Combinations of QT-prolonging drugs: towards disentangling pharmacokinetic and pharmaco-dynamic effects in their potentially additive nature.

Background: 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. Methods: In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses. Results: Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and coadministration of a ‘known’ risk drug as a further risk factor. Conclusions: These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs

Mood stabilisers and pregnancy outcomes - a review

The purpose of this review is to give useful information to guide clinicians when treating pregnant women affected by bipolar disorder. This review focuses on mood stabilizers including lithium, sodium valproate, carbamazepine, oxcarbazepine, gabapentin, lamotrigine and topiramate. Data have been extracted from a MEDLINE search. Data from prospective, retrospective and case-control studies as well as systematic reviews, meta-analysis and data from Pregnancy Registry were included. Major congenital malformations as well as specific malformations were reported for each drug. Preliminary findings seem to identify lamotrigine as one ofthe safest antiepileptic drugs to be used in pregnancy. Teratogenity risk oftopiramate is still largely unknown and there are not enough studies to draw even preliminary conclusions. Preliminary studies failed to report an increased risk for major congenital malformations among gabapentin or.oxcarbazepine exposed pregnancies. Even if raising less concern when compared to valproate, carbamazepine should be avoided for its documented teratogenity risk. Valproate seems to be the worst considering major congenital malformations, specific malformations as,well as its detrimental effects on neurodevelopment. On the other hand, lithium might be considered a good option when treating pregnant women affected by bipolar disorder. Given the limited research on mood stabilizers in pregnancy, clinicians need to be very careful when treating child bearing age women. Clinicians have to balance the potential teratogenityrisk against that of untreated mental illness considering individual circumstances such as severity of illness and risk of relapse

'Can you look me in the face?' Short-term SSRI administration reverts avoidant ocular face exploration in subjects at risk for psychopathology.

Anxiety and depression are associated with altered ocular exploration of facial stimuli, which could have a role in the misinterpretation of ambiguous emotional stimuli. However, it is unknown whether a similar pattern is seen in individuals at risk for psychopathology and whether this can be modified by pharmacological interventions used in these disorders. In Study 1, eye gaze movement during face discrimination was compared in volunteers with high vs low neuroticism scores on the Eysenck Personality Questionnaire. Facial stimuli either displayed a neutral, happy, or fearful expression. In Study 2, volunteers with high neuroticism were randomized in a double-blind design to receive the selective serotonin reuptake inhibitor citalopram (20 mg) or placebo for 7 days. On the last day of treatment, eye gaze movement during face presentation and the recognition of different emotional expressions was assessed. In Study 1, highly neurotic volunteers showed reduced eye gaze towards the eyes vs mouth region of the face compared with low neurotic volunteers. In Study 2, citalopram increased gaze maintenance over the face stimuli compared with placebo and enhanced recognition of positive vs negative facial expressions. Longer ocular exploration of happy faces correlated positively with recognition of positive emotions. Individuals at risk for psychopathology presented an avoidant pattern of ocular exploration of faces. Short-term SSRI administration reversed this bias before any mood or anxiety changes. This treatment effect may improve the capacity to scan social stimuli and contribute to the remediation of clinical symptoms related to interpersonal difficulties

Decreased heart rate variability during emotion regulation in subjects at risk for psychopathology.

BACKGROUND: Dysfunctions in the regulation of emotional responses are related to poor psychological well-being and increased impact of cardiovascular disease. It has been suggested that the relationship between negative affect and higher morbidity could be mediated by a dysregulation of the autonomic nervous system (ANS), for example, of heart rate variability (HRV). Neuroticism is a personality trait associated with a maladaptive emotion regulation and also with alterations in ANS function. However, it is unknown whether subjects with high neuroticism present with specific biases in emotion regulation associated with reduced HRV. METHOD: In total, 33 healthy subjects (n=13, highly neurotic) performed an emotion regulation task, during which they were instructed to either passively view negative pictures or attempt to down-regulate the affect elicited by the images. During the task an electrocardiogram was recorded and HRV was measured by calculation of the high frequency spectrum (HF-HRV). RESULTS: A significant interaction between task condition and personality group was observed on HF-HRV measures (F 1,31=6.569, p=0.016). This was driven by subjects with low neuroticism presenting higher HF-HRV during down-regulation compared to passive exposure to negative stimuli, while subjects with high neuroticism reported an opposite tendency. CONCLUSIONS: Our results show reduced HF-HRV during cognitive reappraisal of negative stimuli in high neuroticism and indicate a specific link between loss of flexibility in the parasympathetic cardiovascular tone and emotion regulation, consistent with previous work. Such findings support the importance of exploring the combination of ANS adaptability and emotional dysregulation in neuroticism as different facets of a common psychosomatic vulnerability factor