about the commonalities and dissimilarities between transporter substrate, ion, and inhibitor binding sites. Mutations that alter the binding affinity or substrate uptake inhibition potency of inhibitors by at least 3-fold are the focus of this review. These findings are clarifying the picture regarding substrate uptake inhibitor/transporter protein interactions at the level of the drug pharmacophore and the amino acid residue, information necessary for rational design of novel medications for substance abuse and a variety of psychiatric disorders.     

Treatment with antidepressants and down regulation of beta-adrenergic receptors

The effect of chronic and acute treatment with several antidepressant drugs and electroconvulsive shock (ECS) on the responsiveness of norepinephrine (NE) receptor coupled adenylate cyclase and beta-adrenergic receptor binding sites in rat brain has been studied by several groups of investigators. It has been consistently reported that chronic administration (2 to 4 weeks of treatment) of antidepressant drugs or ECS causes a decreased accumulation of NE stimulated cyclic AMP accumulation in rat brain. It has also been reported that chronic treatment with antidepressant drugs or ECS causes decreased binding of [³H]dihydroalprenolol (DHA) or [¹²⁵I]hydroxybenzylpindolol (I-HYP) (ligands used for studies of beta-adrenergic receptors) in rat brain. However, such effects are not observed after acute or single administration of these drugs or ECS. Since there appears to be a close correlation between the time course of the effects of these drugs on NE receptor coupled adenylate cyclase and beta-adrenergic receptor binding, and since most of the antidepressant drugs tested thus far produce such effects, it has been suggested that down regulation or decreased responsiveness of beta-adrenergic receptors may be related to the therapeutic effects manifested by antidepressant drugs. These observations offer the possibility that determination of beta-adrenergic receptor responsiveness after chronic treatment with drugs may prove useful in the preclinical screening of potential antidepressant drugs. In this paper, studies related to down regulation of beta-adrenergic receptors, including our own, are reviewed.     

Validation of the Bech–Rafaelsen Melancholia Scale and the Hamilton Depression Scale in patients with major depression; is the total score a valid measure of illness severity?

OBJECTIVE: Evaluation of antidepressant drug efficacy requires adequate rating scales for measuring the severity of depression. However, to measure the illness severity by such a total score, the scale needs to fulfil criteria of unidimensionality. On this background, we aimed at comparing the unidimensionality of the Bech-Rafaelsen Melancholia Scale (MES) and the 17-item Hamilton Depression Rating Scale (HAM-D(17)). METHOD: A total of 1629 patients aged between 18 and 65 years with a major depressive episode were treated openly with sertraline at a fixed oral dose of 50 mg daily during 4 weeks. The HAM-D(17) and the MES were applied at baseline and at weeks 2 and 4. Unidimensionality was tested with Mokken and Rasch analysis. RESULTS: Unidimensionality of the HAM-D(17) could not be confirmed. However, the 6-item Hamilton Depression Subscale (HAM-D(6)), was accepted by the Rasch analysis both at baseline and after 2 and 4 weeks of therapy. For the MES (as well as for the HAM-D(6)), a Loevinger coefficient of homogeneity above 0.40 (suggesting acceptance) was found at week 4. CONCLUSION: The HAM-D(6) and the MES did fulfil criteria for unidimensionality while the HAM-D(17) did not. Therefore, the extended use of the HAM-D(17) in drug trials may be questioned.     

A preliminary open study of the tolerability and effectiveness of nefazodone in major depressive disorder: comparing patients who recently discontinued an SSRI with those on no recent antidepressant treatment

Anecdotal evidence suggests that the recent discontinuation of an SSRI may confound the tolerability of the initiation of nefazodone treatment. We sought to determine whether recent discontinuation of an SSRI interferes with effectiveness and/or tolerability of nefazodone. Twenty-six depressed subjects, 21-63 years old, were recruited at the Massachusetts General Hospital. Thirteen subjects (50%) had discontinued an SSRI within 1-4 weeks due to ineffectiveness and/or side effects. Thirteen subjects (50%) had not taken antidepressants for the previous 6 months. Subjects were administered open nefazodone 50 mg p.o. b.i.d., and doses were increased as tolerated to a maximum of 600 mg/day. Subjects were followed for 12 weeks and were assessed for response and side effects using HAM-D-6 and clinical interviews. Both groups improved significantly on nefazodone; however, there was no statistically significant difference in response (>or=50% decrease in HAM-D-6) rates between completers with prior SSRI treatment (80%) and completers without recent exposure to antidepressants (67%). Response rates based on intent-to-treat (ITT) analysis were 31% for both groups. Association between prior SSRI treatment and discontinuation of nefazodone due to side effects or non-response was not statistically significant. Our study suggests that the rate of negative outcomes with nefazodone is no different whether patients have recently failed an SSRI.     

Folic acid: neurochemistry, metabolism and relationship to depression

The associations of folic acid and its derivatives with depressive disorder are reviewed. Derivatives of folic acid such as biopterins and the synthesis of S-adenosyl methionine (SAM) are known either to be associated with improvement or to have a direct therapeutic effect in depressive disorder. Studies investigating plasma and red cell folic acid levels in depressed patients have used differing assay methodologies which make comparison difficult, although there is substantial evidence of the association between depressive disorder (particularly severe depression) and low folic acid levels. The few studies available suggest folic acid has either antidepressant properties or can act as an augmenting agent for standard antidepressant treatment. A recently discovered genetic variant (5,10 MTHFR) leading to altered folic acid metabolism may explain why some individuals are vulnerable to the effects of folic acid deficiency, despite adequate intake. The links of 5,10 MTHFR to the presence of depressive disorder in the community are being investigated.     

Survey of regional health care providers on selection of treatment for bulimia nervosa

OBJECTIVE: To determine which treatments clinicians currently recommend for patients with bulimia nervosa (BN), to find out if they recommended evidence-based treatments, and to assess availability and clinician satisfaction with treatment options. METHODS: Surveys were sent to 1,263 health care providers in Minnesota, Iowa, and Wisconsin who were likely to encounter patients with BN. These health care providers comprised all primary care clinicians, physician assistants, advanced practice nurses, and all mental health/chemical dependency clinicians (MDs, Clinical Nurse Specialist (CNS), social workers, doctoral and masters-level therapists, and chemical dependency (CD) counselors) affiliated with the Mayo Clinic in Rochester, Minnesota. RESULTS: Evidence-based treatments for BN are recommended consistently and are generally perceived to be available, at least to practitioners affiliated with a large medical center in the Midwest. Clinician satisfaction with treatment options is modest. DISCUSSION: Clinicians are recommending evidence-based treatments for BN patients and find them to be generally available. Modest satisfaction with available treatments may reflect a realistic understanding of treatment options, which need further development.     

Nefazodone for chronic daily headache prophylaxis: an open-label study

OBJECTIVE: To assess effectiveness, tolerability, and safety of nefazodone as a prophylactic agent for chronic daily headache. BACKGROUND: Nefazodone is a potent, selective 5-HT2 antagonist with a distinct and atypical mechanism of action. The evolution of intermittent migraine to chronic daily headache has been linked to up-regulation of 5-HT2 receptors as well as other factors. Other effective migraine prophylactic medications are also 5-HT2 antagonists. Although research has shown nefazodone to be an effective antidepressant with a good tolerability and safety profile, its potential role in headache prophylaxis has not been tested. DESIGN: This was a two-center, open-label study with a 4-week baseline, followed by 12 weeks of treatment with nefazodone at a median dose of 300 mg (mean, 303.66 +/- 65.57 mg; range, 100 to 450 mg depending on tolerability). Potential patients were required to report more than 15 days of headache per month for at least 3 months prior to screening. Only patients with at least 15 days of recorded headache during baseline were included in the final sample (N=52). Most patients (n=48) had a history of migraine based on International Headache Society criteria; 4 had primarily chronic tension-type headache, but with more migrainous features than permitted by International Headache Society criteria for a primary chronic tension-type headache diagnosis. RESULTS: Significant improvement was demonstrated for all headache diary measures, with significance levels ranging from P<.00001 for average intensity, duration, headache index (intensity x duration), peak intensity, headache days per week, and peak impairment, to P<.0033 for severe headache days per week, and P<.0051 for rescue medication days. During the last month of treatment, 71% of the patients completing the study showed at least a 50% reduction in headache index compared to baseline, and 59% had at least a 75% improvement. Visual analog scales completed at 4-week intervals showed significant improvement in patient ratings of overall headache status, quality of life, sleep, mood (P<.00001), and sexual function (P<.00053). Significant improvements were also observed in the Pain Disability Index (P<.00007), Beck Depression Inventory-II (P<.00001), Hamilton Rating Scale for Depression (P<.0008), and Hamilton Psychiatric Rating Scale for Anxiety (P<.00007). Headache indices for patients in the top quartile on the depression and anxiety scales (clinical depression/anxiety) did not differ from the other patients during baseline. However, patients who were depressed or anxious showed significantly more improvement over the course of 12 weeks of treatment (P<.0006 or less for the depression scales, P<.026 for anxiety). Common mild to moderate adverse events reported by 10% or more of the patients included fatigue, nausea, dry mouth, dizziness, sleep disturbance, blurred vision, irritability/nervousness, and sedation. Only 5 of the 52 patients discontinued the study due to adverse events: headache (2 patients), and nausea, sleep disturbance, and a drugged feeling (1 patient each). CONCLUSIONS: These results provide preliminary support for the efficacy of nefazodone in the prophylaxis of chronic daily headache. In this sample, nefazodone was safe and generally well tolerated. Patient ratings of sexual function improved over the course of treatment, in contrast to what is generally observed with most antidepressants. Nefazodone may be particularly beneficial for patients with chronic daily headache and comorbid depression. Further research is indicated.     

Fluoxetine depresses glutamate exocytosis in the rat cerebrocortical nerve terminals (synaptosomes) via inhibition of P/Q-type Ca2+ channels

Fluoxetine, an antidepressant that is used clinically in the treatment of mood disorders, is a selective serotonin reuptake inhibitor. In the present study we investigated the effects of fluoxetine on 4-aminopyridine (4AP)-evoked glutamate release in cerebrocortical nerve terminals (synaptosomes). Fluoxetine suppressed the release of glutamate evoked by 4AP in a concentration-dependent manner. This effect was associated with a reduction in the depolarization-evoked increase in cytosolic free calcium levels in the absence of significant effect on the synaptosomal membrane potential. In addition, both ionomycin- and sucrose-evoked glutamate releases were not affected by fluoxetine, indicating that fluoxetine-mediated inhibition of glutamate release is not a direct effect on the exocytotic machinery. Furthermore, the inhibitory action of fluoxetine was completely abolished in synaptosomes pretreated with P/Q type Ca(2+) channel blocker omega-agatoxin IVA (omega-AgTX IVA) or protein kinase C (PKC) stimulator 4beta-phorbol 12, 13-dibutyrate (PDBu). These results suggest that, in cerebrocortical nerve terminals, fluoxetine inhibits glutamate release through the suppression of P/Q type Ca(2+) channel activity. The presynaptic action of fluoxetine is mediated by a PKC-sensitive signaling pathway. Synapse 48:170-177, 2003.     

Strategies for the rapid treatment of depression

The purpose of this article is to review current literature relating to the determination of the time course of antidepressant effects. Further, this work explores studies examining the safety and effectiveness of pharmacological techniques for accelerating the therapeutic effects of antidepressant medication. A review of the literature pertaining to strategies for accelerating antidepressant medication effects was accomplished using the MEDLINE database, employing the key title words, antidepressant, rapid, and accelerating. A preponderance of evidence suggests that there is a multiple week latency for the onset of action of antidepressant medications. This latency appears to apply to virtually all standard antidepressants and may reflect slow adaptive changes to the inciting event of increased monoamine levels. Several strategies have received attention as potential strategies with which to accelerate the therapeutic effects of antidepressant medications. These include the use of high initial doses of some agents and also the use of initial augmentation strategies. Specifically, studies exist suggesting the acceleration of antidepressant effects using high initial doses of tricyclic antidepressants or venlafaxine, as well as the potential for acceleration by using initial augmentation with psychostimulants, lithium, or pindolol. Considering the morbidity and mortality associated with severe depression, a critical need exist for the exploration of ways in which to achieve antidepressant effects more quickly. A number of preliminary studies suggest strategies for the rapid treatment of depression, each with an apparent high degree of safety. Further investigations in more carefully defined patient populations and utilizing advances in the techniques for assessing antidepressant onset are needed. Copyright 2001 John Wiley & Sons, Ltd.