Assessing the impact of sex on high-frequency repetitive transcranial magnetic stimulation´s clinical response in schizophrenia - results from a secondary analysis.

BACKGROUND: The evidence for repetitive transcranial magnetic stimulation (rTMS) to treat negative symptoms in schizophrenia (SCZ) is increasing, although variable response rates remain a challenge. Subject´s sex critically influences rTMS´ treatment outcomes. Females with major depressive disorder are more likely to respond to rTMS, while SCZ data is scarce. METHODS: Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we assessed the impact of sex on rTMS´ clinical response rate from screening up to 105 days after intervention among SCZ patients. The impact of resting motor threshold (RMT) on response rates was also assessed. RESULTS: 157 patients received either active or sham rTMS treatment. No significant group differences were observed. Linear mixed model showed no effects on response rates (all p > 0.519). Apart from a significant sex*time interaction for the positive subscale of the positive and negative syndrome scale (PANSS) scores (p = 0.032), no other significant effects of sex on continuous PANSS scores were observed. RMT had no effect on response rate. CONCLUSION: In the largest rTMS trial on the treatment of SCZ negative symptoms we did not observe any significant effect of sex on treatment outcomes. Better assessments of sex-related differences could improve treatment individualisation.

Evidence and expert consensus based German guidelines for the use of repetitive transcranial magnetic stimulation in depression.

INTRODUCTION: Non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) offer a promising alternative to psychotherapeutic and pharmacological treatments for depression. This paper aims to present a practical guide for its clinical implementation based on evidence from the literature as well as on the experience of a group of leading German experts in the field. METHODS: The current evidence base for the use of rTMS in depression was examined via review of the literature. From the evidence and from clinical experience, recommendations for the use of rTMS in clinical practice were derived. All members of the of the German Society for Brain Stimulation in Psychiatry and all members of the sections Clinical Brain Stimulation and Experimental Brain Stimulation of the German Society for Psychiatry, Psychotherapy, Psychosomatics and Mental Health were invited to participate in a poll on whether they consent with the recommendations. FINDINGS: Among rTMS experts, a high consensus rate could be identified for clinical practice concerning the setting and the technical parameters of rTMS treatment in depression, indications and contra-indications, the relation of rTMS to other antidepressive treatment modalities and the frequency and management of side effects.

Effects of high-frequency prefrontal rTMS on heart frequency rates and blood pressure in schizophrenia.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a safe non-invasive neuromodulation technique used for the treatment of various neuropsychiatric disorders. The effect of rTMS applied to the cortex on autonomic functions has not been studied in detail in patient cohorts, yet patients who receive rTMS may have disease-associated impairments in the autonomic system and may receive medication that may pronounce autonomic dysfunctions. METHODS: Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we evaluated the effect of rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) on autonomic nervous system-related parameters such as blood pressure (BP) and heart rate (HR) in both reclining and standing postures from screening up to 105 days after intervention among patients with schizophrenia. RESULTS: 157 patients received either active (n = 76) or sham (n = 81) rTMS treatment. Apart from gender no significant group differences were observed. During intervention, Linear Mixed Model (LMM) analyses showed no significant time × group interactions nor time effects for any of the variables (all p > 0.055). During the whole trial beside a significant time × group interaction for diastolic BP (p = 0.017) in the standing posture, no significant time × group interactions for other variables (all p > 0.140) were found. CONCLUSION: These secondary analyses of the largest available rTMS trial on the treatment of negative symptoms in schizophrenia did not show a significant effect of active rTMS compared to sham rTMS on heart rate or blood pressure, neither during the intervention period nor during the follow-up period.

Increased Alexithymia But No Profound Emotion Processing Disorder in Burnout Syndrome.

Our objectives were to investigate alexithymia in burnout patients while controlling for depression and anxiety, as well as to evaluate whether alexithymia may be part of a profound emotional processing disorder or of a mentalization deficit. Alexithymia, depressive, and anxious feelings were compared in patients with burnout, depression, and healthy controls using an age-, sex-, and education-matched cross-sectional design (n = 60). A facial emotion recognition task and an emotional mentalizing performance test as well as physical and emotional violation experiences were conducted. Alexithymia was significantly increased in burnout patients, mediated by negative affect in this group. No impairment of facial emotion recognition or mental attribution could be shown. Burnout patients demonstrated slightly increased emotional abuse experiences in early childhood. The present results corroborate the supposition that alexithymia in burnout primarily depends on affect and may rise due to current strain and overload experience, rather than based on a profound developmental disorder in emotion processing.

The effect of alexithymia and depressive feelings on pain perception in somatoform pain disorder.

OBJECTIVE: To investigate the relationship between alexithymia and depression and their influence on the subjective versus experimental pain perception in somatoform pain disorder. METHODS: Three groups consisting of 40 patients with somatoform pain disorder, 40 patients with depression, and 40 healthy controls were matched. They completed questionnaires regarding alexithymia (TAS26) and depressive feelings (BDI-II). In addition, pain patients rated their subjective pain intensity (NRS). Quantitative sensory testings were conducted in all participants examining temperature (CPT, HPT) and mechanical (MPT, PPT) thresholds. RESULTS: Analysis of variance showed that alexithymia was significantly increased in both patient groups compared to healthy controls, but with the highest amount in somatoform pain. Regression analyses confirmed that this finding was in part due to a high comorbidity of depressive feelings in both patient groups. We found a discrepancy between increased clinical pain ratings and elevated pressure pain thresholds, indicating a less intense mechanical pain perception in somatoform pain. Correlation analyses demonstrated a significant connection of subjective pain ratings and pressure pain thresholds with depressive feelings. CONCLUSION: Contrary to the results of other experimental pain studies on chronic muskuloskeletal pain syndromes, we could not confirm central sensitization in somatoform pain disorder. Our findings place the somatoform pain disorder more in the direction of affective disorder such as depression. These findings may improve a better understanding of the disease and also have direct therapeutic implications. The high occurrence of alexithymia and depressive feelings in somatoform pain should be considered in diagnostic and therapeutic regimens of these patients.

Cognitive Control as a 5-HT1A-Based Domain That Is Disrupted in Major Depressive Disorder.

Heterogeneity within Major Depressive Disorder (MDD) has hampered identification of biological markers (e.g., intermediate phenotypes, IPs) that might increase risk for the disorder or reflect closer links to the genes underlying the disease process. The newer characterizations of dimensions of MDD within Research Domain Criteria (RDoC) domains may align well with the goal of defining IPs. We compare a sample of 25 individuals with MDD compared to 29 age and education matched controls in multimodal assessment. The multimodal RDoC assessment included the primary IP biomarker, positron emission tomography (PET) with a selective radiotracer for 5-HT1A [(11C)WAY-100635], as well as event-related functional MRI with a Go/No-go task targeting the Cognitive Control network, neuropsychological assessment of affective perception, negative memory bias and Cognitive Control domains. There was also an exploratory genetic analysis with the serotonin transporter (5-HTTLPR) and monamine oxidase A (MAO-A) genes. In regression analyses, lower 5-HT1A binding potential (BP) in the MDD group was related to diminished engagement of the Cognitive Control network, slowed resolution of interfering cognitive stimuli, one element of Cognitive Control. In contrast, higher/normative levels of 5-HT1A BP in MDD (only) was related to a substantial memory bias toward negative information, but intact resolution of interfering cognitive stimuli and greater engagement of Cognitive Control circuitry. The serotonin transporter risk allele was associated with lower 1a BP and the corresponding imaging and cognitive IPs in MDD. Lowered 5HT 1a BP was present in half of the MDD group relative to the control group. Lowered 5HT 1a BP may represent a subtype including decreased engagement of Cognitive Control network and impaired resolution of interfering cognitive stimuli. Future investigations might link lowered 1a BP to neurobiological pathways and markers, as well as probing subtype-specific treatment targets.

Efficacy of high-frequency repetitive transcranial magnetic stimulation in schizophrenia patients with treatment-resistant negative symptoms treated with clozapine.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a promising augmentation treatment for schizophrenia, however there are few controlled studies of rTMS augmentation of clozapine. METHODS: Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we examined the impact of rTMS on PANSS total, general, positive and negative symptoms among participants on clozapine. rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) for five treatment sessions/week for 3-weeks as augmentation for patients with a predominant negative syndrome of schizophrenia, as rated on PANSS. RESULTS: 26 participants from the RESIS trial were on clozapine, receiving active (N=12) or sham (N=14) rTMS treatment. In our Linear Mixed Model (LMM) analysis, time×group interactions were significant in the PANSS positive subscale (p=0.003) (not being the corresponding behavioral output for DLPFC stimulation), the PANSS general subscale (p<0.001), the PANSS total scale (p=0.015), but not the PANSS negative subscale (p=0.301) (primary endpoint of the RESIS trial), when all PANSS measurements from screening to day 105 were included. Descriptive data suggests that in the active group the improvement was more pronounced compared to the sham rTMS group. CONCLUSIONS: In this largest available clozapine cohort, active rTMS may be more effective than sham rTMS when added to clozapine for positive and total psychotic symptoms. These findings should be interpreted with caution given this is a secondary analysis with a limited number of participants.

Increased short-interval intracortical inhibition in un-medicated patients with schizophrenia.

BACKGROUND: Schizophrenia is associated with changes in inhibitory and facilitatory brain networks which can be assessed by motor cortex excitability. OBJECTIVE: Here, we investigate differences between large cross-sectional samples of un-medicated and medicated patients with schizophrenia and healthy controls in single- and double-pulse transcranial magnetic stimulation parameters. METHODS: We measured right abductor digiti minimi muscle activity in 71 un-medicated, 43 medicated patients and 131 healthy controls. To exclude sample bias analyses were repeated with groups comparable for age and gender (un-medicated: n = 43; medicated: n = 38; controls: n = 49). RESULTS: Un-medicated patients showed increased short-interval intracortical inhibition (SICI) in contrast to medicated patients and healthy controls. No group differences were found for resting and active motor threshold, cortical silent period and intracortical facilitation. CONCLUSION: Increases in SICI are in contrast to literature and highlight the necessity for large-scaled multi-centric studies with high methodological standards.

Efficacy of high-frequency repetitive transcranial magnetic stimulation on PANSS factors in schizophrenia with predominant negative symptoms - Results from an exploratory re-analysis.

Repetitive transcranial magnetic stimulation (rTMS) applied to the left frontal lobe is discussed to be a promising add-on treatment for negative symptoms in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) has been used as outcome parameter in several previous rTMS trials, but studies focusing on PANSS factor analyses are lacking. For this purpose, we used the available PANSS data of the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial to calculate different literature-based PANSS factors and to re-evaluate the impact of rTMS on negative symptoms in this trial. In an exploratory re-analysis of published data from the RESIS study (Wobrock et al. 2015), we tested the impact of rTMS applied to the left dorsolateral prefrontal cortex on two PANSS factors for negative symptoms in psychotic disorders as well as on a PANSS five-factor consensus model intending to show that active rTMS treatment improves PANSS negative symptom subscores. In accordance to the original analysis, all PANSS factors showed an improvement over time in the active and, to a considerable extent, also in the sham rTMS group. However, comparing the data before and directly after the rTMS intervention, the PANSS excitement factor improved in the active rTMS group significantly more than in the sham group, but this finding did not persist if follow-up data were taken into account. These additional analyses extend the previously reported RESIS trial results showing unspecific improvements in the PANSS positive subscale in the active rTMS group. Our PANSS factor-based approach to investigate the impact of prefrontal rTMS on different negative symptom domains confirmed no overall beneficial effect of the active compared to sham rTMS.

Predicting Response to Repetitive Transcranial Magnetic Stimulation in Patients With Schizophrenia Using Structural Magnetic Resonance Imaging: A Multisite Machine Learning Analysis.

Background: The variability of responses to plasticity-inducing repetitive transcranial magnetic stimulation (rTMS) challenges its successful application in psychiatric care. No objective means currently exists to individually predict the patients' response to rTMS. Methods: We used machine learning to develop and validate such tools using the pre-treatment structural Magnetic Resonance Images (sMRI) of 92 patients with schizophrenia enrolled in the multisite RESIS trial (http://clinicaltrials.gov, NCT00783120): patients were randomized to either active (N = 45) or sham (N = 47) 10-Hz rTMS applied to the left dorsolateral prefrontal cortex 5 days per week for 21 days. The prediction target was nonresponse vs response defined by a ≥20% pre-post Positive and Negative Syndrome Scale (PANSS) negative score reduction. Results: Our models predicted this endpoint with a cross-validated balanced accuracy (BAC) of 85% (nonresponse/response: 79%/90%) in patients receiving active rTMS, but only with 51% (48%/55%) in the sham-treated sample. Leave-site-out cross-validation demonstrated cross-site generalizability of the active rTMS predictor despite smaller training samples (BAC: 71%). The predictive pre-treatment pattern involved gray matter density reductions in prefrontal, insular, medio-temporal, and cerebellar cortices, and increments in parietal and thalamic structures. The low BAC of 58% produced by the active rTMS predictor in sham-treated patients, as well as its poor performance in predicting positive symptom courses supported the therapeutic specificity of this brain pattern. Conclusions: Individual responses to active rTMS in patients with predominant negative schizophrenia may be accurately predicted using structural neuromarkers. Further multisite studies are needed to externally validate the proposed treatment stratifier and develop more personalized and biologically informed rTMS interventions.

Pain modulation by intranasal oxytocin and emotional picture viewing - a randomized double-blind fMRI study.

The hormone oxytocin has been hypothesized to influence the emotional dimension of pain. This randomized, placebo-controlled, double-blind, crossover study explored whether intranasal oxytocin and emotional context can affect heat pain perception in 30 healthy male volunteers. After receiving 36 IU oxytocin or placebo, participants underwent functional Magnetic Resonance Imaging (fMRI) during which noxious and non-noxious thermode heat stimuli were applied. Simultaneously, scenes from the International Affective Pictures System (IAPS) with positive, neutral, and negative emotional valence were shown. Heat intensity and unpleasantness ratings were obtained. The activity of whole-brain correlates of heat processing was quantified via multi-voxel pattern analysis. We observed no appreciable main effects of oxytocin on ratings or neural pain correlates. Effects of emotional picture valence on ratings were smaller than reported in previous studies. Nevertheless, oxytocin was found to significantly enhance the influence of picture valence on unpleasantness ratings at noxious heat levels. No corresponding changes in whole-brain correlates of heat intensity processing were found. Our study provides evidence that intranasal oxytocin increases the effects of emotional context on the subjective unpleasantness of experimental heat pain. Future studies are needed to determine whether this effect can be utilized in clinical settings.

Impaired Recognition of Facially Expressed Emotions in Different Groups of Patients with Sleep Disorders.

INTRODUCTION: Recently it has been shown that acute sleep loss has a direct impact on emotional processing in healthy individuals. Here we studied the effect of chronically disturbed sleep on emotional processing by investigating two samples of patients with sleep disorders. METHODS: 25 patients with psychophysiologic insomnia (23 women and 2 men, mean age: 51.6 SD; 10.9 years), 19 patients with sleep apnea syndrome (4 women and 15 men, mean age: 51.9; SD 11.1) and a control sample of 24 subjects with normal sleep (15 women and 9 men, mean age 45.3; SD 8.8) completed a Facial Expressed Emotion Labelling (FEEL) task, requiring participants to categorize and rate the intensity of six emotional expression categories: anger, anxiety, fear, happiness, disgust and sadness. Differences in FEEL score and its subscales among the three samples were analysed using ANOVA with gender as a covariate. RESULTS: Both patients with psychophysiologic insomnia and patients with sleep apnea showed significantly lower performance in the FEEL test as compared to the control group. Differences were seen in the scales happiness and sadness. Patient groups did not differ from each other. CONCLUSION: By demonstrating that previously known effects of acute sleep deprivation on emotional processing can be extended to persons experiencing chronically disturbed sleep, our data contribute to a deeper understanding of the relationship between sleep loss and emotions.

Cognitive Effects of High-Frequency rTMS in Schizophrenia Patients With Predominant Negative Symptoms: Results From a Multicenter Randomized Sham-Controlled Trial.

Cognitive impairments are one of the main contributors to disability and poor long-term outcome in schizophrenia. Proof-of-concept trials indicate that repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) has the potential to improve cognitive functioning. We analyzed the effects of 10-Hz rTMS to the left DLPFC on cognitive deficits in schizophrenia in a large-scale and multicenter, sham-controlled study. A total of 156 schizophrenia patients with predominant negative symptoms were randomly assigned to a 3-week intervention (10-Hz rTMS, 15 sessions, 1000 stimuli per session) with either active or sham rTMS. The Rey Auditory Verbal Learning Test, Trail Making Test A and B, Wisconsin Card Sorting Test, Digit Span Test, and the Regensburg Word Fluency Test were administered before intervention and at day 21, 45, and 105 follow-up. From the test results, a neuropsychological composite score was computed. Both groups showed no differences in any of the outcome variables before and after intervention. Both groups improved markedly over time, but effect sizes indicate a numeric, but nonsignificant superiority of active rTMS in certain cognitive tests. Active 10-Hz rTMS applied to the left DLPFC for 3 weeks was not superior to sham rTMS in the improvement of various cognitive domains in schizophrenia patients with predominant negative symptoms. This is in contrast to previous preliminary proof-of-concept trials, but highlights the need for more multicenter randomized controlled trials in the field of noninvasive brain stimulation.

Theory of Mind and Emotional Awareness in Chronic Somatoform Pain Patients.

OBJECTIVE: The present study aimed at investigating whether chronic pain patients are impaired in Theory of Mind (ToM), or Emotional Awareness. METHODS: Thirty inpatients suffering from chronic somatoform pain, as well as thirty healthy controls matched for age, sex, and education were recruited. ToM abilities were measured using the Frith-Happé animation task, in which participants interpret video-clips depicting moving geometric forms that mimic social interactions. The responses given were scored for appropriateness and the degree of inferred intentionality according to established protocols. Emotional awareness was measured using the Levels of Emotional Awareness Scale (LEAS), for which participants provide written descriptions of feelings in imaginary emotional situations. Standardized scoring was performed to capture the number and quality of emotional terms used. RESULTS: Responses lengths were similar in both groups and for both tasks. Patients attained significantly lower intentionality but not appropriateness scores when interpreting ToM interactions. No significant group differences were found when interpreting goal directed interactions. Emotional awareness scores were significantly lower in patients compared to healthy controls. CONCLUSIONS: Our results suggest that chronic pain patients are impaired in mentalizing and emotional awareness. Future studies are needed to determine whether these ToM and emotional awareness deficits contribute to the etiology of somatoform pain and whether addressing these deficits in therapeutic interventions can improve polymodal pain therapy.

Effects of intranasal oxytocin on thermal pain in healthy men: a randomized functional magnetic resonance imaging study.

OBJECTIVE: Intranasal oxytocin has been shown to affect human social and emotional processing, but its potential to affect pain remains elusive. This randomized, placebo-controlled, double-blind, crossover trial investigated the effect of intranasal oxytocin on the perception and processing of noxious experimental heat in 36 healthy male volunteers. METHODS: Thermal thresholds were determined according to the Quantitative Sensory Testing protocol. A functional magnetic resonance imaging experiment including intensity and unpleasantness ratings of tonic heat was used to investigate the effects of oxytocin within the brain. RESULTS: Thirty men (aged 18-50 years) were included in the study. Intranasal oxytocin had no significant effect on thermal thresholds, but significantly (t = -2.06, p = .046) reduced heat intensity ratings during functional magnetic resonance imaging. The effect on intensity ratings was small (-3.46 points on a 100-point visual analog scale [95% confidence interval {CI} = -6.86 to -0.07] and independent of temperature. No effects of oxytocin on stimulus- or temperature-related processing were found at the whole-brain level at a robust statistical threshold. A region of interest analysis indicated that oxytocin caused small but significant decreases in left (-0.045%, 95% CI = -0.087 to -0.003, t = -2.19, p = .037) and right (-0.051%, 95% CI = -0.088 to -0.014], t = -2.82, p = .008) amygdala activity across all temperatures. CONCLUSIONS: The present study provides evidence for a significant but subtle inhibitory effect of oxytocin on thermal stimulus ratings and concurrent amygdala activity. Neither of the two effects significantly depended of temperature; therefore, the hypothesis of a pain-specific effect of oxytocin could not be confirmed. TRIAL REGISTRATION: EUDRA-CT 2009-015115-40.

Left prefrontal high-frequency repetitive transcranial magnetic stimulation for the treatment of schizophrenia with predominant negative symptoms: a sham-controlled, randomized multicenter trial.

BACKGROUND: Investigators are urgently searching for options to treat negative symptoms in schizophrenia because these symptoms are disabling and do not respond adequately to antipsychotic or psychosocial treatment. Meta-analyses based on small proof-of-principle trials suggest efficacy of repetitive transcranial magnetic stimulation (rTMS) for the treatment of negative symptoms and call for adequately powered multicenter trials. This study evaluated the efficacy of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex for the treatment of predominant negative symptoms in schizophrenia. METHODS: A multicenter randomized, sham-controlled, rater-blinded and patient-blinded trial was conducted from 2007-2011. Investigators randomly assigned 175 patients with schizophrenia with predominant negative symptoms and a high-degree of illness severity into two treatment groups. After a 2-week pretreatment phase, 76 patients were treated with 10-Hz rTMS applied 5 days per week for 3 weeks to the left dorsolateral prefrontal cortex (added to the ongoing treatment), and 81 patients were subjected to sham rTMS applied similarly. RESULTS: There was no statistically significant difference in improvement in negative symptoms between the two groups at day 21 (p = .53, effect size = .09) or subsequently through day 105. Also, symptoms of depression and cognitive function showed no differences in change between groups. There was a small, but statistically significant, improvement in positive symptoms in the active rTMS group (p = .047, effect size = .30), limited to day 21. CONCLUSIONS: Application of active 10-Hz rTMS to the left dorsolateral prefrontal cortex was well tolerated but was not superior compared with sham rTMS in improving negative symptoms; this is in contrast to findings from three meta-analyses.

Are dysfunctional attitudes and beliefs about sleep unique to primary insomnia?

OBJECTIVE: Dysfunctional thinking about sleep is a central aspect in the perpetuation of primary insomnia and a target symptom of cognitive behavioral therapy for insomnia (CBT-I). Insomnia symptoms also occur in other sleep disorders, but it is not known to what extent it is related to dysfunctional thinking about sleep. METHODS: The Dysfunctional Beliefs and Attitudes about Sleep Scale (DBAS) was administered to inpatients at a sleep center. The following groups were included: 34 patients with primary insomnia (PI), 30 patients with sleep apnea syndrome (SAS), 31 patients with restless legs syndrome (RLS), 26 patients with SAS comorbid with RLS (SAS + RLS), and 24 patients with idiopathic hypersomnia or narcolepsy. Eighty-four healthy subjects served as a control group. The DBAS scores were compared across the different sleep disorders and correlated with polysomnographic (PSG) variables, subjective sleep parameters, scores of the Beck Depression Inventory (BDI), and the Regensburg Insomnia Scale (RIS; measuring psychological symptoms of insomnia). RESULTS: Compared to healthy controls, DBAS scores were increased in PI, RLS and RLS + SAS. There was a low correlation between DBAS scores and PSG variables, moderate correlations between DBAS and subjective sleep parameters and BDI scores (r = 0.528), and a high correlation between DBAS and the RIS score (r = 0.603). CONCLUSION: The observation of increased DBAS scores in other sleep disorders besides primary insomnia underscores the usefulness of a broadened diagnostic procedure and suggests that CBT-I modules may be a complementary treatment tool for these disorders.

Sleep quality during exam stress: the role of alcohol, caffeine and nicotine.

Academic exam stress is known to compromise sleep quality and alter drug consumption in university students. Here we evaluated if sleeping problems and changes in legal drug consumption during exam stress are interrelated. We used the Pittsburgh Sleep Quality Index (PSQI) to survey sleep quality before, during, and after an academic exam period in 150 university students in a longitudinal questionnaire study. Self-reports of alcohol, caffeine, and nicotine consumption were obtained. The Perceived Stress Questionnaire (PSQ-20) was used as a measure of stress. Sleep quality and alcohol consumption significantly decreased, while perceived stress and caffeine consumption significantly increased during the exam period. No significant change in nicotine consumption was observed. In particular, students shortened their time in bed and showed symptoms of insomnia. Mixed model analysis indicated that sex, age, health status, as well as the amounts of alcohol and caffeine consumed had no significant influence on global sleep quality. The amount of nicotine consumed and perceived stress were identified as significant predictors of diminished sleep quality. Nicotine consumption had a small-to-very-small effect on sleep quality; perceived stress had a small-to-moderate effect. In conclusion, diminished sleep quality during exam periods was mainly predicted by perceived stress, while legal drug consumption played a minor role. Exam periods may pose an interesting model for the study of stress-induced sleeping problems and their mechanisms.