Evaluation of a QT nomogram for risk assessment after antidepressant overdose

AIMS

A QT-heart rate nomogram has recently been proposed as a means of identifying patients at risk of torsades de pointes after antidepressant overdose, based on published cases of drug-induced torsades de pointes. The present study sought to examine the performance of the nomogram in patients who ingest an antidepressant overdose but do not develop arrhythmia.

METHODS

A retrospective case control study of patients presenting to hospital after overdose of citalopram, mirtazapine and venlafaxine was carried out. The primary outcome variable was QT higher than the nomogram, and was compared with occurrence of QT_c (QT corrected by Bazett''s formula) greater than ≥440 ms and QT_c≥500 ms, with comparison between drugs. Data are expressed as proportions in each group with 95% confidence intervals.

RESULTS

There were 858 electrocardiograms from 541 patients. QT was higher than the nomogram in 2.4% (1.4, 4.1%), whereas QT_c was ≥440 ms in 23.1% (95% CI 19.8, 26.8%), and QT_c was ≥500 ms in 1.1% (0.5, 2.5%). Citalopram overdose was more likely to be associated with QT higher than the nomogram compared with the other agents (difference 7.0%, 95% CI 2.9, 11.9%, P = 0.001) and more likely to be associated with QT_c≥440 ms (difference = 11.0%, 95% CI 2.6, 19.0%, P = 0.013).

CONCLUSIONS

The QT nomogram was associated with a lower false positive rate than widely accepted QT_c criteria, and allowed detection of different effects of individual drugs. The nomogram offers potential advantages over QT_c criteria and merits further investigation in a clinical setting.     

Chronic Fluoxetine Increases Extra-Hippocampal Neurogenesis in Adult Mice

Background:

Chronic treatment with antidepressants has been shown to enhance neurogenesis in the adult mammalian brain. Although this effect was initially reported to be restricted to the hippocampus, recent work has suggested that fluoxetine, a selective serotonin reuptake inhibitor, also promotes neurogenesis in the cortex. However, whether antidepressants target neural progenitor cells in other brain regions has not been examined.

Methods:

Here, we used BrdU labeling and immunohistochemistry with a transgenic mouse line in which nestin+ neural progenitor cells can be inducibly labeled with the fluorescent protein, Tomato, following tamoxifen administration. We investigated the effects of chronic fluoxetine on cell proliferation and nestin+ progenitor cells in periventricular areas in the medial hypothalamus and medial habenula, two brain areas involved in stress and anxiety responses.

Results:

Our data provide the first in vivo evidence that fluoxetine promotes cell proliferation and neurogenesis and increases the mRNA levels of BDNF in the hypothalamus and habenula.

Conclusions:

By identifying novel cellular targets of fluoxetine, our results may provide new insight into the mechanisms underlying antidepressant responses.     

Utility of organotypic raphe slice cultures to investigate the effects of sustained exposure to selective 5-HT reuptake inhibitors on 5-HT release

BACKGROUND AND PURPOSE

Selective 5-hydroxytryptamine (5-HT, serotonin) reuptake inhibitors (SSRIs) are widely used antidepressants and their therapeutic effect requires several weeks of drug administration. The delayed onset of SSRI efficacy is due to the slow neuroadaptive changes of the 5-hydroxytryptaminergic (5-HTergic) system. In this study, we examined the acute and chronic effects of SSRIs on the 5-HTergic system using rat raphe slice cultures.

EXPERIMENTAL APPROACH

For organotypic raphe slice cultures, mesencephalic coronal sections containing dorsal and median raphe nuclei were prepared from neonatal Wistar rats and cultured for 14–16 days.

KEY RESULTS

Acute treatment with citalopram, paroxetine or fluoxetine (0.1–10 µM) in the slice cultures slightly increased extracellular 5-HT levels, while sustained exposure for 4 days augmented the elevation of 5-HT level in a time-dependent manner. Sustained exposure to citalopram had no effect on tissue contents of 5-HT and its metabolite, expression of tryptophan hydroxylase or the membrane expression of 5-HT transporters. The augmented 5-HT release was attenuated by Ca²⁺-free incubation medium or treatment with tetrodotoxin. Experiments with 5-HT_1A/B receptor agonists and antagonists revealed that desensitization of 5-HT₁ autoreceptors was not involved in the augmentation of 5-HT release. Finally, co-treatment with an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate, but not an N-methyl-d-aspartate, receptor antagonist, suppressed this augmentation.

CONCLUSION AND IMPLICATIONS

These results suggest that sustained exposure to SSRIs induces the augmentation of exocytotic 5-HT release, which is caused, at least in part, by the activation of AMPA/kainate receptors in the raphe slice cultures.     

The antidepressant bupropion exerts alleviating properties in an ovariectomized osteoporotic rat model

Aim:

Depression is a risk factor for impaired bone mass and micro-architecture, but several antidepressants were found to increase the incidence of osteoporotic fractures. In the present study we used ovariectomized (OVX) rats as a model of osteoporosis to investigate the effects of the antidepressant bupropion on the femoral bones.

Methods:

OVX animals were treated with bupropion (30, 60 mg·kg⁻¹·d⁻¹) for six weeks. Bone turnover biomarkers (urinary DPD/Cr ratio, serum BALP, OC, TRAcP 5b, CTX and sRANKL levels) and inflammatory cytokines (TNF-α, IL-1β and IL-6) were determined using ELISA. Inductively coupled plasma mass spectroscopy (ICP-MS) was used to determine the femoral bone mineral concentrations. The cortical and trabecular morphometric parameters of femoral bones were determined using micro-CT scan and histopathology.

Results:

In OVX rats, the levels of bone turnover biomarkers and inflammatory cytokines were significantly elevated and femoral bone Ca²⁺ and PO₄³⁻ concentrations were significantly reduced. Moreover, cortical and trabecular morphometric parameters and histopathology of femoral bones were severely altered by ovariectomy. Bupropion dose-dependently inhibited the increases in bone turnover biomarkers and inflammatory cytokines. OVX rats treated with the high dose of bupropion showed normal mineral concentrations in femoral bones. The altered morphometric parameters and histopathology of femoral bones were markedly attenuated by the treatment.

Conclusion:

Bupropion exerts osteo-protective action in OVX rats through suppressing osteoclastogenesis-inducing factors and inflammation, which stabilize the osteoclasts and decrease bone matrix degradation or resorption.     

Preclinical characterization of WAY-211612: a dual 5-HT uptake inhibitor and 5-HT1A receptor antagonist and potential novel antidepressant

Background and purpose

As a combination of 5-HT selective reuptake inhibitor (SSRI) with 5-HT_1A receptor antagonism may yield a rapidly acting antidepressant, WAY-211612, a compound with both SSRI and 5-HT_1A receptor antagonist activities, was evaluated in preclinical models.

Experimental approach

Occupancy studies confirmed the mechanism of action of WAY-211612, while its in vivo profile was characterized in microdialysis and behavioural models.

Key results

WAY-211612 inhibited 5-HT reuptake (K_i = 1.5 nmol·L⁻¹; K_B = 17.7 nmol·L⁻¹) and exhibited full 5-HT_1A receptor antagonist activity (K_i = 1.2 nmol·L⁻¹; K_B = 6.3 nmol·L⁻¹; I_max 100% in adenyl cyclase assays; K_B = 19.8 nmol·L⁻¹; I_max 100% in GTPγS). WAY-211612 (3 and 30 mg·kg⁻¹, po) occupied 5-HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5-HT_1A receptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY-211612 (3–30 mg·kg⁻¹, po) raised levels of cortical 5-HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg·kg⁻¹, s.c.) and a 5-HT_1A antagonist (WAY-100635; 0.3 mg·kg⁻¹, s.c). WAY-211612 (3.3–30 mg·kg⁻¹, s.c.) decreased aggressive behaviour in the resident-intruder model, while increasing the number of punished crossings (3–30 mg·kg⁻¹, i.p. and 10–56 mg·kg⁻¹, po) in the mouse four-plate model and decreased adjunctive drinking behaviour (56 mg·kg⁻¹, i.p.) in the rat scheduled-induced polydipsia model.

Conclusions and implications

These findings suggest that WAY-211612 may represent a novel antidepressant.     

Effect of acute paracetamol overdose on changes in serum and urine electrolytes

What is already known about this subject

• Paracetamol causes renal failure in overdose. Experimental studies have shown that paracetamol can inhibit COX II systemically in a manner similar to selective COX-II inhibitors.
• In overdose nonsteroidal anti-inflammatory drugs such as ibuprofen, cause dose-dependent increase in urinary potassium excretion (FeK) and sodium retention, probably due to vasoconstriction.

What this study adds

• Paracetamol overdose is associated with dose-related hypokalaemia and kaliuresis of short duration (<24 h), suggesting a specific renal effect of paracetamol in overdose.
• This effect seems likely to be via cyclo-oxygenase inhibition and may be separate from the nephrotoxic effects of paracetamol.

Aims

To investigate the effects of acute paracetamol overdose on renal function, serum and urine electrolyte excretion in man.

Methods

Two studies were performed in patients admitted with paracetamol overdose: a retrospective study examining changes in serum electrolytes, and a prospective study evaluating changes in serum and urine electrolytes. A control group with SSRI overdose was included in the prospective study.

Results

There was a significant dose-dependent relationship between admission (4 h) paracetamol concentration and fall in serum potassium in the retrospective study (P < 0.01) and a significant positive relationship between serum paracetamol at 4 h and fractional excretion of potassium at 12 h postingestion (P < 0.01) in the prospective study. No changes were seen in the control group. No cases developed renal failure.

Conclusions

Paracetamol overdose is associated with dose-related hypokalaemia, and kaliuresis of short duration (<24 h), suggesting a specific renal effect of paracetamol in overdose perhaps via cyclo-oxygenase inhibition. This effect seems distinct from any nephrotoxic effect of paracetamol.     

Trends in antidepressant overdoses

BACKGROUND: Debate continues about antidepressants and suicide. However, there are few recent nation-wide data about antidepressant overdoses. The purpose of this study was to describe United States trends from 1983 through 2003 in antidepressant overdoses as well as trends in health care utilization and mortality. METHODS: Data were obtained from the American Association of Poison Control Centers' (AAPPC) Toxic Exposure Surveillance System (TESS), the National Hospital Ambulatory Medical Care Survey (NHAMCS) of emergency departments, and the National Hospital Discharge Survey(NHDS). RESULTS: Antidepressant overdose reports rose dramatically in the United States (from 0.61 per 10,000 population in 1983 to 3.26 per 10,000 population in 2003) chiefly due to the rise in selective serotonin reuptake inhibitor (SSRI) ingestion. However, fatalities per antidepressant overdose report declined from 73 per 10,000 reported ingestions to 32 per 10,000 ingestions. Tricyclic antidepressant (TCA) overdoses had higher rates of hospitalization (78.7 vs. 64.7% hospitalized) and much higher fatality rates than did SSRI overdose reports (0.73 vs. 0.14% mortality). If the 55,977 SSRI overdoses in 2003 had represented TCA overdoses, then (other things being equal) approximately 410 fatalities would have been expected but only 106 people died. Emergency department visits associated with antidepressant overdose increased along with all emergency department visits. Hospitalization associated with antidepressant overdose increased in the early 1980s but then reached a plateau while overall hospitalizations declined. CONCLUSIONS: The dramatic rise in United States antidepressant overdoses has not been reflected in antidepressant overdose fatalities nor in hospitalizations. If the marked increase in antidepressant overdoses in the United States had involved TCAs rather than SSRIs, then there would have been roughly 300 excess deaths annually.     

A systematic, updated review on the antidepressant agomelatine focusing on its melatonergic modulation

Objective:

To present an updated, comprehensive review on clinical and pre-clinical studies on agomelatine.

Method:

A MEDLINE, Psycinfo and Web of Science search (1966-May 2009) was performed using the following keywords: agomelatine, melatonin, S20098, efficacy, safety, adverse effect, pharmacokinetic, pharmacodynamic, major depressive disorder, bipolar disorder, Seasonal Affective Disorder (SAD), Alzheimer, ADHD, Generalized Anxiety Disorder (GAD), Panic Disorder (PD), Obsessive-Compulsive Disorder (OCD), anxiety disorders and mood disorder.

Study collection and data extraction:

All articles in English identified by the data sources were evaluated. Randomized, controlled clinical trials involving humans were prioritized in the review. The physiological bases of melatonergic transmission were also examined to deepen the clinical comprehension of agomelatine’ melatonergic modulation.

Data synthesis:

Agomelatine, a melatonergic analogue drug acting as MT₁/MT₂ agonist and 5-HT_2C antagonist, has been reported to be an effective antidepressant therapy.

Conclusions:

Although a bias in properly assessing the “sleep core” of depression may still exist with current screening instruments, therefore making difficult to compare agomelatine’ efficacy to other antidepressant ones, comparative studies showed agomelatine to be an intriguing option for depression and, potentially, for other therapeutic targets as well.     

Selective serotonin re-uptake inhibiting antidepressants and the risk of overanticoagulation during acenocoumarol maintenance treatment

AIM

The aim of this study was to investigate the effects of co-medication with selective serotonin re-uptake inhibitors (SSRIs) on overanticoagulation during acenocoumarol maintenance treatment.

METHODS

All subjects from The Rotterdam Study who received acenocoumarol maintenance treatment between April 1 1991 and September 9 2009 were followed for the event of an international normalized ratio (INR) ≥6, until death, end of treatment or end of the study period. With the Andersen-Gill extension of the Cox proportional hazards model, risks for repeated events of overanticoagulation in relation to concomitant SSRI use were calculated.

RESULTS

The risk for overanticoagulation during acenocoumarol maintenance treatment was increased in combination with fluvoxamine (HR 2.63, 95% CI 1.49, 4.66) and venlafaxine (HR 2.19, 95% CI 1.21, 3.99). There was no increase in risk for the other SSRIs, but numbers of exposed cases were low for all SSRIs except paroxetine.

CONCLUSION

Fluvoxamine and venlafaxine were associated with a more than double risk of INR values ≥6 in acenocoumarol treated subjects.     

The effect of selective serotonin re-uptake inhibitors on the risk of myocardial infarction in a cohort of patients with depression

AIM

To evaluate whether selective serotonin re-uptake inhibitor (SSRI) exposure influences the risk of myocardial infarction (MI) in patients with depression.

METHODS

This study included 693 patients with MI (cases) and 2772 controls. Conditional logistic regression was used to calculate the odds ratio (OR).

RESULTS

SSRI exposure may be associated with a reduced MI risk (OR = 0.77, 95% CI 0.57, 1.03). However, reduced risk was only observed with longer term use (OR = 0.73, 95% CI 0.53, 1.00) and not with shorter term use (OR = 1.15, 95% CI: 0.65, 2.05).

CONCLUSIONS

Only longer term use of SSRIs was associated with reduced MI risk, suggesting that other mechanisms, besides an acute anti-platelet effect, may reduce MI risk.     

Evidence for a differential opioidergic involvement in the analgesic effect of antidepressants: prediction for efficacy in animal models of neuropathic pain?

BACKGROUND AND PURPOSE

Antidepressants are one of the recommended treatments for neuropathic pain. However, their analgesic action remains unpredictable, and there are no selection criteria for clinical use. Better knowledge of their mechanism of action could help highlight differences underlying their unequal efficacy.

EXPERIMENTAL APPROACH

We compared the activity of a tricyclic antidepressant (clomipramine) with selective 5-HT and noradrenaline reuptake inhibitors (milnacipran and duloxetine) in streptozocin-induced diabetic and chronic constriction nerve injury-induced neuropathic rats, after repeated injections. We looked for an opioidergic mechanism in their action.

KEY RESULTS

Abolition of mechanical hyperalgesia was observed in mononeuropathic rats after five injections of clomipramine (5 mg·kg⁻¹, s.c.) and milnacipran (10 or 20 mg·kg⁻¹, i.p.) and in diabetic rats after clomipramine. An additional antinociceptive effect was obtained with five injections of duloxetine (3 mg·kg⁻¹, i.p.) in both models and milnacipran (10 mg·kg⁻¹, i.p.) in diabetic rats. These effects were observed with plasma antidepressant concentrations similar to those found in patients treated for neuropathic pain. Naloxone (1 mg·kg⁻¹, i.v.) only suppressed the anti-hyperalgesic effects of clomipramine in both models of pain and of milnacipran in the traumatic model.

CONCLUSIONS AND IMPLICATIONS

The opioid system appears to be involved in the mechanism of action of antidepressants that only have an anti-hyperalgesic effect but not in those that have a stronger (i.e. antinociceptive) effect. These differences between the antidepressants occurred whatever the aetiology of the neuropathy and, if confirmed in clinical trials, could be used to decide which antidepressant is administered to a patient with neuropathic pain.     

Predictive factors for generalized seizures after deliberate citalopram overdose

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Citalopram is a common means of self-poisoning in young adults.
• Generalized seizures are a recognised complication after selective serotonin reuptake inhibitor overdose (including citalopram overdose).

WHAT THIS STUDY ADDS

• The minimum stated citalopram dose associated with seizures in the absence of co-ingested drugs was 400 mg.
• Co-ingestion of a tricyclic antidepressant or venlafaxine confers a 15-fold increased risk of seizures.

AIMS

Seizures are a recognized complication of citalopram overdose. The present study sought to establish risk factors for seizures in this high-risk patient group, including stated dose ingested, co-ingested drugs or ethanol, and electrolyte disturbances.

METHODS

A retrospective casenote review was carried out of patients who attended the Emergency Department due to citalopram overdose between January 2000 and July 2007 inclusive. Stepwise logistic regression analysis considered age, gender, stated citalopram dose, acute ethanol consumption, co-ingested drugs, administration of activated charcoal, and hyponatraemia.

RESULTS

There were 241 patients (177 women), and the median (interquartile range) stated citalopram dose was 300 mg (200 to 600 mg). Generalized seizures occurred in 18 patients (7.5%). Logistic regression analysis found co-ingested tricyclic antidepressants or venlafaxine predicted seizures with odds ratio = 15 (95% confidence interval 3, 75). In the absence of co-ingested drugs, the minimum citalopram dose associated with seizures was 400 mg. Odds ratio for seizures = 1.1 (95% confidence interval 1.0, 1.2) for every 100 mg increment in citalopram dose. Seizures were associated with a greater need for invasive ventilatory support, higher creatine kinase activity, and prolonged hospital stay.

CONCLUSIONS

Generalized seizures are an important manifestation of citalopram toxicity, and cannot be explained solely by electrolyte disturbances or co-ingestion of other drugs or ethanol. The strongest predictors of seizures in this patient series were ingestion of high citalopram dosages and co-ingestion of drugs capable of lowering seizure threshold.     

S100B Serum Levels Predict Treatment Response in Patients with Melancholic Depression

Background:

There is an ongoing search for biomarkers in psychiatry, for example, as diagnostic tools or predictors of treatment response. The neurotrophic factor S100 calcium binding protein B (S100B) has been discussed as a possible predictor of antidepressant response in patients with major depression, but also as a possible biomarker of an acute depressive state. The aim of the present study was to study the association of serum S100B levels with antidepressant treatment response and depression severity in melancholically depressed inpatients.

Methods:

After a wash-out period of 1 week, 40 inpatients with melancholic depression were treated with either venlafaxine or imipramine. S100B levels and Hamilton Depression Rating Scale (HAM-D) scores were assessed at baseline, after 7 weeks of treatment, and after 6 months.

Results:

Patients with high S100B levels at baseline showed a markedly better treatment response defined as relative reduction in HAM-D scores than those with low baseline S100B levels after 7 weeks (P=.002) and 6 months (P=.003). In linear regression models, S100B was a significant predictor for treatment response at both time points. It is of interest to note that nonresponders were detected with a predictive value of 85% and a false negative rate of 7.5%. S100B levels were not associated with depression severity and did not change with clinical improvement.

Conclusions:

Low S100B levels predict nonresponse to venlafaxine and imipramine with high precision. Future studies have to show which treatments are effective in patients with low levels of S100B so that this biomarker will help to reduce patients’ burden of nonresponding to frequently used antidepressants.     

Antidepressant- and anxiolytic effects of the novel melatonin agonist Neu-P11 in rodent models

Aim:

To investigate the potential antidepressant and anxiolytic effects of Neu-P11, a novel melatonin agonist, in two models of depression in rats and a model of anxiety in mice.

Methods:

In the learned helplessness test (LH), Neu-P11 or melatonin (25–100 mg/kg, ip) was administered to rats 2 h before the beginning of the dark phase once a day for 5 days and the number of escape failures and intertrial crossings during the test phase were recorded. In the forced swimming test (FST), rats received a single or repeated administration of Neu-P11 (25–100 mg/kg, ip). The total period of immobility during the test phase was assessed. In the elevated plus-maze test (EPM), mice were treated with Neu-P11 (25–100 mg/kg, ip) or melatonin in the morning or in the evening and tested 2 h later. The percentage of time spent in the open arms and the open arms entries were assessed.

Results:

In the LH test, Neu-P11 but not melatonin significantly decreased the escape deficit and had no effect on the intertrial crossings. In the FST, a single or repeated administration of Neu-P11, either in the morning or in the evening, significantly decreased the duration of immobility. In the EPM test, Neu-P11 significantly increased the percentage of time spent in the open arms and the open arms entries irrespective to the time of administration. Melatonin was effective only when administered in the afternoon.

Conclusion:

The results demonstrate that Neu-P11 exerts antidepressant and anxiolytic activities in rodent models.