Major depressive disorder (MDD) is a common psychiatric disorder and leading cause of disability worldwide. It is associated with increased mortality, especially from suicide. Heritability of MDD is ...estimated around 40%, suggesting that genotyping is a promising field for research into the development of MDD. According to the dopamine theory of affective disorders, a deficiency in dopaminergic neurotransmission may play a role in the major symptoms of MDD. Specific polymorphisms in genes that affect dopamine transmission could increase susceptibility to MDD. To determine the extent to which these genes influence vulnerability to MDD, we discuss genes for crucial steps in dopamine neurotransmission: synthesis, signalling and inactivation. The val158met polymorphism of the COMT gene exemplifies the lack of consensus in the literature: although it is one of the most reported polymorphisms that relates to MDD vulnerability, its role is not corroborated by meta-analysis. Gene-gene interactions and gene-environment interactions provide more explanatory potential than single gene associations. Two notable exceptions are the DRD4 and DAT gene: both have variable tandem repeat polymorphisms which may have a "single gene" influence on susceptibility to MDD.
Recent studies with intravenous (i.v.) application of ketamine show remarkable but short-term success in patients with MDD. Studies in patients with chronic pain have used different ketamine ...applications for longer time periods. This experience may be relevant for psychiatric indications.
To review the literature about the dosing regimen, duration, effects and side-effects of oral, intravenous, intranasal and subcutaneous routes of administration of ketamine for treatment-resistant depression and pain.
Searches in PubMed with the terms 'oral ketamine', 'depression', 'chronic pain', 'neuropathic pain', 'intravenous ketamine', 'intranasal ketamine' and 'subcutaneous ketamine' yielded 88 articles. We reviewed all papers for information about dosing regimen, number of individuals who received ketamine, number of ketamine days per study, results and side-effects, as well as study quality.
Overall, the methodological strength of studies investigating the antidepressant effects of ketamine was considered low, regardless of the route of administration. The doses for depression were in the lower range compared with studies that investigated analgesic use. Studies on pain suggested that oral ketamine may be acceptable for treatment-resistant depression in terms of tolerability and side-effects.
Oral ketamine, given for longer time periods in the described doses, appears to be well tolerated, but few studies have systematically examined the longer-term negative consequences. The short- and longer-term depression outcomes as well as side-effects need to be studied with rigorous randomised controlled trials.
•Noninvasive neurostimulation could treat treatment resistant depression.•transcranial Pulsed Electromagnetic Fields uses weak electromagnetic fields.•Stimulation using too weak electromagnetic ...fields has no antidepressant effect.
Noninvasive neurostimulation with transcranial Pulsed Electromagnetic Fields (tPEMF) may be a promising method for treatment resistant depression (TRD). Studies shown substantial improvement of depressive symptoms in patients with TRD, but there is no information on long-term antidepressant effects. The aim of this study was to investigate the short- and long-term efficacy of tPEMF in participants with TRD.
Eligible participants with TRD in this sham-controlled double-blind multicenter trial were randomly assigned to five weeks either daily active or sham tPEMF. Severity of depression and anxiety was assessed pre- and directly post-treatment and five and fifteen weeks post-treatment. Primary outcome was change on the 17-item Hamilton depression rating scale directly post-treatment. Secondary outcome was change on the Hamilton-17 during follow-up and change on the Inventory of Depressive Symptomatology Self-Report and the Beck Anxiety Index.
Of the 55 included participants, 50 completed the treatment protocol. Depressive symptoms improved over time in both groups. The improvement continued until the last follow-up measure. There was no difference in outcome between the active and the sham group on change in depression post-treatment or on any secondary measure.
Treatment with this type of active tPEMF was not superior to sham in patients with TRD. This is in contrast to a previous study using a similar design and power calculation, but a higher magnetic field strength, that reported improvement of depression after treatment with tPEMF compared to sham. An important limitation of our study was the fact that no different dosing regimens were tried.
BackgroundRecent studies with intravenous (i.v.) application of ketamine showremarkable but short-term success in patients with MDD. Studies inpatients with chronic pain have used different ketamine ...applications forlonger time periods. This experience may be relevant for psychiatricindications.AimsTo review the literature about the dosing regimen, duration, effects andside-effects of oral, intravenous, intranasal and subcutaneous routes ofadministration of ketamine for treatment-resistant depression andpain.MethodSearches in PubMed with the terms ‘oral ketamine’, ‘depression’, ‘chronicpain’, ‘neuropathic pain’, ‘intravenous ketamine’, ‘intranasal ketamine’and ‘subcutaneous ketamine’ yielded 88 articles. We reviewed all papersfor information about dosing regimen, number of individuals who receivedketamine, number of ketamine days per study, results and side-effects, aswell as study quality.ResultsOverall, the methodological strength of studies investigating theantidepressant effects of ketamine was considered low, regardless of theroute of administration. The doses for depression were in the lower rangecompared with studies that investigated analgesic use. Studies on painsuggested that oral ketamine may be acceptable for treatment-resistantdepression in terms of tolerability and side-effects.ConclusionsOral ketamine, given for longer time periods in the described doses,appears to be well tolerated, but few studies have systematicallyexamined the longer-term negative consequences. The short- andlonger-term depression outcomes as well as side-effects need to bestudied with rigorous randomised controlled trials.
Background Major depressive disorder (MDD), panic disorder, and social anxiety disorder are among the most prevalent and frequently co-occurring psychiatric disorders in adults and may be ...characterized by a common deficiency in processing of emotional information. Methods We used functional magnetic resonance imaging during the performance of an emotional word encoding and recognition paradigm in patients with MDD ( n = 51), comorbid MDD and anxiety ( n = 59), panic disorder and/or social anxiety disorder without comorbid MDD ( n = 56), and control subjects ( n = 49). In addition, we studied effects of illness severity, regional brain volume, and antidepressant use. Results Patients with MDD, prevalent anxiety disorders, or both showed a common hyporesponse in the right hippocampus during positive (>neutral) word encoding compared with control subjects. During negative encoding, increased insular activation was observed in both depressed groups (MDD and MDD + anxiety), whereas increased amygdala and anterior cingulate cortex activation during positive word encoding were observed as depressive state-dependent effects in MDD only. During recognition, anxiety patients showed increased inferior frontal gyrus activation. Overall, effects were unaffected by medication use and regional brain volume. Conclusions Hippocampal blunting during positive word encoding is a generic effect in depression and anxiety disorders, which may constitute a common vulnerability factor. Increased insular and amygdalar involvement during negative word encoding may underlie heightened experience of, and an inability to disengage from, negative emotions in depressive disorders. Our results emphasize a common neurobiological deficiency in both MDD and anxiety disorders, which may mark a general insensitiveness to positive information.
There is a severe lack of knowledge regarding the brain regions involved in human sexual performance in general, and female orgasm in particular. We used 15O‐H2O positron emission tomography to ...measure regional cerebral blood flow (rCBF) in 12 healthy women during a nonsexual resting state, clitorally induced orgasm, sexual clitoral stimulation (sexual arousal control) and imitation of orgasm (motor output control). Extracerebral markers of sexual performance and orgasm were rectal pressure variability (RPstd) and perceived level of sexual arousal (PSA). Sexual stimulation of the clitoris (compared to rest) significantly increased rCBF in the left secondary and right dorsal primary somatosensory cortex, providing the first account of neocortical processing of sexual clitoral information. In contrast, orgasm was mainly associated with profound rCBF decreases in the neocortex when compared with the control conditions (clitoral stimulation and imitation of orgasm), particularly in the left lateral orbitofrontal cortex, inferior temporal gyrus and anterior temporal pole. Significant positive correlations were found between RPstd and rCBF in the left deep cerebellar nuclei, and between PSA and rCBF in the ventral midbrain and right caudate nucleus. We propose that decreased blood flow in the left lateral orbitofrontal cortex signifies behavioural disinhibition during orgasm in women, and that deactivation of the temporal lobe is directly related to high sexual arousal. In addition, the deep cerebellar nuclei may be involved in orgasm‐specific muscle contractions while the involvement of the ventral midbrain and right caudate nucleus suggests a role for dopamine in female sexual arousal and orgasm.
Abstract Cerebrovascular P-glycoprotein (P-gp) acts at the blood–brain barrier (BBB) as an active cell membrane efflux pump for several endogenous and exogenous compounds. Age-associated decline in ...P-gp function could facilitate the accumulation of toxic substances in the brain, thus increasing the risk of neurodegenerative pathology with aging. We hypothesised a regionally reduced BBB P-gp function in older healthy subjects. We studied cerebrovascular P-gp function using 11 C-verapamil positron emission tomography (PET) in seventeen healthy volunteers with age 18–86. Logan analysis was used to calculate the distribution volume (DV) of 11 C-verapamil in the brain. Statistical Parametric Mapping was used to study specific regional differences between the older compared with the younger adults. Older subjects showed significantly decreased P-gp function in internal capsule and corona radiata white matter and in orbitofrontal regions. Decreased BBB P-gp function in those regions could thus explain part of the vulnerability of the aging brain to white matter degeneration. Moreover, decreased BBB P-gp function with aging could be a mechanism by which age acts as the main risk factor for the development of neurodegenerative disease.
Genetic variation in the catechol-O-methyltransferase (COMT) Val158Met polymorphism has been shown to influence performance on cognitive and emotional tasks. Specifically, it has been suggested that ...the Met allele might be less advantageous than the Val allele with respect to emotional processing.
This study addresses the question whether the presence of the Met allele is directly related to both lower emotional verbalizing proficiency and differences in brain activation during emotional processing. Specifically, we investigated whether COMT genotype would be associated with differences in activation in cortical midline structures during valence evaluation of words.
Forty participants ranging from low to high on the verbalizing subscale of the Bermond–Vorst Alexithymia Questionnaire (BVAQ) were genotyped for the COMT Val158Met polymorphism. During fMRI, they evaluated the valence of emotional words.
Met homozygotes reported more difficulties in verbalizing their feelings. In addition, the Met allele was associated with attenuated brain activation in posterior cingulate gyrus and precuneus during valence evaluation.
We conclude that the Met allele modulates neural activation in regions associated with emotional awareness. Our findings may contribute to understanding the neural correlates of susceptibility for affective disorders.
► Met allele of COMT Val158Met polymorphism was associated with reduced emotional brain activation. ► This concerned posterior cingulate gyrus and precuneus during a task of valence evaluation. ► The Met allele homozygotes reported difficulties in verbalizing their feelings. ► Met allele may be associated with reduced activation of areas subserving emotional awareness. ► This may contribute to susceptibility for affective disorders.
•30-min transcranial pulsed electromagnetic fields stimulation does not relieve neuropathic pain in patients.•30-min transcranial pulsed electromagnetic fields stimulation does not change heat pain ...thresholds in neuropathic pain patients.•Warmth and heat pain detection showed strong time dependence, independent of transcranial pulsed electromagnetic field or sham stimulation.
Neuromodulation is nowadays investigated as a promising method for pain relief. Research indicates that a single 30-minute stimulation with transcranial pulsed electromagnetic fields (tPEMF) can induce analgesic effects. However, it is unknown whether tPEMF can induce analgesia in neuropathic pain patients.
To evaluate the effect of tPEMF on spontaneous pain and heat pain in neuropathic pain patients.
This study had a randomized double-blind crossover design. Twenty neuropathic pain patients received 30-minutes of tPEMF and 30-minutes sham stimulation. Primary outcomes were pain intensity, pain aversion and heat pain. Secondary outcomes included affect, cognition, and motor function, to investigate safety, tolerability and putative working mechanisms of tPEMF. Outcomes were assessed before, during and after stimulation.
No differences in analgesic effects between tPEMF and sham stimulation were found for pain intensity, pain aversion or heat pain. No differences between tPEMF and sham stimulation were observed for affect, motor, and cognitive outcomes.
A single 30-minute tPEMF stimulation did not induce analgesic effects in neuropathic pain patients, compared to sham. Further study is needed to determine whether prolonged stimulation is necessary for analgesic effects.
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