Investigating heart rate variability measures during pregnancy as predictors of postpartum depression and anxiety: an exploratory study.

Perinatal affective disorders are common, but standard screening measures reliant on subjective self-reports might not be sufficient to identify pregnant women at-risk for developing postpartum depression and anxiety. Lower heart rate variability (HRV) has been shown to be associated with affective disorders. The current exploratory study aimed to evaluate the predictive utility of late pregnancy HRV measurements of postpartum affective symptoms. A subset of participants from the BASIC study (Uppsala, Sweden) took part in a sub-study at pregnancy week 38 where HRV was measured before and after a mild stressor (n = 122). Outcome measures were 6-week postpartum depression and anxiety symptoms as quantified by the Edinburgh Postnatal Depression Scale (EPDS) and the Beck Anxiety Inventory (BAI). In total, 112 women were included in a depression outcome analysis and 106 women were included in an anxiety outcome analysis. Group comparisons indicated that lower pregnancy HRV was associated with depressive or anxious symptomatology at 6 weeks postpartum. Elastic net logistic regression analyses indicated that HRV indices alone were not predictive of postpartum depression or anxiety outcomes, but HRV indices were selected as predictors in a combined model with background and pregnancy variables. ROC curves for the combined models gave an area under the curve (AUC) of 0.93 for the depression outcome and an AUC of 0.83 for the anxiety outcome. HRV indices predictive of postpartum depression generally differed from those predictive of postpartum anxiety. HRV indices did not significantly improve prediction models comprised of psychological measures only in women with pregnancy depression or anxiety.

Neural correlates of individual differences in multimodal emotion recognition ability.

Studies have reported substantial variability in emotion recognition ability (ERA) - an important social skill - but possible neural underpinnings for such individual differences are not well understood. This functional magnetic resonance imaging (fMRI) study investigated neural responses during emotion recognition in young adults (N = 49) who were selected for inclusion based on their performance (high or low) during previous testing of ERA. Participants were asked to judge brief video recordings in a forced-choice emotion recognition task, wherein stimuli were presented in visual, auditory and multimodal (audiovisual) blocks. Emotion recognition rates during brain scanning confirmed that individuals with high (vs low) ERA received higher accuracy for all presentation blocks. fMRI-analyses focused on key regions of interest (ROIs) involved in the processing of multimodal emotion expressions, based on previous meta-analyses. In neural response to emotional stimuli contrasted with neutral stimuli, individuals with high (vs low) ERA showed higher activation in the following ROIs during the multimodal condition: right middle superior temporal gyrus (mSTG), right posterior superior temporal sulcus (PSTS), and right inferior frontal cortex (IFC). Overall, results suggest that individual variability in ERA may be reflected across several stages of decisional processing, including extraction (mSTG), integration (PSTS) and evaluation (IFC) of emotional information.

A challenge to the expected: Lack of longitudinal associations between the early caregiving environment, executive functions in toddlerhood, and self-regulation at 6 years.

Previous research and theory indicate an importance of the quality of the early caregiving environment in the development of self-regulation. However, it is unclear how attachment security and maternal sensitivity, two related but distinct aspects of the early caregiving environment, may differentially predict self-regulation at school start and whether a distinction between hot and cool executive function is informative in characterizing such predictions through mediation. In a 5-year longitudinal study (n = 108), we examined these associations using measures of maternal sensitivity and attachment security at 10-12 months, executive function at 4 years, and self-regulation at 6 years. Surprisingly, and despite methodological rigor, we found few significant bivariate associations between the study variables. We found no credible evidence of a longitudinal association between maternal sensitivity or attachment security in infancy and self-regulation at 6 years, or between executive function at 4 years and self-regulation at 6 years. The lack of bivariate longitudinal associations precluded us from building mediation models as intended. We discuss our null findings in terms of their potential theoretical implications, as well as how measurement type, reliability, and validity, may play a key role in determining longitudinal associations between early caregiving factors and later self-regulation and related abilities. RESEARCH HIGHLIGHTS: The early caregiving environment has been implicated in the development of later self-regulation, which includes more basic skills, such as hot and cool executive functions (EF). In a 5-year longitudinal study, with a sample of 108 children, we rigorously measured aspects of early caregiving, EF, and self-regulation. We found no significant longitudinal associations between early caregiving and self-regulation at 6 years, nor between EF at 4 years and self-regulation at 6 years. These null results highlight the complexity of modeling self-regulation development and raise critical questions about general methodological conventions within self-regulation development research.

The influence of anterior cingulate GABA+ and glutamate on emotion regulation and reactivity in adolescents and adults.

During adolescence, emotion regulation and reactivity are still developing and are in many ways qualitatively different from adulthood. However, the neurobiological processes underpinning these differences remain poorly understood, including the role of maturing neurotransmitter systems. We combined magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (dACC) and self-reported emotion regulation and reactivity in a sample of typically developed adolescents (n = 37; 13-16 years) and adults (n = 39; 30-40 years), and found that adolescents had higher levels of glutamate to total creatine (tCr) ratio in the dACC than adults. A glutamate Í age group interaction indicated a differential relation between dACC glutamate levels and emotion regulation in adolescents and adults, and within-group follow-up analyses showed that higher levels of glutamate/tCr were related to worse emotion regulation skills in adolescents. We found no age-group differences in gamma-aminobutyric acid+macromolecules (GABA+) levels; however, emotion reactivity was positively related to GABA+/tCr in the adult group, but not in the adolescent group. The results demonstrate that there are developmental changes in the concentration of glutamate, but not GABA+, within the dACC from adolescence to adulthood, in accordance with previous findings indicating earlier maturation of the GABA-ergic than the glutamatergic system. Functionally, glutamate and GABA+ are positively related to emotion regulation and reactivity, respectively, in the mature brain. In the adolescent brain, however, glutamate is negatively related to emotion regulation, and GABA+ is not related to emotion reactivity. The findings are consistent with synaptic pruning of glutamatergic synapses from adolescence to adulthood and highlight the importance of brain maturational processes underlying age-related differences in emotion processing.

A Psychometric Evaluation of the Expanded Version of the Inventory of Depression and Anxiety Symptoms (IDAS-II) in Children and Adolescents.

The expanded version of the Inventory of Depression and Anxiety Symptoms (IDAS-II) is a self-report measure of 18 empirically derived internalizing symptom dimensions. The measure has shown good psychometric properties in adults but has never been evaluated in children and adolescents. A Swedish version of the IDAS-II was administered to 633 children and adolescents (Mage =16.6 [SD = 2.0]) and 203 adults (Mage = 35.4 [SD = 12.1]). The model/data fit of the 18-factor structure was excellent in both samples and measurement invariance across age groups was supported. All scales showed good to excellent internal consistency and psychometric properties replicated in the younger youth sample (< 16 years). Among youth, good convergent validity was established for all scales and divergent validity for most scales. The IDAS-II was better at identifying youth with current mental health problems than an internationally recommended scale of internalizing symptoms. In conclusion, the IDAS-II shows promise as a measure of internalizing symptoms in youth.

Endogenous noise of neocortical neurons correlates with atypical sensory response variability in the Fmr1-/y mouse model of autism.

Excessive neural variability of sensory responses is a hallmark of atypical sensory processing in autistic individuals with cascading effects on other core autism symptoms but unknown neurobiological substrate. Here, by recording neocortical single neuron activity in a well-established mouse model of Fragile X syndrome and autism, we characterized atypical sensory processing and probed the role of endogenous noise sources in exaggerated response variability in males. The analysis of sensory stimulus evoked activity and spontaneous dynamics, as well as neuronal features, reveals a complex cellular and network phenotype. Neocortical sensory information processing is more variable and temporally imprecise. Increased trial-by-trial and inter-neuronal response variability is strongly related to key endogenous noise features, and may give rise to behavioural sensory responsiveness variability in autism. We provide a novel preclinical framework for understanding the sources of endogenous noise and its contribution to core autism symptoms, and for testing the functional consequences for mechanism-based manipulation of noise.

Acute low dose caffeine affects behavior profile and activity, an examination of male rats with high or low anxiety-like behavior.

Anxiety disorders affect up to one third of the population. Caffeine, an adenosine receptor antagonist, is thought to have a dose-dependent effect on anxiety. We recently showed that a high dose of caffeine (50 mg/kg) differentially affected anxiety-like behavior in rats with high or low baseline anxiety-like behavior, replicating findings using relatively high doses in human patient samples. It is not known if low doses of caffeine have similar effects. The elevated plus maze (EPM) was used to categorize male Wistar rats (13 weeks of age) into groups of high or low anxiety-like behavior. Behavior was evaluated using the multivariate concentric square field (MCSF) test and the EPM after a low 10 mg/kg dose of caffeine. Multivariate data analysis demonstrated that caffeine decreased the differences between the high and low anxiety group, whereas the separation remained for the high and low control groups. For the caffeine treated rats, univariate statistics showed an increase in parameters regarding activity in the EPM and duration in the slope of the MCSF. Regarding risk-taking, shelter-seeking, and exploratory behavior, caffeine did not affect the groups differently. In conclusion, these results demonstrate increased activity in the caffeine-treated rats, together with a potentially anxiolytic effect and increased impulsivity that did not differ between the baseline anxiety groups. In contrast to high caffeine doses, a low dose does not generally affect rats with high anxiety at baseline differently than rats with low anxiety-like behavior. Further studies are warranted to fully elucidate the effects of caffeine in anxiety.

Acute caffeine differently affects risk-taking and the expression of BDNF and of adenosine and opioid receptors in rats with high or low anxiety-like behavior.

Anxiety disorders are common psychiatric conditions with a partially elucidated neurobiology. Caffeine, an unspecific adenosine receptor antagonist, is a common psychostimulant with anxiogenic effects in sensitive individuals. High doses of caffeine produce anxiety-like behavior in rats but it is not known if this is specific for rats with high baseline anxiety-like behavior. Thus, the aim of this study was to investigate general behavior, risk-taking, and anxiety-like behavior, as well as mRNA expression (adenosine A2A and A1, dopamine D2, and, µ, κ, δ opioid, receptors, BDNF, c-fos, IGF-1) in amygdala, caudate putamen, frontal cortex, hippocampus, hypothalamus, after an acute dose of caffeine. Untreated rats were screened using the elevated plus maze (EPM), giving each rat a score on anxiety-like behavior based on their time spent in the open arms, and categorized into a high or low anxiety-like behavior group accordingly. Three weeks after categorization, the rats were treated with 50 mg/kg caffeine and their behavior profile was studied in the multivariate concentric square field (MCSF) test, and one week later in the EPM. qPCR was performed on selected genes and corticosterone plasma levels were measured using ELISA. The results demonstrated that the high anxiety-like behavior rats treated with caffeine spent less time in risk areas of the MCSF and resituated towards the sheltered areas, a behavior accompanied by lower mRNA expression of adenosine A2A receptors in caudate putamen and increased BDNF expression in hippocampus. These results support the hypothesis that caffeine affects individuals differently depending on their baseline anxiety-like behavior, possibly involving adenosine receptors. This highlights the importance of adenosine receptors as a possible drug target for anxiety disorders, although further research is needed to fully elucidate the neurobiological mechanisms of caffeine on anxiety disorders.

Blinding integrity of dorsomedial prefrontal intermittent theta burst stimulation in depression.

Background: The antidepressant effect of repetitive transcranial magnetic stimulation (rTMS) is partly placebo, making blinding integrity important. Blinding of high-frequency rTMS and intermittent theta burst stimulation (iTBS) has been reported as successful at study end. However, blinding integrity at study start is rarely reported. The aim of this study was to investigate blinding integrity during a treatment course of iTBS over the dorsomedial prefrontal cortex (DMPFC) in depression. Methods: Forty-nine patients with depression from a double-blind-designed randomized controlled trial (NCT02905604) were included. Patients received either active or sham iTBS over the DMPFC with a placebo coil. The sham group received iTBS-synchronized transcutaneous electrical nerve stimulation. Results: After one session, 74% of participants were able to correctly guess their treatment allocation. This was above chance level (p = 0.001). The percentage dropped to 64% and 56% after the fifth and last sessions. Belonging to the active group influenced the choice to guess "active" (odds ratio: 11.7, 95% CI 2.5-53.7). A higher treatment intensity of the sham treatment increased the probability to guess "active", but pain did not influence the choice. Conclusions: Blinding integrity in iTBS trials must be investigated at study start to avoid uncontrolled confounding. Better sham methods are needed.

Striatal dopamine transporter and receptor availability correlate with relative cerebral blood flow measured with [11C]PE2I, [18F]FE-PE2I and [11C]raclopride PET in healthy individuals.

The aim of this retrospective study was to investigate relationships between relative cerebral blood flow and striatal dopamine transporter and dopamine D2/3 availability in healthy subjects. The data comprised dynamic PET scans with two dopamine transporter tracers [11C]PE2I (n = 20) and [18F]FE-PE2I (n = 20) and the D2/3 tracer [11C]raclopride (n = 18). Subjects with a [11C]PE2I scan also underwent a dynamic scan with the serotonin transporter tracer [11C]DASB. Binding potential (BPND) and relative tracer delivery (R1) values were calculated on regional and voxel-level. Striatal R1 and BPND values were correlated, using either an MRI-based volume of interest (VOI) or an isocontour VOI based on the parametric BPND image. An inter-tracer comparison between [11C]PE2I BPND and [11C]DASB R1 was done on a VOI-level and simulations were performed to investigate whether the constraints of the modeling could cause correlation of the parameters. A positive association was found between BPND and R1 for all three dopamine tracers. A similar correlation was found for the inter-tracer correlation between [11C]PE2I BPND and [11C]DASB R1. Simulations showed that this relationship was not caused by cross-correlation between parameters in the kinetic model. In conclusion, these results suggest an association between resting-state striatal dopamine function and relative blood flow in healthy subjects.

Progressive Voxel-Wise Homotopic Connectivity from childhood to adulthood: Age-related functional asymmetry in resting-state functional magnetic resonance imaging.

Homotopic connectivity during resting state has been proposed as a risk marker for neurologic and psychiatric conditions, but a precise characterization of its trajectory through development is currently lacking. Voxel-Mirrored Homotopic Connectivity (VMHC) was evaluated in a sample of 85 neurotypical individuals aged 7-18 years. VMHC associations with age, handedness, sex, and motion were explored at the voxel-wise level. VMHC correlates were also explored within 14 functional networks. Primary and secondary outcomes were repeated in a sample of 107 adults aged 21-50 years. In adults, VMHC was negatively correlated with age only in the posterior insula (false discovery rate p < .05, >30-voxel clusters), while a distributed effect among the medial axis was observed in minors. Four out of 14 considered networks showed significant negative correlations between VMHC and age in minors (basal ganglia r = -.280, p = .010; anterior salience r = -.245, p = .024; language r = -.222, p = .041; primary visual r = -.257, p = .017), but not adults. In minors, a positive effect of motion on VMHC was observed only in the putamen. Sex did not significantly influence age effects on VMHC. The current study showed a specific decrease in VMHC for minors as a function of age, but not adults, supporting the notion that interhemispheric interactions can shape late neurodevelopment.

Dorsal anterior cingulate cortex activity during cognitive challenge in social anxiety disorder.

BACKGROUND: Social anxiety disorder (SAD) is associated with aberrant emotional information processing while little is known about non-emotional cognitive processing biases. The dorsal anterior cingulate cortex (dACC) has been implicated in SAD neuropathology and is activated both by emotional and non-affective cognitive challenges like the Multisource Interference Task (MSIT). METHODS: Here, we used fMRI to compare dACC activity and test performance during MSIT in 69 SAD patients and 38 healthy controls. In addition to patient-control comparisons, we examined whether neural activity in the dACC correlated with social anxiety, trait anxiety or depression levels. RESULTS: The MSIT activated the dACC as expected but with no differences in task performance or neural reactivity between SAD patients and controls. There were no significant correlations between dACC activity and social or trait anxiety symptom severity. In patients, there was a significant negative correlation between dACC activity and depressive symptoms. CONCLUSIONS: In absence of affective challenge, we found no disorder-related cognitive profile in SAD patients since neither MSIT task performance nor dACC neural activity deviated in patients relative to controls.

Investigations on the donor limb after harvest of lymphatic vessels for lymphedema surgery.

OBJECTIVE: Microsurgical lymphatic vessel transplantation is one of the well-established therapies for lymphedema. Lymphatic vessels are harvested from a healthy thigh and transplanted into lymphedematous limbs to create a lymphatic bypass. Its benefit on lymphatic drainage has already been proven. However, to the best of our knowledge, the effect on the lymphatic function of the donor site has not yet been studied. Our aim was to evaluate the long-term postoperative lymphatic function in the donor site by clinical and scintigraphic examinations and a patient questionnaire. METHODS: A consecutive series of 25 women (mean age, 57.2 years) who had undergone follow-up after lymph vessel transplantation to treat secondary lymphedema of the arm comprised the study group. Lymphatic vessel function of the donor site was evaluated by circumferential measurements of the limb and, in nine cases, by lymphatic scintigraphy. Additionally, a questionnaire was used to assess the patients' pre- and postoperative complaints for the donor limb and quality of life. Separately, the medical records of 100 patients who had undergone lymphatic harvest and been followed up were reviewed for documented signs of lymphatic function of the donor limb. RESULTS: The lymphatic grafts were harvested from the thigh (left, n = 9; right, n = 16) and transplanted to bridge the region of lymphatic obstruction in the axilla. The mean follow-up period was 4.5 years after surgery. None of the patients had shown significant changes in the circumference of the donor limb or pathologic findings via lymphatic scintigraphy. None of the patients had reported any impairment in the donor leg or showed symptoms of postoperative lymphedema or erysipelas. CONCLUSIONS: Our results have shown that harvesting lymphatic vessels from the thigh for lymphatic vessel transplantation is possible without significant donor site morbidity.

Pupil dilation during negative prediction errors is related to brain choline concentration and depressive symptoms in adolescents.

Depressive symptoms are associated with altered pupillary responses during learning and reward prediction as well as with changes in neurometabolite levels, including brain concentrations of choline, glutamate and gamma-aminobutyric acid (GABA). However, the full link between depressive symptoms, reward-learning-related pupillary responses and neurometabolites is yet to be established as these constructs have not been assessed in the same individuals. The present pilot study, investigated these relations in a sample of 24 adolescents aged 13 years. Participants completed the Revised Child Anxiety and Depression Scale (RCADS) and underwent a reward learning task while measuring pupil dilation and a single voxel dorsal anterior cingulate cortex (dACC) MEGA-PRESS magnetic resonance spectroscopy scan assessing choline, glutamate and GABA concentrations. Pupil dilation was related to prediction errors (PE) during learning, which was captured by a prediction error-weighted pupil dilation response index (PE-PDR) for each individual. Higher PE-PDR scores, indicating larger pupil dilations to negative prediction errors, were related to lower depressive symptoms and lower dACC choline concentrations. Dorsal ACC choline was positively associated with depressive symptoms, whereas glutamate and GABA were not related to PE-PDR or depressive symptoms. The findings support notions of cholinergic involvement in depressive symptoms and cholinergic influence on reward-related pupillary response, suggesting that pupillary responses to negative prediction errors may hold promise as a biomarker of depressive states.

Serotonin and dopamine transporter availability in social anxiety disorder after combined treatment with escitalopram and cognitive-behavioral therapy.

Selective serotonin reuptake inhibitors (SSRIs) and internet-based cognitive behavioral therapy (ICBT) are recommended treatments of social anxiety disorder (SAD), and often combined, but their effects on monoaminergic signaling are not well understood. In this multi-tracer positron emission tomography (PET) study, 24 patients with SAD were randomized to treatment with escitalopram+ICBT or placebo+ICBT under double-blind conditions. Before and after 9 weeks of treatment, patients were examined with positron emission tomography and the radioligands [11C]DASB and [11C]PE2I, probing the serotonin (SERT) and dopamine (DAT) transporter proteins respectively. Both treatment combinations resulted in significant improvement as measured by the Liebowitz Social Anxiety Scale (LSAS). At baseline, SERT-DAT co-expression was high and, in the putamen and thalamus, co-expression showed positive associations with symptom severity. SERT-DAT co-expression was also predictive of treatment success, but predictor-outcome associations differed in direction between the treatments. After treatment, average SERT occupancy in the SSRI + ICBT group was >80%, with positive associations between symptom improvement and occupancy in the nucleus accumbens, putamen and anterior cingulate cortex. Following placebo+ICBT, SERT binding increased in the raphe nuclei. DAT binding increased in both groups in limbic and striatal areas, but relations with symptom improvement differed, being negative for SSRI + ICBT and positive for placebo + ICBT. Thus, serotonin-dopamine transporter co-expression exerts influence on symptom severity and remission rate in the treatment of social anxiety disorder. However, the monoamine transporters are modulated in dissimilar ways when cognitive-behavioral treatment is given concomitantly with either SSRI-medication or pill placebo.

Prevention of Postoperative Peritendinous Adhesions with Bioresorbable Suprathel Barrier Membrane.

Postoperative adhesions can deteriorate clinical outcomes in tendon repair surgery significantly. Thus, the use of artificial membranes as a tendon sheath substitute has become popular and well studied in the last years. We performed a case series of three patients using a novel synthetic membrane (Suprathel) for complex reconstructive surgery and traumatic tendon repair surgery. All patients recovered well with no significant adverse effects and showed good clinical function afterward. Therefore, we concluded that Suprathel might be another potential candidate to prevent postoperative peritendinous adhesions. Further studies will be necessary to determine the effect of this bioresorbable barrier membrane.

Application of positron emission tomography in psychiatry-methodological developments and future directions.

Mental disorders represent an increasing source of disability and high costs for societies globally. Molecular imaging techniques such as positron emission tomography (PET) represent powerful tools with the potential to advance knowledge regarding disease mechanisms, allowing the development of new treatment approaches. Thus far, most PET research on pathophysiology in psychiatric disorders has focused on the monoaminergic neurotransmission systems, and although a series of discoveries have been made, the results have not led to any material changes in clinical practice. We outline areas of methodological development that can address some of the important obstacles to fruitful progress. First, we point towards new radioligands and targets that can lead to the identification of processes upstream, or parallel to disturbances in monoaminergic systems. Second, we describe the development of new methods of PET data quantification and PET systems that may facilitate research in psychiatric populations. Third, we review the application of multimodal imaging that can link molecular imaging data to other aspects of brain function, thus deepening our understanding of disease processes. Fourth, we highlight the need to develop imaging study protocols to include longitudinal and interventional paradigms, as well as frameworks to assess dimensional symptoms such that the field can move beyond cross-sectional studies within current diagnostic boundaries. Particular effort should be paid to include also the most severely ill patients. Finally, we discuss the importance of harmonizing data collection and promoting data sharing to reach the desired sample sizes needed to fully capture the phenotype of psychiatric conditions.

Evaluating an internet-delivered fear conditioning and extinction protocol using response times and affective ratings.

Pavlovian fear conditioning is widely used to study mechanisms of fear learning, but high-throughput studies are hampered by the labor-intensive nature of examining participants in the lab. To circumvent this bottle-neck, fear conditioning tasks have been developed for remote delivery. Previous studies have examined remotely delivered fear conditioning protocols using expectancy and affective ratings. Here we replicate and extend these findings using an internet-delivered version of the Screaming Lady paradigm, evaluating the effects on negative affective ratings and response time to an auditory probe during stimulus presentation. In a sample of 80 adults, we observed clear evidence of both fear acquisition and extinction using affective ratings. Response times were faster when probed early, but not later, during presentation of stimuli paired with an aversive scream. The response time findings are at odds with previous lab-based studies showing slower as opposed to faster responses to threat-predicting cues. The findings underscore the feasibility of employing remotely delivered fear conditioning paradigms with affective ratings as outcome. Findings further highlight the need for research examining optimal parameters for concurrent response time measures or alternate non-verbal indicators of conditioned responses in Pavlovian conditioning protocols.

Detecting fine and elaborate movements with piezo sensors provides non-invasive access to overlooked behavioral components.

Behavioral phenotyping devices have been successfully used to build ethograms, but many aspects of behavior remain out of reach of available phenotyping systems. We now report on a novel device, which consists in an open-field platform resting on highly sensitive piezoelectric (electromechanical) pressure-sensors, with which we could detect the slightest movements (up to individual heart beats during rest) from freely moving rats and mice. The combination with video recordings and signal analysis based on time-frequency decomposition, clustering, and machine learning algorithms provided non-invasive access to previously overlooked behavioral components. The detection of shaking/shivering provided an original readout of fear, distinct from but complementary to behavioral freezing. Analyzing the dynamics of momentum in locomotion and grooming allowed to identify the signature of gait and neurodevelopmental pathological phenotypes. We believe that this device represents a significant progress and offers new opportunities for the awaited advance of behavioral phenotyping.

Effects of caffeine on anxiety and panic attacks in patients with panic disorder: A systematic review and meta-analysis.

BACKGROUND: Caffeine has been purported to have anxiogenic and panicogenic properties, specifically salient in patients with panic disorder (PD). However, compilations of the magnitude of the effect of caffeine on anxiety and panic attacks are lacking and potential dose-response relationships have not been examined. OBJECTIVES: In the present systematic review and meta-analysis, we aimed to examine the acute effects of placebo-controlled caffeine challenge on occurrence of panic attacks and subjective anxiety in patients with PD and healthy controls (HC), including dose-response relationships. METHODS: Systematic searches were performed in six databases. We included blinded placebo-controlled studies of acute caffeine challenge on panic attacks and/or subjective anxiety in adult patients with PD. RESULTS: Of the 1893 identified articles, ten met our inclusion criteria. The 9 studies investigating panic attacks included 237 patients, of which 51.1% had a panic attack following caffeine, but none after placebo. Six of these studies compared 128 patients with 115 healthy controls (HC), finding that patients (53.9%) were more vulnerable than HC (1.7%) for panic attacks following caffeine (log RR: 3.47; 95% CI 2.06-4.87). Six studies investigated subjective anxiety in 121 patients and 111 HC following caffeine, with an overall effect indicating increased sensitivity to the anxiogenic effects of caffeine in the patient group (Hedges' g = 1.02 [95% CI: 0.09-1.96]). The restricted range of caffeine employed [400-750 mg] and few studies (3) not using 480 mg prevented any meaningful analysis of a dose-response relationship. LIMITATIONS: Of the ten studies included, only 2 reported anxiety data for the placebo condition, precluding a proper meta-analysis comparing anxiogenic effects of caffeine and placebo. The restricted dose range used prevented assessment of dose-response relationships. CONCLUSIONS: The results confirm that caffeine at doses roughly equivalent to 5 cups of coffee induces panic attacks in a large proportion of PD patients and highly discriminates this population from healthy adults. Caffeine also increases anxiety in PD patients as well as among healthy adults at these doses although the exact relationship between caffeine-induced anxiety and panic attacks remains uncertain. The results suggest that caffeine targets important mechanisms related to the pathophysiology of PD. IMPLICATIONS: Future studies should employ a wider range of caffeine doses and investigate contributions of biological and psychological mechanisms underlying the anxiogenic and panicogenic effects of caffeine. In the clinic, patients with PD should be informed about the panicogenic and anxiogenic effects of caffeine, with the caveat that little is known regarding smaller doses than 480 mg. Registration. PROSPERO (www.crd.york.ac.uk/prospero) registration number CRD42019120220.