Effect of lipid emulsion on neuropsychiatric drug-induced toxicity: A narrative review.

Lipid emulsion has been shown to effectively relieve refractory cardiovascular collapse resulting from toxic levels of nonlocal anesthetics. The goal of this study was to examine the effect of lipid emulsions on neuropsychiatric drug-induced toxicity using relevant case reports of human patients, with a particular focus on the Glasgow Coma Scale (GCS) score and corrected QT interval, to analyze drugs that frequently require lipid emulsion treatment. The following keywords were used to retrieve relevant case reports from PubMed: "antidepressant or antipsychotic drug or amitriptyline or bupropion or citalopram or desipramine or dosulepin or dothiepin or doxepin or escitalopram or fluoxetine or haloperidol or olanzapine or phenothiazine or quetiapine or risperidone or trazodone" and "lipid emulsion or Intralipid." Lipid emulsion treatment reversed the corrected QT interval prolongation and decreases in Glasgow Coma Scale scores caused by toxic doses of neuropsychiatric drugs, especially lipid-soluble drugs such as amitriptyline, trazodone, quetiapine, lamotrigine, and citalopram. The log P (octanol/water partition coefficient) of the group which required more than 3 lipid emulsion treatments was higher than that that of the group which required less than 3 lipid emulsion treatments. The main rationale to administer lipid emulsion as an adjuvant was as follows: hemodynamic depression intractable to supportive treatment (88.3%) > lipophilic drugs (8.3%) > suspected overdose or no spontaneous breathing (1.6%). Adjuvant lipid emulsion treatment contributed to the recovery of 98.30% of patients with neuropsychiatric drug-induced toxicity. However, further analyses using many case reports are needed to clarify the effects of lipid emulsion resuscitation.

Improved Pharmacokinetic and Pharmacodynamic Profile of Deuterium-Reinforced Tricyclic Antidepressants Doxepin, Dosulepin, and Clomipramine in Animal Models.

BACKGROUND AND OBJECTIVES: Doxepin, dosulepin, and clomipramine are tricyclic antidepressants (TCAs) that act as serotonin and noradrenaline reuptake inhibitors. The metabolites formed by N-dealkylation of these tricyclic antidepressants contribute to overall poor pharmacokinetics and efficacy. Deuteration of the methyl groups at metabolically active sites has been reported to be a useful strategy for developing more selective and potent antidepressants. This isotopic deuteration can lead to better bioavailability and overall effectiveness. The objective is to study the effect of site-selective deuteration of TCAs on their pharmacokinetic and pharmacodynamic profile by comparison with their nondeuterated counterparts. METHODS: In the current study, the pharmacokinetic profile and antidepressant behavior of deuterated TCAs were evaluated using the forced swim test (FST) and tail suspension test (TST), using male Wistar rats and male Swiss albino mice, respectively; additionally, a synaptosomal reuptake study was carried out. RESULTS: Compared with the nondeuterated parent drugs, deuterated forms showed improved efficacy in the behavior paradigm, indicating improved pharmacological activity. The pharmacokinetic parameters indicated increased maximum concentration in the plasma (Cmax), elimination half-life (t1/2), and area under the concentration-time curve (AUC)  in deuterated compounds. This can have a positive clinical impact on antidepressant treatment. Synaptosomal reuptake studies indicated marked inhibition of the reuptake mechanism of serotonin (5-HT) and norepinephrine. CONCLUSIONS: Deuterated TCAs can prove to be potentially better molecules in the treatment of neuropsychiatric disorders as compared with nondeuterated compounds. In addition, we have demonstrated a concept that metabolically active, site-selective deuteration can be beneficial for improving the pharmacokinetic and pharmacodynamic profiles of TCAs. A further toxicological study of these compounds is needed to validate their future clinical use.

Antidepressant prescribing patterns and adverse events following introduction of a National Prescribing Indicator to monitor dosulepin usage in Wales.

AIMS: Limiting use of the antidepressant dosulepin has been encouraged due to associated risks of toxicity. In April 2011, the All Wales Medicines Strategy Group introduced a National Prescribing Indicator (NPI) to monitor dosulepin usage. The aim of this study was to investigate antidepressant prescribing patterns, and selected adverse events in patients prescribed dosulepin following introduction of the NPI. METHODS: An e-cohort study was conducted. Adult patients receiving regular dosulepin prescriptions between October 2010 and March 2011 were included. Characteristics of patients who were continued on dosulepin, were switched to an alternative antidepressant or whose dosulepin was discontinued following introduction of the NPI were compared. RESULTS: In total, 4121 patients were included. Of these, 1947 (47%) continued dosulepin, 1487 (36%) were switched and 692 (17%) discontinued. Of the 692 who discontinued, 92% did not receive a prescription for another antidepressant during the follow-up period. Patients whose dosulepin was discontinued were older and were less commonly coprescribed benzodiazepines. During follow-up, recorded incidence of selected adverse events was low across all groups and no significant difference was observed. CONCLUSION: Over half of patients had discontinued dosulepin at the end of the period when the NPI was in place. Further interventions may have been required to have a greater impact on prescribing. This study provides some reassurance that dosulepin discontinuation can be a successful strategy, and that the risk of the adverse events investigated was unlikely to have been greater in those who had dosulepin discontinued than in those in whom dosulepin had been continued.

Multi-dimensional relationships among dementia, depression and prescribed drugs in England and Wales hospitals.

BACKGROUND: Dementia is a group of symptoms that largely affects older people. The majority of patients face behavioural and psychological symptoms (BPSD) during the course of their illness. Alzheimer's disease (AD) and vascular dementia (VaD) are two of the most prevalent types of dementia. Available medications provide symptomatic benefits and provide relief from BPSD and associated health issues. However, it is unclear how specific dementia, antidepressant, antipsychotic, antianxiety, and mood stabiliser drugs, used in the treatment of depression and dementia subtypes are prescribed in hospital admission, during hospital stay, and at the time of discharge. To address this, we apply multi-dimensional data analytical approaches to understand drug prescribing practices within hospitals in England and Wales. METHODS: We made use of the UK National Audit of Dementia (NAD) dataset and pre-processed the dataset. We evaluated the pairwise Pearson correlation of the dataset and selected key data features which are highly correlated with dementia subtypes. After that, we selected drug prescribing behaviours (e.g. specific medications at the time of admission, during the hospital stay, and upon discharge), drugs and disorders. Then to shed light on the relations across multiple features or dimensions, we carried out multiple regression analyses, considering the number of dementia, antidepressant, antipsychotic, antianxiety, mood stabiliser, and antiepileptic/anticonvulsant drug prescriptions as dependent variables, and the prescription of other drugs, number of patients with dementia subtypes (AD/VaD), and depression as independent variables. RESULTS: In terms of antidepressant drugs prescribed in hospital admission, during stay and discharge, the number of sertraline and venlafaxine prescriptions were associated with the number of VaD patients whilst the number of mirtazapine prescriptions was associated with frontotemporal dementia patients. During admission, the number of lamotrigine prescriptions was associated with frontotemporal dementia patients, and with the number of valproate and dosulepin prescriptions. During discharge, the number of mirtazapine prescriptions was associated with the number of donepezil prescriptions in conjunction with frontotemporal dementia patients. Finally, the number of prescriptions of donepezil/memantine at admission, during hospital stay and at discharge exhibited positive association with AD patients. CONCLUSION: Our analyses reveal a complex, multifaceted set of interactions among prescribed drug types, dementia subtypes, and depression.

Effect of Sertraline, Dosulepin, and Venlafaxine on Non-BDNF Neurotrophins in Patients With Depression: A Cohort Study.

BACKGROUND: The neurotrophic hypothesis of depression has been mostly studied with a focus on brain-derived neurotrophic factor (BDNF) leading to lack of data on non-BDNF neurotrophins (NTs). The aim of this study was to evaluate the effect of antidepressant drugs on changes in serum nerve growth factor (NGF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). METHODS: A prospective cohort study was conducted on 105 patients with depression who were subgrouped to the group 1 (mild and moderate depression without somatic syndrome treated with sertraline), group 2 (mild and moderate depression with somatic syndrome treated with dosulepin), and group 3 (severe depression without psychotic symptoms treated with venlafaxine). At baseline, the severity of depression (Montgomery-Asberg Depression Rating Scale [MADRS]), serum NGF, NT-3, and NT-4 were estimated. Thirty-five healthy volunteers were recruited as controls for a baseline comparison of NTs. All patients were followed up after 6 weeks to evaluate the changes in NT levels and correlate it with the change in MADRS scores. RESULTS: At baseline, NT levels were significantly lower in patients with depression in comparison with healthy control. In group 1, serum NGF, NT-3, and NT-4 level were found to increase significantly after treatment, whereas changes in groups 2 and 3 were statistically not significant. Montgomery-Asberg Depression Rating Scale score and serum NGF at baseline had an inverse relation (r = -0.648), whereas the change in MADRS score in sertraline group had a positive correlation (r = 0.86) with the change of serum NGF. CONCLUSIONS: Monotherapy with sertraline increased the level of non-BDNF NTs; however, treatment with dosulepin and venlafaxine did not produce any significant changes in patients with depression.

Validated spectrophotometric and spectrofluorimetric methods for determination of dapoxetine hydrochloride and dosulepin hydrochloride in their dosage forms using mercurochrome.

Validated, simple, rapid and sensitive spectrophotometric and spectrofluorimetric methods were developed for the determination of dapoxetine HCl and dosulepin HCl. The spectrophotometric method (I) was based on a binary complex formation between each drug and mercurochrome (MER) in acetate buffer (pH 3.5) with maximum absorbance at 557 nm. Calibration graphs were linear over the range 2.0-20.0 and 2.0-24.0 µg/ml, detection limits were 0.23 and 0.41 µg/ml and quantitation limits were 0.71 and 1.26 µg/ml for dapoxetine HCl and dosulepin HCl, respectively. Spectrofluorimetric method (II) was based on the measurement of the quantitative quenching effect of each drug on the native fluorescence of MER at the same pH. Fluorescence quenching of MER was measured at 538 nm after excitation at 470 nm. Calibration graphs were linear over the range 0.5-10.0 and 0.4-10.0 µg/ml, detection limits were 0.17 and 0.12 µg/ml and quantitation limits were 0.5 and 0.36 µg/ml for dapoxetine HCl and dosulepin HCl, respectively. Statistical comparison of results with those obtained by reported methods provided good agreement and revealed that there were no significant differences in accuracy and precision between methods. The proposed methods were applied successfully to analyse commercial tablets and capsules containing the studied drugs.

Spectroscopic, electrochemical and molecular docking studies of dothiepin and doxepin with bovine serum albumin and DNA base.

The interaction of dothiepin (DOT) and doxepin (DOX) with bovine serum albumin (BSA) and a DNA base (adenine) was studied using UV-visible, fluorescence, attenuated total reflection-infra-red (ATR-IR), cyclic voltammetry and molecular docking methods. Strong fluorescence quenching was observed upon interaction of DOT and DOX with BSA/adenine and the mechanism suggested static quenching. Hydrophobic and hydrogen bonding interactions were the predominant intermolecular forces needed to stabilize the copolymer. Upon addition of the drugs: (i) the tautomeric equilibrium structure of the adenine was changed; and (ii) the oxidation and the reduction peaks of the adenine/BSA interaction shifted towards high and low potentials, respectively. In ATR-IR, the band shift of amides I and II indicated a change in secondary structure of BSA upon binding to DOT and DOX drugs. The reduction in voltammetric current in the presence of BSA/adenine was attributed to slow diffusion of BSA/adenine binding with DOX/DOT. The docking method indicated that the drug moiety interacted with the BSA molecule. Copyright © 2016 John Wiley & Sons, Ltd.

A change in the trend in dosulepin usage following the introduction of a prescribing indicator but not after two national safety warnings.

WHAT IS KNOWN AND OBJECTIVE: The tricyclic antidepressant dosulepin has been associated with an increased risk of toxicity in overdose compared with other antidepressants. In the UK, the MHRA and NICE have issued advice on the prescribing of dosulepin, and a National Prescribing Indicator (NPI) to monitor usage was introduced in Wales in 2011. The aim of this study was to assess whether trends in dosulepin usage in Wales and NE England changed following the two pieces of safety guidance and the introduction of the National Prescribing Indicator in Wales. METHODS: Primary care dosulepin usage in the 12 months prior to and following MHRA safety advice (in 2007), NICE guideline CG90 (in 2009) and the introduction of the NPI (in 2011) was obtained. Usage was measured using defined daily doses (DDDs) per 1000 prescribing units (PUs). The trends in the 12 months prior to and following the introduction of prescribing advice and the NPI were compared using an autoregressive integrated moving average (ARIMA) model. RESULTS AND DISCUSSION: In Wales, the trend in dosulepin usage did not change significantly prior to and following the MHRA advice: -0·18 and -0·43 DDDs/1000PUs per month, respectively (P = 0·07), or prior to and following NICE CG90: -0·30 and -0·49 DDDs/1000PUs per month, respectively (P = 0·35). In the 12 months prior to and following the introduction of the NPI, the trend was -0·45 and -0·98 DDDs/1000PUs per month, respectively (P = 0·001). In NE England, the trend did not alter significantly following the NICE advice or the introduction of the NPI in Wales. WHAT IS NEW AND CONCLUSION: The trend in dosulepin usage in Wales altered significantly following the introduction of the NPI, but not after the other prescribing advice. This association, coupled with the absence of a significant change in NE England over the same period, provided some evidence of the effectiveness of the NPI in prompting a change in prescribing behaviour in Wales.

Hyponatraemia and confusion in a 70-year-old female when bupropion was added to dothiepin and escitalopram.

OBJECTIVE: Hyponatraemia secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a well-recorded adverse event observed in elderly patients on antidepressant treatment. Bupropion is an antidepressant agent usually reserved as an augmentation strategy for treatment-resistant depression. While hyponatraemia is not a documented side effect of bupropion, there are a few cases outside of Australia reported in the literature. We report on a case of hyponatraemia observed on bupropion initiation in a 70-year-old female patient with treatment-resistant depression. We present a discussion of the possible mechanism of action for the hyponatraemia observed in our case and prior reported cases. CONCLUSIONS: Our case and review of the available literature highlights the dangers of polypharmacy in the management of treatment-resistant depression. Our findings suggest that the association of hyponatraemia with bupropion in our and subsequent cases was likely the result of medication interaction and not a direct side effect of bupropion. Where bupropion is being used as an augmenting agent in the treatment of depression we would suggest checking of serum sodium prior to commencement of bupropion, and monitoring thereafter. This is especially important in elderly patients where other risk factors for hyponatraemia are likely to be present.

Effect of cytochrome P450 2C19 and 2C9 amino acid residues 72 and 241 on metabolism of tricyclic antidepressant drugs.

Although cytochromes P450 2C9 (CYP2C9) and 2C19 (CYP2C19) have 91% amino acid identity, they have different substrate specificities. Previous studies have suggested that several amino acid residues may be involved in substrate specificity. In this study, we focused on the roles of two amino acids, residues 72 and 241. The amino acids in these positions have opposite charges in CYP2C9 and 2C19; the former has lysines in both positions (Lys72 and Lys241), and the latter has glutamic acids (Glu72 and Glu241). Reciprocal mutants for both CYP2C19 and 2C9 were produced, and their metabolic activities and spectroscopic properties were examined using three tricyclic antidepressant (TCA) drugs: amitriptyline, imipramine, and dothiepin. Although CYP2C19 wild-type (WT) had a high metabolic activity for all three drugs, the E72K mutation decreased enzymatic activity by 29-37%, while binding affinities were diminished 2.5- to 20-fold. On the other hand, low activity and low affinity of CYP2C9 WT were recovered notably by K72E mutation. The metabolic activities and binding affinities were minimally affected by CYP2C19 E241K and CYP2C9 K241E mutations. We could also show linear correlations between metabolic activities and binding affinities, and hence we conclude that amino acid residue 72 plays a key role in TCA drug metabolism by limiting the binding affinities of CYP2C19 and CYP2C9.

Comparison of cytochrome p450 mediated metabolism of three central nervous system acting drugs.

The investigation of cytochrome P450 (CYP) mediated metabolism reactions by determination of enzyme kinetic parameters, Michaelis constant (K(m)), maximum reaction velocity (V(max)), and intrinsic clearance (CL(int)) is important aspects in discovery and development of drugs. The kinetic parameters can be used to predict the clearance prior to human administration and for better understanding the mechanism of clearance in vivo. In this study, the metabolic activities of three major hepatic CYP isoforms (2C19, 2D6, and 3A4) were investigated on structurally different central nervous system (CNS) acting drugs, amitriptyline, fluphenazine, and dothiepin. By using our novel in vitro evaluation system, we could compare the kinetic parameters for the metabolism of fluphenazine and dothiepin for the first time. Comparing CL(int) values thus obtained, we concluded that 2C19 could be predominant for metabolic activity on tricyclic antidepressants as expected, but not on phenothiazine-related antipsychotic drugs. Since the metabolism of CNS drugs is susceptible to single nucleotide polymorphisms of human gene, our results suggest that phenothiazine could be an alternative to clinical application of CNS drugs.

"Lipid rescue" for tricyclic antidepressant cardiotoxicity.

BACKGROUND: Tricyclic antidepressant (TCA) toxicity results predominantly from myocardial sodium-channel blockade. Subsequent ventricular dysrhythmias, myocardial depression, and hypotension cause cardiovascular collapse. Animal studies have demonstrated the effectiveness of intravenous lipid-emulsion in treating TCA cardiotoxicity. CASE REPORT: We report a case of dothiepin (tricyclic antidepressant) overdose causing refractory cardiovascular collapse, which seemed to be successfully reversed with lipid-emulsion therapy (Intralipid(®); Fresenius, Cheshire, UK). CONCLUSIONS: Lipid emulsions are a potentially novel therapy for reversing cardiotoxicity seen in TCA overdose. Research is required into the role of lipid emulsion in the management of poisoning by oral lipophilic agents.

Tricyclic antidepressant overdose in a toddler treated with intravenous lipid emulsion.

We report a case that involves the use of intravenous lipid emulsion as an antidote for a drug overdose involving a 20-month-old girl who had ingested a potentially lethal amount of the tricyclic antidepressant (TCA) dothiepin. The patient's condition continued to deteriorate despite implementation of standard pediatric treatment recommendations for TCA toxicity. Administration of intravenous lipid emulsion in addition to standard therapy (including sodium bicarbonate) and direct-current cardioversion for ventricular arrhythmia led to a successful outcome. The case report is followed by a review of the current evidence underlying this novel therapy and the background on its use. TCA toxicity is addressed specifically.

Successful reversal of life threatening cardiac effect following dosulepin overdose using intravenous lipid emulsion.

CONTEXT. We report a successful acute reversal of potential life threatening QRS complex widening and prolonged QT interval following dosulepin overdose using intravenous lipid emulsion 20% in an unstable patient. CASE DETAILS. A 36-year-old female following the ingestion of 5.25 g of dosulepin. On submission the QRS complex was 120 ms and the QT interval was 348 ms (BP 129/71 mmHg, HR 113 beats/min). Her level of consciousness deteriorated and the patient had episodes of seizures. The patient received bicarbonate, 200 mmol, and assisted ventilation. Ninety minutes following submission, the QRS complex was 158 ms and the QT interval was 422 ms (BP 118/55 mmHg, HR 91 beats/min), and to treat the intoxication intravenous lipid emulsion 20% was dosed as 1.5 ml/kg (100 ml) in 5 min followed by 400 ml in 20 min. Blood pressure was immediately stabilised and the monitored QRS complex narrowed and QT interval became shorter. DISCUSSION. Cyclic antidepressants affect the cardiac conduction system and the myocardium. The exact mechanism of action from intravenous lipid emulsions may not be determined from the data presented, and the obtained effect does not rule out the supposed effects of alkalinisation and supported ventilation. However, the effects of the treatment of the severe dosulepin intoxication support the theory of intravenous lipid emulsions creating an intravenous lipid sink for drugs with high lipid solubility.

Brugada like pattern in ECG with drug overdose.

Tricyclic antidepressants (TCAs) may have dangerous cardiac effects in overdose. ECG is useful as both a screening tool for tricyclic antidepressant exposure and as a prognostic indicator. TCA overdose may produce various ECG changes. We report a case of Dothiepin overdose resulting in Brugada like pattern including RBBB which resolved spontaneously.

Suspected antidepressant-induced switch to mania in unipolar depression: a first-person narrative.

BACKGROUND: Antidepressant-induced switch to mania has not been thoroughly characterized in bipolar disorder and is even less well understood in unipolar depression. METHOD AND RESULTS: I describe, as a first-person narrative, my own experience of psychotic mania, which was suspected to have been induced by the tricyclic antidepressant, dosulepin. I have had a 16-year history of depression and was receiving sertraline 50 mg od when I was prescribed, off licence, dosulepin 25 mg 1-2 nocte for insomnia. Within days, I developed mild hypomanic symptoms and returned to my GP, who discontinued dosulepin but continued treatment with sertraline. I was also referred for psychiatric assessment. Two months later, I was detained under Section II of the Mental Health Act 1983 and admitted to hospital with psychotic manic symptoms. CONCLUSION: More understanding of antidepressant-induced switch to mania is needed in unipolar depression. My case study highlights the need for prompt specialist care for patients with depression reporting even mild, sub-threshold symptoms of mania.

A comparative study of non-fatal self-poisoning with antidepressants relative to prescribing in three centres in England.

BACKGROUND: Antidepressants are used frequently in non-fatal self-poisoning. There are national guidelines for prescribing antidepressants. There have been few investigations of how non-fatal self-poisoning with antidepressants varies in relation to prescribing and to patient characteristics. METHODS: A comparative study of the use of specific antidepressants (amitriptyline and dosulepin (tricyclics), citalopram, fluoxetine, paroxetine and sertraline (selective serotonin reuptake inhibitors) and venlafaxine (serotonin norepinephrine reuptake inhibitor)) for non-fatal self-poisoning (episode-based), relative to prescribing, in three centres in England, 2004 to 2006. RESULTS: There was marked variation between centres in the ratio of rates of self-poisoning to prescribing for specific antidepressants. Higher rates of self-poisoning relative to prescribing for all antidepressants combined, and for venlafaxine, were found in the centre with greater proportions of patients with a history of self-harm and/or previous psychiatric treatment. Within each centre, higher rates of self-poisoning relative to prescribing were found for citalopram and fluoxetine than amitriptyline. However, rates of self-poisoning relative to prescribing for either amitriptyline or dosulepin were also similar to sertraline, which is of concern given the known toxicity of tricyclics. LIMITATIONS: An ecological study, where prescriptions were for all indications and not specifically for the patients who self-poisoned. CONCLUSIONS: Marked differences found in ratios of self-poisoning with antidepressants to levels of prescribing, in three centres in England, are likely to reflect differences in both prescribing practices (despite clear national guidance) and patient characteristics. Risk of overdose and toxicity should be considered when local prescribing policy and clinical practice relating to antidepressants are under review.

Brugada-like ECG pattern induced by tricyclic antidepressants.

We present the case report of a 57-year-old woman with severe monointoxication with dosulepine (Prothiaden) who developed a Brugada-like electrocardiographic pattern. In tricyclic antidepressants (TCAs) poisoning the Brugada-like pattern on electrocardiogram is a characteristic albeit rare manifestation of the frequently occurring conduction abnormalities in the myocardium and its recognition is imperative as it is associated with a higher degree of morbidity and mortality. An overview of the literature is given and recommendations concerning treatment of TCA-induced arrhythmias are provided. After successful treatment, the electrocardiogram in the patient normalized. However, 4 days after intoxication, the ajmaline test was positive (pharmacological induction of a type I Brugada-like pattern), but a subsequent one, repeated after 11 days, was reportedly normal, probably because of the slow clearance of dosulepine. This raises questions about the specificity of ajmaline testing for Brugada syndrome in patients taking dosulepine and perhaps other TCAs and neuroleptic agents.