Combinations of QTc-prolonging drugs: towards disentangling pharmacokinetic and pharmacodynamic effects in their potentially additive nature

Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug-drug interactions

Antipsychotic Dose Mediates the Association between Polypharmacy and Corrected QT Interval

Antipsychotic (AP) drugs have the potential to cause prolongation of the QT interval corrected for heart rate (QTc). As this risk is dose-dependent, it may be associated with the number of AP drugs concurrently prescribed, which is known to be associated with increased cumulative equivalent AP dosage. This study analysed whether AP dose mediates the relationship between polypharmacy and QTc interval. We used data from a cross-sectional survey that investigated the prevalence of QTc lengthening among people with psychiatric illnesses in Italy. AP polypharmacy was tested for evidence of association with AP dose and QTc interval using the Baron and Kenny mediational model. A total of 725 patients were included in this analysis. Of these, 186 (26%) were treated with two or more AP drugs (AP polypharmacy). The mean cumulative AP dose was significantly higher in those receiving AP polypharmacy (prescribed daily dose/defined daily dose = 2.93, standard deviation 1.31) than monotherapy (prescribed daily dose/defined daily dose = 0.82, standard deviation 0.77) (z = -12.62, p < 0.001). Similarly, the mean QTc interval was significantly longer in those receiving AP polypharmacy (mean = 420.86 milliseconds, standard deviation 27.16) than monotherapy (mean = 413.42 milliseconds, standard deviation 31.54) (z = -2.70, p = 0.006). The Baron and Kenny mediational analysis showed that, after adjustment for confounding variables, AP dose mediates the association between polypharmacy and QTc interval. The present study found that AP polypharmacy is associated with QTc interval, and this effect is mediated by AP dose. Given the high prevalence of AP polypharmacy in real-world clinical practice, clinicians should consider not only the myriad risk factors for QTc prolongation in their patients, but also that adding a second AP drug may further increase risk as compared with monotherapy

Effectiveness of lithium in subjects with treatment-resistant depression and suicide risk: results and lessons of an underpowered randomised clinical trial

BACKGROUND: As lithium treatment might be effective in reducing the risk of deliberate self-harm (DSH) in adult patients with unipolar affective disorders, we designed a pragmatic randomised trial to assess its efficacy in more than 200 patients with treatment-resistant depression. However, we randomised 56 patients only. The aim of this report is therefore twofold: first, to disseminate the results of this underpowered study which may be incorporated into future meta-analytical reviews; second, to analyse some critical aspects of the study which might explain failure to reach the target sample size.METHODS: We carried out a randomised, parallel group, assessor-blinded superiority clinical trial. Adults with a diagnosis of major depression, an episode of DSH in the previous 12 months and inadequate response to at least two antidepressants given sequentially at an adequate dose for an adequate time for the current depressive episode were allocated to add lithium to usual care (intervention arm) versus usual care alone (control arm). Suicide completion and acts of DSH during the 12 months of follow-up constituted the composite primary outcome.RESULTS: Of 58 patients screened for inclusion, 29 were allocated to lithium plus usual care and 27 were assigned to usual care without lithium. Six patients in the lithium plus usual care group and seven in the usual care group committed acts of DSH during the follow-up phase. The survival probability did not differ between the two treatment arms (Chi2 = 0.17, p =0.676). With regard to changes in the severity of depressive symptomatology from baseline to endpoint, no significant differences were detected.CONCLUSIONS: The present study failed to achieve the minimum sample size needed to detect a clinically meaningful difference between the two treatment arms. Consequently, the finding that lithium, in addition to usual care, did not exert a positive effect in terms of reduction of DSH after 12 months of follow-up is likely due to the lack of sufficient statistical power to detect a difference, if a difference existed. The dissemination of the results of this underpowered study will inform future meta-analytical reviews on lithium and suicide-related outcomes.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00927550

Pharmacological treatments of panic disorder. A systematic review and meta-analysis of antidepressants versus placebo studies

L\u2019attacco di panico \ue8 un episodio in cui la paura o l\u2019ansia si manifestano con almeno 4 di 13 sintomi caratteristici sia psichici che fisici. L\u2019attacco ha in genere un inizio repentino con un picco di intensit\ue0 raggiunto nell\u2019arco di 10 minuti.Il trattamento del Disturbo da Attacchi di panico (DAP) include sia interventi psicologici che farmacologici, spesso usati in combinazione.Alla luce della complessit\ue0 di tale condizione e della mancanza di dati prodotti da revisioni sistematiche sull\u2019argomento, abbiamo considerato l\u2019importanza di condurre una revisione sistematica che tenga conto di tutti gli interventi farmacologici attualmente disponibili, utilizzando la tecnica della Network Meta-Analysis (NMA), per poter valutare, quali tra i trattamenti attualmente a disposizione, sono pi\uf9 efficaci e tollerabili.OBIETTIVI: determinare l\u2019efficacia, la tollerabilit\ue0 e gli effetti collaterali degli antidepressivi in confronto al placebo nel trattamento del DAP con o senza agorafobia.METODI: Il mio lavoro \ue8 parte di un progetto pi\uf9 ampio, la Network Meta-Analysis (NMA), che coinvolge altri membri internazionali del CCDAN (Cochrane Collaboration Neurosis and Anxiety group). Per questo lavoro sono stati coinvolti due revisori, AC e la sottoscritta (MC). I due revisori hanno indipendentemente analizzato le referenze e gli abstracts (1383) forniti dal CCDAN relative all\u2019argomento, selezionandone 104 come adatte alla revisione. Sono stati poi cercati e trovate le pubblicazioni corrispondenti, dalla lettura delle quali \ue8 stato possibile identificare 42 studi. Una volta selezionati gli studi, abbiamo indipendentemente estratto i dati, effettuata una valutazione della qualit\ue0 degli studi usando il \u201crisk of bias tool\u201d fornito dal Cochrane Handbook. I dati estratti sono stati inseriti e rielaborati utilizzando il software Review Manager versione 5.3, sia per le misure di esito primarie (tasso di risposta al trattamento e pazienti che hanno abbandonato lo studio) che secondarie.RISULTATI: i risultati di questa meta-analisi ampliano le attuali evidenze relative all\u2019efficacia degli antidepressivi nei pazienti affetti da Disturbo da Attacchi di Panico. Un dato interessante emerso \ue8 che il trattamento con i triciclici sembrava essere pi\uf9 accettabile rispetto al placebo, dato che non \ue8 stato riscontrato nei confronti tra le altri classi di antidepressivi verso placebo. Una spiegazione potrebbe essere il fatto che sono pochi gli studi su triciclico che riportano \u201cil numero di pazienti che riferiscono almeno un effetto collaterale\u201d , e ci\uf2 potrebbe essere indicativo di una bias di segnalazione (\u201creporting bias\u201d). CONCLUSIONI: i risultati di questa meta-analisi sono in linea con ci\uf2 che \ue8 gi\ue0 risaputo, cio\ue8 che gli antidepressivi sono superiori rispetto al placebo nel trattamento del DAP, in termini di efficacia, di tollerabilit\ue0, di riduzione dell\u2019ansia e dei sintomi depressivi e nel migliorare il funzionamento sociale.Ci\uf2 conferma quello che viene suggerito dalle linee guida internazionali (APA 2009, BAP 2005 and NICE 2011), cio\ue8 l\u2019uso dell\u2019antidepressivo come trattamento di prima scelta in associazione con la CBT (terapia cognitivo-comportamentale). Il dato inusuale riguarda la tollerabilit\ue0 dei TCA. Possiamo ipotizzare che il beneficio prodotto sui sintomi da attacchi di panico possa compensare il profilo di bassa tollerabilit\ue0 in termini di aderenza al trattamento. Questo dato potrebbe indurci a riconsiderare i triciclici, in particolare l\u2019imipramina, come possibile prima scelta nel trattamento di quelle forme di DAP dove i livelli di ansia sono particolarmente intensi, sfruttando il profilo particolarmente sedativo di questi antidepressivi. Alla luce della qualit\ue0 delle evidenze possiamo infine affermare che sarebbe necessario condurre altri studi con pi\uf9 alto livello di qualit\ue0, in particolare con una maggiore attenzione nel riportare le procedure di randomizzazione e un minore coinvolgimento delle case farmaceutiche per evitare che ci\uf2 possa essere fuorviante rispetto alle conclusioni.A panic attack is a discrete period of fear or anxiety with a rapid onset, reaching a peak within 10 minutes and in which at least 4 of 13 characteristic symptoms, involv-ing both bodily systems and fearful cognitions, are experienced. The treatment of panic disorder (PD) includes psychological and pharmacological interventions, often used in combination. Given the complexity of the condition and the lack of recent data from systematic reviews in PD we have considered the importance of carrying out a comprehensive review of available drug options, in the framework of network meta-analysis (NMA), to assess which treatments, if any, are the most effective and safe. OBJECTIVES: To determine the efficacy, the acceptability and the adverse effects of anti-depressants in comparison to placebo in the treatment of PD with or without agora-phobia.METHODS: My work is part of a bigger project, a network meta-analysis (NMA), involving other international members of the Cochrane Collaboration Neurosis and Anxiety group (CCDAN).The second reviewer (AC) and I (MC) independently checked the references provid-ed by the CCDAN search and selected 104 out of 1383 abstracts and references, as eligible for our review, of which we retrieved the corresponding full texts, whereas possible. We selected 42 eligible studies, we extracted the data, we performed the \u201cquality assessment\u201d of each study using the \u201crisk of bias tool\u201d provided by the Cochrane Handbook. We performed the data entry using Review Manager 5.3 ver-sion and we got results for the primary outcomes (response rate and drop-outs) and secondary outcomes.RESULTS: The results of this meta-analysis expand current evidence on the efficacy of antidepressants in patients with panic disorder. Interestingly, treatment with TCAs was more acceptable than placebo, while treatment with other antidepressants, when compared to placebo, was not associated with a better acceptability profile. In terms of number of patients experiencing at least one adverse effect, there were too few studies reporting data, and this might be suggestive of a reporting bias.CONCLUSIONS: These results are consistent with the fact that antidepressants, which are widely used in people affected by panic disorder, are better than placebo, in terms of effectiveness and tolerability, and also reducing symptoms of anxiety and depression and improving social functioning. This confirms what is already suggested by the international guidelines (APA 2009, BAP 2005 and NICE 2011), where their use is suggested as first line treatment together with CBT. The unusual data regards TCAs tolerability. We might hypothesize that the benefit of the TCAs over panic symptoms might compensate the low tolerability profile in terms of adherence to treatment. So this could suggest us to reconsider this class of antidepressants (in par-ticular imipramine) as a possibile first choice of treatment, maybe for more severe cases, taking advantage of their sedative profile, in those cases where anxiety raises particularly high levels. There is a need of studies with a higher quality, in particular better reporting of the randomization process and less sponsorship bias that could have influenced the results

Immagine corporea: confronto tra pazienti con disturbi del comportamento alimentare e pazienti con altri disturbi psichiatrici afferenti al Servizio di Psicoterapia del Policlinico \u201cG.B. Rossi\u201d in Verona

Immagine corporea: confronto tra pazienti con disturbi del comportamento alimentare e pazienti con altri disturbi psichiatrici afferenti al Servizio di Psicoterapia del Policlinico \u201cG.B. Rossi\u201d in Veron

Data from: Antipsychotic dose mediates the association between polypharmacy and corrected QT interval

Antipsychotic (AP) drugs have the potential to cause prolongation of the QT interval corrected for heart rate (QTc). As this risk is dose-dependent, it may be associated with the number of AP drugs concurrently prescribed, which is known to be associated with increased cumulative equivalent AP dosage. This study analysed whether AP dose mediates the relationship between polypharmacy and QTc interval. We used data from a cross-sectional survey that investigated the prevalence of QTc lengthening among people with psychiatric illnesses in Italy. AP polypharmacy was tested for evidence of association with AP dose and QTc interval using the Baron and Kenny mediational model. A total of 725 patients were included in this analysis. Of these, 186 (26%) were treated with two or more AP drugs (AP polypharmacy). The mean cumulative AP dose was significantly higher in those receiving AP polypharmacy (prescribed daily dose/defined daily dose = 2.93, standard deviation 1.31) than monotherapy (prescribed daily dose/defined daily dose = 0.82, standard deviation 0.77) (z = −12.62, p < 0.001). Similarly, the mean QTc interval was significantly longer in those receiving AP polypharmacy (mean = 420.86 milliseconds, standard deviation 27.16) than monotherapy (mean = 413.42 milliseconds, standard deviation 31.54) (z = −2.70, p = 0.006). The Baron and Kenny mediational analysis showed that, after adjustment for confounding variables, AP dose mediates the association between polypharmacy and QTc interval. The present study found that AP polypharmacy is associated with QTc interval, and this effect is mediated by AP dose. Given the high prevalence of AP polypharmacy in real-world clinical practice, clinicians should consider not only the myriad risk factors for QTc prolongation in their patients, but also that adding a second AP drug may further increase risk as compared with monotherapy

Antidepressants and benzodiazepines for panic disorder in adults

A panic attack is a discrete period of fear or anxiety that has a rapid onset, reaches a peak within 10 minutes and in which at least four of 13 characteristic symptoms are experienced, including racing heart, chest pain, sweating, shaking, dizziness, flushing, stomach churning, faintness and breathlessness. Panic disorder is common in the general population with a lifetime prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions. Amongst pharmacological agents, antidepressants and benzodiazepines are the mainstay of treatment for panic disorder. Different classes of antidepressants have been compared; and the British Association for Psychopharmacology, and National Institute for Health and Care Excellence (NICE) consider antidepressants (mainly selective serotonin reuptake inhibitors (SSRIs)) as the first-line treatment for panic disorder, due to their more favourable adverse effect profile over monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). In addition to antidepressants, benzodiazepines are widely prescribed for the treatment of panic disorder

Benzodiazepines versus placebo for panic disorder in adults

BackgroundPanic disorder is characterised by recurrent unexpected panic attacks consisting of a wave of intense fear that reaches a peak within a few minutes. Panic disorder is a common disorder, with an estimated lifetime prevalence of 1% to 5% in the general population and a 7% to 10% prevalence in primary care settings. Its aetiology is not fully understood and is probably heterogeneous.Panic disorder is treated with psychological and pharmacological interventions, often used in combination. Although benzodiazepines are frequently used in the treatment of panic disorder, guidelines recommend antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as first-line treatment for panic disorder, particularly due to their lower incidence of dependence and withdrawal reaction when compared to benzodiazepines. Despite these recommendations, benzodiazepines are widely used in the treatment of panic disorder, probably because of their rapid onset of action.ObjectivesTo assess the efficacy and acceptability of benzodiazepines versus placebo in the treatment of panic disorder with or without agoraphobia in adults.Search methodsWe searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR Studies and References), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950-), Embase (1974-), and PsycINFO (1967-) up to 29 May 2018. We handsearched reference lists of relevant papers and previous systematic reviews. We contacted experts in the field for supplemental data.Selection criteriaAll double-blind (blinding of patients and personnel) controlled trials randomising adults with panic disorder with or without agoraphobia to benzodiazepine or placebo.Data collection and analysisTwo review authors independently checked the eligibility of studies and extracted data using a standardised form. Data were then entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details, settings, and outcome measures in terms of efficacy, acceptability, and tolerability.Main resultsWe included 24 studies in the review with a total of 4233 participants, of which 2124 were randomised to benzodiazepines and 1475 to placebo. The remaining 634 participants were randomised to other active treatments in three-arm trials. We assessed the overall methodological quality of the included studies as poor. We rated all studies as at unclear risk of bias in at least three domains. In addition, we judged 20 of the 24 included studies as having a high risk of bias in at least one domain.Two primary outcomes of efficacy and acceptability showed a possible advantage of benzodiazepines over placebo. The estimated risk ratio (RR) for a response to treatment was 1.65 (95% confidence interval (CI) 1.39 to 1.96) in favour of benzodiazepines, which corresponds to an estimated number needed to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 7). The dropout rate was lower among participants treated with benzodiazepines (RR 0.50, 95% CI 0.39 to 0.64); the estimated NNTB was 6 (95% CI 5 to 9). We rated the quality of the evidence as low for both primary outcomes. The possible advantage of benzodiazepine was also seen for remission (RR 1.61, 95% CI 1.38 to 1.88) and the endpoint data for social functioning (standardised mean difference (SMD) -0.53, 95% CI -0.65 to -0.42), both with low-quality evidence. We assessed the evidence for the other secondary outcomes as of very low quality. With the exception of the analyses of the change score data for depression (SMD -0.22, 95% CI -0.48 to 0.04) and social functioning (SMD -0.32, 95% CI -0.88 to 0.24), all secondary outcome analyses showed an effect in favour of benzodiazepines compared to placebo. However, the number of dropouts due to adverse effects was higher with benzodiazepines than with placebo (RR 1.58, 95% CI 1.16 to 2.15; low-quality evidence). Furthermore, our analyses of adverse events showed that a higher proportion of participants experienced at least one adverse effect when treated with benzodiazepines (RR 1.18, 95% CI 1.02 to 1.37; low-quality evidence).Authors' conclusionsLow-quality evidence shows a possible superiority of benzodiazepine over placebo in the short-term treatment of panic disorders. The validity of the included studies is questionable due to possible unmasking of allocated treatments, high dropout rates, and probable publication bias. Moreover, the included studies were only short-term studies and did not examine the long-term efficacy nor the risks of dependency and withdrawal symptoms. Due to these limitations, our results regarding the efficacy of benzodiazepines versus placebo provide only limited guidance for clinical practice. Furthermore, the clinician's choice is not between benzodiazepines and placebo, but between benzodiazepines and other agents, notably SSRIs, both in terms of efficacy and adverse effects. The choice of treatment should therefore be guided by the patient's preference and should balance benefits and harms from treatment in a long-term perspective

Azapirones versus placebo for panic disorder in adults

BACKGROUND: Panic disorder is common in the general population. It is often associated with other psychiatric disorders, such as drug dependence, major depression, bipolar disorder, social phobia, specific phobia and generalised anxiety disorder. Azapirones are a class of drugs used as anxiolytics. They are associated with less drowsiness, psychomotor impairment, alcohol potentiation and potential for addiction or abuse than benzodiazepines. However, azapirones are not widely used in the treatment of panic disorder and evidence for their efficacy is unclear. It is important to find out if azapirones are effective and acceptable in the treatment of panic disorder. OBJECTIVES: To assess the effects of azapirones on panic disorder in adults, specifically:1. to determine the efficacy of azapirones in alleviating symptoms of panic disorder, with or without agoraphobia, in comparison with placebo;2. to review the acceptability of azapirones in panic disorder, with or without agoraphobia, in comparison with placebo; and3. to investigate adverse effects of azapirones in panic disorder with or without agoraphobia, including general prevalence of adverse effects, compared with placebo. SEARCH METHODS: We searched the Cochrane Depression Anxiety and Neurosis Group Trials Specialised Register (CCDANCTR, search date: 10th January 2014), which includes relevant randomised controlled trials from The Cochrane Library (all years), MEDLINE (1950-), EMBASE (1974-), and PsycINFO (1967-). SELECTION CRITERIA: Randomised controlled trials that compared azapirones with placebo for panic disorder in adults. DATA COLLECTION AND ANALYSIS: Three review authors independently identified studies, assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: Three studies involving 170 participants compared the azapirone buspirone with placebo. No study provided enough usable information on our primary efficacy outcome (response). For our primary acceptability outcome, moderate-quality evidence indicated that azapirones had lower acceptability than placebo: risk ratio (RR) for dropouts for any reason 2.13 (95% confidence interval (CI) 1.11 to 4.07; 3 studies, 170 participants. Evidence for secondary efficacy outcomes were of low quality. Results on efficacy between azapirone and placebo in terms of agoraphobia (standardised mean difference (SMD) -0.01, 95% CI -0.56 to 0.53; 1 study, 52 participants), general anxiety (mean difference (MD) -2.20, 95% CI -5.45 to 1.06; 2 studies, 115 participants) and depression (MD -1.80, 95% CI -5.60 to 2.00; 1 study, 52 participants) were uncertain. None of the studies provided information for the assessment of allocation concealment or sequence generation. Conflicts of interest were not explicitly expressed. The risk of attrition bias was rated high for all three studies. Information on adverse effects other than dropouts for any reason was insufficient to include in the analyses. AUTHORS' CONCLUSIONS: The efficacy of azapirones is uncertain due to the lack of meta-analysable data for the primary outcome and low-quality evidence for secondary efficacy outcomes. A small amount of moderate-quality evidence suggested that the acceptability of azapirones for panic disorder was lower than for placebo. However, only trials of one azapirone (namely buspirone) were included in this review; this, combined with the small sample size, limits our conclusions. If further research is to be conducted, studies with larger sample sizes, with different azapirones and with less risk of bias are necessary to draw firm conclusions regarding azapirones for panic disorder

Flow chart of inclusion and exclusion criteria of cohort of patients treated with antipsychotic drugs.

<p>Flow chart of inclusion and exclusion criteria of cohort of patients treated with antipsychotic drugs.</p