Literatur und medizinische Studien zu den von uns erfolgreich durchgeführten Therapieverfahren. Studien zur Wirksamkeit von Ketamininfusionen bei schwerer Depression, rTMS Behandungen während der Schwangerschaft und andere Therapiemethoden wie EMDR, Neurofeedback, HRV Biofeedback und tDCS.
Studien zum Einsatz von Ketamin
Background. There are few studies on ketamine and its properties to work with addiction (alcohol, opioid, cannabis, and cocaine use disorder). The studies show that ketamine treatment can help reduce craving and support abstinence . Hypnotherapy is an evidence-based treatment gaining popularity for treating addiction, but not everybody can be hypnotized due to different levels of suggestibility. Our clinical practice has observed that people who are not highly hypnotizable, such as patients with obsessive-compulsive disorders, become more suggestible accompanied by our newly developed method called “Ketamine-Hypnosis package” (KHP). In this case report and study, we want to explore and evaluate the potential of KHP in working with addiction. Diagnostic and a qualitative content analysis should give profound insights into the treatment process and method.
Case Report. The subject is a 48-year-old male German Social Worker with treatment-resistant depression, suicidal thoughts, obsessive behavior, and several forms of addiction. The patient received a 10-day treatment at Instituto Dr. Scheib, with Diagnostic, rTMS, neurofeedback, and four sessions of KHP. Every Ketamine infusion remained with a standard dose of 0.5 mg/kg R-Ketamine for about 45 minutes.
Results. Primary outcome measures included change in depression as measured by the BDI-II with a reduction from 44, highly depressed, to a score of 3, no depression, and change of symptoms measured by the SCL-90 R that showed a clear reduction in almost every factor vs. baseline. The qualitative content analysis of the KHP sessions identified nine categories; Setting, Intervention, Body, Control, Feelings, Insights/Realizations, Addiction, Depression and Imagery. QEEG measurements before and after treatment showed a pattern of over-representation of slow brain activity with closed eyes, which can be observed in fluctuating concentration and volatile impulse control. Follow-Up Data with BDI-II one week after treatment showed factor 3 and 5 weeks after treatment factor 15.
Conclusions. The 10-day-treatment program improved numerous important treatment outcomes in one substance-dependent adult engaged in hypnotherapeutic modification, including promoting less substance abuse, diminishing craving, and reducing the risk of relapse. Further research is needed to replicate these promising results in a larger sample.
Opioid addiction in the United States currently presents a national crisis despite availability of different treatments. Prior findings suggest that both repetitive transcranial magnetic stimulation (rTMS) and subanesthetic dose of ketamine are efficacious in patients with opioid use disorders (OUD) when administered in isolation. However, their therapeutic value may be undermined by varying clinical responses that tend to dissipate with treatment cessation. There has been no study to date that has used a combination of both for OUD, and there are still many unanswered questions with respect to both. TIMBER (Trauma Interventions using Mindfulness Based Extinction and Reconsolidation of memories) therapy attempts to alter the expression of emotionally charged memories such as traumatic memories, and has been successfully tried in chronic post-traumatic stress disorder (PTSD) and in combination with memory-altering pharmacotherapy like ketamine infusion. By a combination of extinction and reconsolidation of memory approaches, TIMBER works to not over-flood and/or retraumatize as is seen in other treatment approaches. TIMBER involves a balanced combination of both the memory extinction and memory reconsolidation approaches (rather than extinction-only approaches) which explains its superior efficacy in PTSD and benefit in substance use disorders.
Opioid addiction in the United States (US) currently presents a national crisis despite availability of different treatments. Over 2.1 million people were diagnosed with opioid use disorder (OUD) in 2016 . Prior findings suggest that both repetitive transcranial magnetic stimulation (rTMS) and subanesthetic dose of ketamine are efficacious in patients with OUD when administered in isolation [1-4]. However, their therapeutic value may be undermined by varying clinical responses that tend to dissipate with treatment cessation. There has been no study to date that has used a combination of both for OUD, and there are still many unanswered questions with respect to both. Trauma Interventions using Mindfulness Based Extinction and Reconsolidation of memories (TIMBER) attempts to alter the expression of emotionally charged memories such as traumatic memories, and has been successfully tried in chronic post-traumatic stress disorder (PTSD) alone, or in combination with memory-altering pharmacotherapy like ketamine infusion [5-7]. By a combination of extinction and re-consolidation of memory approaches, TIMBER works to not over-flood and/or re-traumatize as is seen in other treatment approaches. At the present time, TIMBER has been shown to be efficacious in targeting trauma memories and their expressions in PTSD patients .
TIMBER uses all eight limbs of Yoga including the focused attention meditation and mindfulness meditation, the five-factor model of trauma or addiction experience, and integrates the principles of cognitive behavioral therapy (CBT) (mindfulness-based graded exposure therapy: MB-GET) with the neurobiology of emotionally charged traumatic or addiction memories. With respect to applying the translational model of TIMBER for drug addiction, the key steps are:
1. Inducing a mindful state (calm, alert but non-reactive) by use of a standardized meditation protocol (StaMP).
2. Creating drug-cues evoked controlled arousal response using a scripted brief narrative of the addiction experience by using the Buddha’s Five Factor Model (thoughts, feelings, memories, sensations/perceptions, and urges/impulses related to the addiction experience).
3. Using the mindfulness-based graded exposure therapy (MB-GET) and the TIMBER methods to decrease the arousal responses.
4. Using the already created mindful state to cognitively reprocess and reappraise the drug-related emotionally charged memories so that the drug-related emotionally charged memories are extinguished and de-conditioned from the cues and re-consolidated/updated as new memories.
TIMBER involves a balanced combination of both the memory extinction and memory reconsolidation approaches (rather than extinction only approaches) which likely explains its superior efficacies in PTSD and possibly in our future studies on drug addiction as well. The case series presented here is the extended application of the proof of concept model of TIMBER in three patients with chronic OUD.
Materials & Methods
The study is an open-label proof of concept study designed to test the feasibility and efficacy of ketamine, rTMS, and TIMBER in patients with OUD. The study included three patients all with a diagnosis of OUD. The primary outcome measure was percent reduction in cravings using the opiate use craving scale from baseline to the fifth rTMS session.
The following interventions were used:
1. Ketamine was given as a single infusion of 0.75 mg/kg weight-based dose capped at 745 mg total, administered over a 45 minute period. A one week washout period followed prior to the start of rTMS.
2. rTMS was performed for five sessions of 10 Hz and 3000 stimulation pulses applied to the right dorsolateral pre-frontal cortex (DLPFC) over one to two weeks.
3. Five sessions of TIMBER mindfulness-based therapy was carried out during the same two weeks period that rTMS was performed.
4. Home practice was then carried out two times daily with additional sessions on an as-needed basis whenever cravings were present.
Cravings were measured using the Opiate Craving Scale. Arousal responses were measured by a multi-system biofeedback bundle that comprised of real-time electroencephalogram (EEG), heart rate variability, and breath response pattern guided focused attention and mindfulness meditation practice (three minutes before rTMS, 21 minutes during, and three minutes after administration of rTMS).
In our open-label pilot study sample that consisted of three subjects with opiate use disorder (two with heroin use disorder and one with oxycodone use disorder), the participants rated their craving on the Opiate Craving Scale (OCS: scores range 0-30), five minutes before and five minutes after the rTMS stimulation . They rated their level of mindfulness pre-infusion baseline and after completing five sessions of TMS+mindfulness using the Assessment Scale for Mindfulness Interventions (ASMI) [6,7].
In these three subjects, at baseline, the mean OCS was 23.6 (SD 4.2), which indicates a high level. The OCS reduced to 8.2 (SD 2.7) after five sessions of TMS and mindfulness. Similarly, at baseline, their mean ASMI was 28.45 (SD 9.61). After five sessions of TMS and mindfulness, the mean ASMI was 49. 67 (SD 7.72) indicating a significant increase in mindfulness (Table 1).
Collectively all of these therapeutic interventions show promise as individual treatments for maintenance of abstinence in OUD, particularly improvement in cravings and increased motivation to quit. Significant long-term improvements in complete abstinence have been demonstrated with the use of ketamine following extended inpatient treatment [3,4], and ketamine reduced physiological response during opioid withdrawal . However, these studies on the use of ketamine are limited by their use of low-dose ketamine as the comparison group rather than a true placebo. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique currently approved for major depressive disorder. rTMS is currently being pursued as a treatment for substance use disorder. Preliminary data looking at treatment with rTMS to the dorsolateral pre-frontal cortex (DLPFC) has shown reduction in cravings in alcohol, cocaine, and nicotine use disorders . Single session rTMS studies have demonstrated that applying excitatory rTMS to the DLPFC can decrease cue-induced craving in nicotine, cocaine, and alcohol use disordered populations. The mechanism of rTMS success in treating addiction is thought to involve increased dopamine function in the shell region of the nucleus accumbuns .
Single session studies have only found small temporary reductions in craving, however more frequent sessions could lead to longer durations and greater reductions in cravings. The largest such clinical trial (n=130 smokers) demonstrated that 13 sessions of DLPFC rTMS resulted in six month tobacco abstinence rates of 33% . Trauma memories lay at the core of the pathogenesis of PTSD. TIMBER therapy attempts to alter the expression of emotionally charged memories such as traumatic memories, and has been successfully tried in chronic PTSD alone or in combination with memory altering pharmacotherapy like ketamine infusion [5,7]. There are many similarities between the emotionally charged memories common in PTSD, and the emotionally charged memories associated with addiction. Exposure to environmental cues such as people, places, or drug paraphernalia lead to a state of arousal and strong emotional response that often results in relapse for patients attempting to maintain sobriety. The use of mindfulness-based graded exposure therapy (MB-GET) and the TIMBER methods to decrease the arousal responses will extinguish drug-related emotionally charged memories while replacing them with new more adaptive memories. TIMBER aims to restructure cognitions and emotions, which prevents reactivity of the underlying memories in trauma .
A number of important questions remain. It is unclear how each of these modalities will function in combination and in comparison to a true placebo group. It is unclear what role baseline levels of desire to quit, motivation for treatment, and prior periods of abstinence have on the achievement and maintenance of abstinence. The groups chosen for the ketamine studies were treatment-seeking and completed three months of residential treatment prior to treatment with ketamine infusion [3,4]. The abstinence rates at one- and two-year follow-up for ketamine are promising; unique genetic and socioeconomic factors must be considered [3,4]. To date there is limited work examining the effect of rTMS on craving in OUD. However, preliminary data indicates significant possibility of reduced craving with multiple sessions of rTMS. While TIMBER methods have been successfully used to treat PTSD, this method has yet to be applied to substance use disorders on a mass scale. TIMBER involves a balanced combination of both the memory extinction and memory reconsolidation approaches (rather than extinction only approaches) and has possible implications for substance use disorder.
Combination therapy with ketamine, rTMS and TIMBER is feasible in patients with OUD. Although an open-label proof of concept study, the data suggests that the combination therapy reduces craving, promotes abstinence, and reduces the amount used in patients with OUD. Combination therapy allows patients to be actively involved in their care by engaging in meditative therapy-based techniques that directly result in a calmer state of mind. This protocol allows concurrent implementation of three individually effective interventions in combination for a compounding synergistic effect.
Link to publication: https://europepmc.org/article/pmc/pmc7779150#free-full-text
Available online 11 December 2020
Authors: Jiaqi Xiong1 Orly Lipsitz3 David Chen-Li3 Joshua D.Rosenblat123 Nelson B.Rodrigues3 Isabelle Carvalho3 Leanna M.W. Lui3 Hartej Gill34 Flora Narsi3 Rodrigo B. Mansur3 Yena Lee3 Roger S. McIntyre1234
• Single-dose intravenous ketamine/intranasal esketamine has rapid and robust acute effects in reducing suicidal ideation (SI).
• Future high-quality research on the anti-SI efficacy of alternative administration routes (i.e. intramuscular, subcutaneous, oral/sublingual) and formulations of ketamine is needed.
• Dosage, routes of administration, and formulations are factors to be considered for optimizing SI treatment using ketamine.
The efficacy of ketamine in reducing suicidal ideation (SI) has been previously reported. We aimed to evaluate acute anti-SI effects of single-dose ketamine in different formulations/routes of administration by pooling results from randomized controlled trials (RCTs). A systematic search was conducted on Cochrane, Embase, Medline, and PubMed from inception to July 1st, 2020. Studies were selected based on pre-determined eligibility criteria. Effect sizes of different formulations/routes at various time points were computed using random-effects models. With data from nine eligible RCTs (n=197), the pooled effect size for anti-SI effects at 24-hour time point was 1.035 (N=6, CI: 0.793 to 1.277, p<0.001) for intravenous (IV) racemic ketamine and 1.309 (N=1, CI: 0.857 to 1.761, p<0.001) for intranasal (IN) esketamine. An additional five RCTs were available for qualitative analysis. RCTs were identified for oral/sublingual ketamine for depression, however, none of these trials reported anti-SI effects preventing quantitative analysis for these routes of delivery. No RCTs for intramuscular (IM) ketamine were identified. The findings suggest that single-dose IV ketamine/IN esketamine is associated with robust reductions in suicidal thoughts at 2-hour, 4-hour, and 24-hour post-intervention. In addition, future studies on IM/oral/sublingual ketamine and comparative studies are warranted to evaluate the anti-SI efficacy of distinct formulations and routes of administration.
Volume 105, 8 March 2021, 110126
Authors: Orly Lipsitzab Roger S.McIntyreabcd Nelson B.Rodriguesab Tyler S. Kasterdh Danielle S. Chaab Elisa Brietzkejk Hartej Gillab Flora Nasria Kangguang Linef Mehala Subramaniapillaiab Kevin Kratiukb Kayla Teopizb Leanna M.W. Luia Yena Leeab Roger Hog Margarita Shekotikhinaabi Rodrigo B. Mansurad Joshua D. Rosenblatabcd
• Early symptom improvement was associated with greater antidepressant effects following four ketamine infusions.
• ~40% of individuals with early improvement responded to the full treatment course versus 14–19% in non-early improvers.
• 58% of individuals who did not experience early improvement experienced a partial to full response after the fourth infusion.
Early symptomatic improvement with monoamine-based antidepressants is predictive of treatment response. The objective of this study was to determine if early symptomatic improvements with intravenous (IV) ketamine predicted treatment response to an acute course of four infusions.
134 adults with treatment resistant depression (TRD) received four ketamine infusions over one to two weeks. Depressive symptoms were measured using the Quick Inventory for Depressive Symptomatology Self-Report16 (QIDS-SR16) at baseline and post-infusions 1, 2, 3, and 4. Early improvement was defined as ≥20% reduction in QIDS-SR16 scores after the first or second infusion. Linear models were used to determine whether early improvement was associated with post-infusion 4 QIDS-SR16 scores after controlling for baseline characteristics.
Early improvement post-infusion 1 (β = −3.52, 95% BCa CI [−5.40, −1.78]) and 2 (β = −3.16, 95% BCa CI [−5.75, −1.59]) both significantly predicted QIDS-SR16scores post-infusion 4. Early improvers had significantly lower QIDS-SR16 scores at post-infusion 4 (post-infusion 1 improvers: M = 9.8, SD = 4.5; post-infusion 2 improvers: M = 10.6, SD = 5.7) compared to non-early improvers (post-infusion 1 non-improvers: M = 13.7, SD = 5.8; post-infusion 2 non-improvers: M = 14.1, SD = 5.3) when controlling for baseline characteristics. The majority (58%) of individuals who did not improve post-infusions 1 or 2 still experienced an antidepressant response or partial response (≥20% reduction in QIDS-SR16) post-infusion 4.
This is a post-hoc analysis of an open-label study.
Early improvement was associated with greater antidepressant effects following a course of four ketamine infusions. However, individuals who did not show early improvements still had a high likelihood of experiencing clinically significant symptom reduction after the fourth infusion, suggesting that completing four infusions, regardless of early symptom changes, is appropriate and merited.
Steven R.D. Best a,*, Dan G. Pavel b, Natalie Haustrup c
a The Neuroscience Center, Deerfield, IL, USA
b PathFinder, Brain SPECT Imaging, Deerfield, IL, USA
c Haustrup Scientific Consulting, Cambridge, UK
A R T I C L E I N F O
Keywords: Psychiatry, Neurology, TMS, Depression, Ketamine, Comorbidity, Biomarker, Combination
A B S T R A C T
Background: Both transcranial magnetic stimulation (TMS) and infused ketamine are recognized treatments for patients suffering from major depressive disorder (MDD). A novel therapy named combination TMS with ketamine (CTK) is introduced. This retrospective review examined the safety and clinical benefits of CTK in patients suffering from treatment-resistant depression (TRD) during the routine practice of psychiatry in a private clinic.
Methods: TRD patients (N . 28) received a coincident application of high-output TMS (30 minutes) with biomarker-determined ketamine infusions (20 minutes). Frequency of treatment was dependent on patient responsiveness (10–30 sessions). Clinical global impression (CGI) data was collected pre- and post-treatment and then two years later.
Results: The mean reduction in CGI severity for the patient group following CTK was 4.46 0.54 at a 99% confidence interval and was deemed statistically significant using a paired t-test (α . 0.01, t . 22.81 p < 0.0001).
This reduction was sustained for two years following treatment completion and this remission was deemed statistically significant by a second paired t-test (α . 0.01, t . 27.36, p < 0.0001).
Limitations: Retrospective review of a limited number of patients undergoing CTK in a clinical practice.
Conclusions: This clinical review indicated that CTK is an effective, long-term therapy (after two years) and can be used for TRD patients. The coincident administration of ketamine allowed for higher TMS intensities than otherwise would be tolerated by patients. Further studies for optimization of CTK are warranted.
Treatment-resistant depression refers to a major depressive disorder (MDD) with a lack of clinically meaningful improvement to an appropriate course (adequate dose over 6–8 weeks) of at least two antidepressants from different pharmacological classes, prescribed for adequate duration, with adequate affirmation of treatment adherence (Little, 2009; EMA Guidelines, 2013). It is estimated that between 15% and 33% of patients will not respond to multiple interventions and therefore be classed as suffering from treatment-resistant depression (Little, 2009).
The sequenced treatment alternatives to relieve depression (STAR*D) trial explored the effectiveness of alternative treatments for treatment-resistant depression patients and predicted that only a third of the 20 million Americans suffering from MDD would achieve remission (Warden et al., 2007). Continued depressive symptoms have been linked to social issues, a greater risk of suicide and mortality and ultimately results in increased health-care costs (Lepine and Briley, 2011; Kellar et al., 2016).
The cause of such depressive disorders remains unclear. However, it is commonly agreed that it relates to a system disorder affecting pathways between cortical, subcortical and limbic sites, along with the neurotransmitter and molecular mediators (Mayberg et al., 2005). Patients with unipolar depression have been shown to have prefrontal abnormalities, predominantly on the left and decreased neuronal activities in the dorsolateral prefrontal cortex (PFC) regions, as well as in the rostral anterior cingulate cortex (ACC) areas, closely connected to the dorsolateral PFC (Baeken and De Raedt, 2011).
Research has shown a strong negative correlation between the ACC
* Corresponding author.
E-mail address: firstname.lastname@example.org (S.R.D. Best).
Contents lists available at ScienceDirect
journal homepage: www.heliyon.com
Received 28 February 2019; Received in revised form 31 May 2019; Accepted 26 July 2019
2405-8440/© 2019 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
- Jerome H Taylor,
- Angeli Landeros-Weisenberger,
- Catherine Coughlin,
- Jilian Mulqueen,
- Jessica A Johnson,
- Daniel Gabriel,
- Margot O Reed,
- Ewgeni Jakubovski&
- Michael H Bloch
Many patients with social anxiety disorder (SAD) experience inadequate symptom relief from available treatments. Ketamine is a potent N-methyl-D-aspartate receptor antagonist with a potentially novel mechanism of action for the treatment of anxiety disorders. Therefore, we conducted a double-blind, randomized, placebo-controlled crossover trial in 18 adults with DSM-5 SAD and compared the effects between intravenous ketamine (0.5 mg/kg over 40 min) and placebo (normal saline) on social phobia symptoms. Ketamine and placebo infusions were administered in a random order with a 28-day washout period between infusions. Ratings of anxiety were assessed 3-h post-infusion and followed for 14 days. We used linear mixed models to assess the impact of ketamine and placebo on anxiety symptoms. Outcomes were blinded ratings on the Liebowitz Social Anxiety Scale (LSAS) and self-reported anxiety on a visual analog scale (VAS-Anxiety). We also used the Wilcoxon signed-rank test to compare the proportion of treatment responders. Based on prior studies, we defined response as a greater than 35% LSAS reduction and 50% VAS-Anxiety reduction. We found ketamine resulted in a significantly greater reduction in anxiety relative to placebo on the LSAS (Time × Treatment: F9,115=2.6, p=0.01) but not the VAS-Anxiety (Time × Treatment: F10,141=0.4, p=0.95). Participants were significantly more likely to exhibit a treatment response after ketamine infusion relative to placebo in the first 2 weeks following infusion measured on the LSAS (33.33% response ketamine vs0% response placebo, Wilcoxon signed-rank test z=2.24, p=0.025) and VAS (88.89% response ketamine vs 52.94% response placebo, Wilcoxon signed-rank test z=2.12, p=0.034). In conclusion, this proof-of-concept trial provides initial evidence that ketamine may be effective in reducing anxiety.
Paul Glue, Shona Neehoff, Amandine Sabadel, …
First Published September 17, 2019 Research Article Find in PubMed
We previously reported that ketamine has anxiolytic effects in patients with treatment-resistant generalized anxiety and social anxiety disorders.
The purpose of this study was to replicate our earlier report about ketamine‘s anxiolytic activity, using a more robust study design.
This was a double-blind, psychoactive-controlled ascending dose study in 12 patients with treatment-resistant generalized anxiety and social anxiety disorders who were not currently depressed. Ascending doses of ketamine (0.25, 0.5, 1 mg/kg) were administered at weekly intervals, and midazolam 0.01 mg/kg, the control, was randomly inserted into the ketamine dose sequence. Assessments included ratings of anxiety and dissociation, safety and tolerability, and blood samples for ketamine pharmacokinetics and BDNF concentrations.
Improvements in anxiety ratings occurred within an hour of ketamine dosing, and persisted for up to 1 week. A dose-response profile was noted for anxiolytic effects, dissociative side effects, and changes in blood pressure and heart rate after ketamine dosing. Midazolam had minor brief effects on anxiety ratings. Ketamine was safe and well tolerated. Ketamine pharmacokinetics were correlated with dissociation ratings. Serum BDNF concentrations declined over time and were similar for all treatments.
Ketamine may be a potential therapeutic option for patients with treatment-resistant generalized anxiety and social anxiety disorders.
Jennifer L. Phillips1,2, Sandhaya Norris1,2, Jeanne Talbot1,2, Taylor Hatchard1, Abigail Ortiz 1, Meagan Birmingham1, Olabisi Owoeye1,2, Lisa A. Batten1 and Pierre Blier1,2,3
Repeated administration of subanesthetic intravenous ketamine may prolong the rapid decrease in suicidal ideation (SI) elicited by single infusions. The purpose of this secondary analysis was to evaluate reduction in SI with a single ketamine infusion compared with an active control, and prolonged suppression of SI with repeated and maintenance infusions. Thirty-seven participants with treatment-resistant depression (TRD) and baseline SI first received a single ketamine infusion during a randomized, double-blind crossover with midazolam. Following relapse of depressive symptoms, participants received six open-label ketamine infusions administered thrice-weekly over 2 weeks. Antidepressant responders (≥50% decrease in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) received four further open-label infusions administered once-weekly. Changes in SI were assessed with the suicide items on the MADRS (item 10, MADRS-SI) and the Quick Inventory of Depressive Symptomatology-Self Report (item 12, QIDS-SI). Linear mixed models revealed that compared with midazolam, a single ketamine infusion elicited larger reduction in SI (P = 0.01), with maximal effects measured at 7 days postinfusion (P < 0.001, Cohen’s d = 0.83). Participants had cumulative reductions in MADRS-SI scores with repeated infusions (P < 0.001), and no further change with maintenance infusions (P = 0.94). QIDS-SI results were consistent with MADRS-SI. Overall, 69% of participants had a complete alleviation of SI following repeated infusions. In TRD, single and repeated ketamine infusions resulted in decreases in SI which were maintained with once-weekly maintenance infusions. This study adds to the growing body of research suggesting ketamine as a possible novel treatment strategy for SI in mood disorders.
Neuropsychopharmacology (2019) 0:1–7; https://doi.org/10.1038/s41386-019-0570-x
Muris Humoa, Beyza Ayazgökab, Léa J.Beckera, Elisabeth Waltispergera, Tomi Rantamäkicd, Ipek Yalcina
Volume 100, 8 June 2020,
Chronic pain produces psychologic distress, which often leads to mood disorders such as depression. Co-existing chronic pain and depression pose a serious socio-economic burden and result in disability affecting millions of individuals, which urges the development of treatment strategies targeting this comorbidity. Ketamine, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, is shown to be efficient in treating both pain and depression-related symptoms. However, the molecular characteristics of its role in chronic pain-induced depression remain largely unexplored. Hence, we studied the behavioral and molecular effects of a single systemic administration of ketamine (15 mg/kg, i.p.) on mechanical hypersensitivity and depressive-like consequences of chronic neuropathic pain. We showed that ketamine transiently alleviated mechanical hypersensitivity (lasting <24 h), while its antidepressant effect was observed even 72 h after administration. In addition, ketamine normalized the upregulated expression of the mitogen activated protein kinase (MAPK) phosphatase 1 (MKP-1) and the downregulated phosphorylation of extracellular signal-regulated kinase (pERK) in the anterior cingulate cortex (ACC) of mice displaying neuropathic pain-induced depressive-like behaviors. This effect of ketamine on the MKP-1 was first detected 30 min after the ketamine administration and persisted until up to 72 h. Altogether, these findings provide insight into the behavioral and molecular changes associated with single ketamine administration in the comorbidity of chronic pain and depression.
Aust N Z J Psychiatry. 2020 Jan;54(1):29-45. doi: 10.1177/0004867419883341. Epub 2019 Nov 15.
Ketamine may reduce suicidal ideation in treatment-resistant depression. But it is not known how quickly this occurs and how long it persists. We undertook a systematic review and meta-analysis to determine the short- and long-term effectiveness of ketamine for suicidality.
CENTRAL, EMBASE, Medline, and PsycINFO were searched until 12 December 2018. Randomised controlled trials of ketamine or esketamine reporting data on suicidal ideation, self-harm, attempted or completed suicide in adults diagnosed with any psychiatric disorder were included. Two reviewers independently extracted data, and certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation tool. Standardised mean difference was used for continuous outcomes.
Twenty-five reports from 15 independent trials, with a total of 572 participants diagnosed with predominately affective disorders, were included. The evidence was rated moderate to low. In most trials, ketamine was administered at 0.5 mg/kg via a single intravenous infusion over a 30- to 45-minute period. Only a single trial of intranasal esketamine was identified. At 4 hours post-infusion, treatment with ketamine was associated with a significant reduction in suicidal ideation scores (standardised mean difference = -0.51, 95% confidence interval = [-1.00, -0.03]), which persisted until 72 hours post-infusion (time points between 12 and 24 hours: standardised mean difference = -0.63, 95% confidence interval = [-0.99, -0.26]; between 24 and 72 hours: standardised mean difference = -0.57, 95% confidence interval = [-0.99, -0.14]), but not thereafter. However, there was marked heterogeneity of results. In a single trial of esketamine, marginal effects on suicidal ideation were observed. In terms of actual suicidal behaviour, there were virtually no data on effects of ketamine or esketamine.
A single infusion of ketamine may have a short-term (up to 72 hours) beneficial impact on suicidal thoughts. While confirmation of these results in further trials is needed, they suggest possible use of ketamine to treat acute suicidality. Means of sustaining any anti-suicidal effect need to be found.
In the present article, we report on the case of a 23-year-old woman with a history of treatment-resistant depression who achieved significant symptom improvement with a novel treatment consisting of ketamine, a dissociative anesthetic, and external neuromodulation with transcranial magnetic stimulation (TMS). This case highlights the need for further investigation of treatments pairing external neuromodulation with dissociative anesthetics.
Despite advances in pharmacological treatment, approximately half of patients fail to achieve full remission, prompting researchers to look beyond conventional antidepressant medications . Recent research has examined transcranial magnetic stimulation (TMS and its variant rTMS), in which an electromagnetic stimulator positioned at the scalp induces a change in local and distant electric field conditions and may cause an associated depolarization of neurons . When used to stimulate the dorsolateral prefrontal cortex, rTMS has been associated with significant antidepressant effects , and is an FDA-approved treatment for depression. However, it is difficult to achieve remission with rTMS alone. A separate body of research has investigated intravenous ketamine, an N-methyl-D-aspartate (NMDA) antagonist [4–8]. In contrast to typical antidepressant medications that take effect within several weeks, ketamine provides relief within 2 h and lasts between four and seven days, after which relapse is common [4,5]. To date, little is known about the possible synergistic effects of combined rTMS/ketamine treatment for depression.
One study found that a factor underlying treatment resistance in depression is abnormal function in a thalamocortical circuit involving the anterior cingulate cortex (ACC), among other areas [9,11]. Accordingly, the first author hypothesized stimulating the ACC with TMS would restore normal functioning in the relevant circuit, thereby improving response to ketamine. We report on a depressed patient treated with a novel combined ketamine/TMS technique who showed substantial improvement in depression symptomatology at the end of treatment, and again at follow-up 483 days later. An IRB exemption was obtained from an independent accredited agency.
Case Report. Patient X is a 23-year-old woman who presented with a 9-year history of depression that did not respond to treatment with sertraline, buprorion, paroxetine, or stimulants. She also presented with attention deficit disorder that was treated with amphetamine from intake through follow-up. Her past history included diagnoses of anorexia nervosa and substance abuse (cocaine) that were in full remission at intake. Patient X was systematically assessed for psychopathology by an independent licensed psychologist at the outset of treatment. The primary assessment instruments were the Beck Depression Inventory-II (BDI-II) and the Personality Assessment Inventory (PAI). PAI subscale scores greater than 70 indicate clinically significant difficulties. Results of this assessment suggested that Patient X exhibited moderate levels of depression (BDI-II = 17, PAI DEP T = 84) consisting predominantly of depressed mood (PAI DEP-A T = 83), low self-esteem (PAI DEP-C T = 87), and suicidal ideation (PAI SUI T = 62). In addition, the initial assessment suggested significant difficulties in developing and maintaining a sense of life purpose and self-identity (PAI BOR-I T = 80), problematic alcohol use (PAI ALC = 66), and concentration difficulties (PAI SCZ-T T = 73). After this comprehensive assessment, Patient X’s mood was assessed during each treatment by the first author using a visual analog scale. In this measure, Patient X indicated where her mood fell along a continuum from “the worst I can imagine feeling” to “the best I can imagine feeling.”
Prior to beginning combined treatment, Patient X was given 2 days of rTMS pretreatment (four treatments per day of 30 min with 45 min of rest between treatments). Combined ketamine/TMS treatment began the following day and continued at weekly intervals for 13 weeks. Fifteen years of observational evidence from our clinic suggested that this duration produced clinically significant results. Combined treatment consisted of 40 min of 1 Hz continuous TMS with an intravenous ketamine infusion administered concurrent to and bracketed within the middle 30 min of TMS, resulting in 5 min of TMS pre- and postinfusion. The dosage of infused ketamine increased gradually from 30 mg at the first treatment to 100 mg at the last treatment. During combined treatment, the TMS head coil (manufactured by Neotonus) was positioned at the midline of the scalp to achieve maximal stimulation of the medial prefrontal area that overlays the anterior cingulate, a region implicated in depression . While direct stimulation of the anterior cingulate is not likely given its subcortical position and the limited electromagnetic field penetration of TMS coils , we hypothesized that indirect stimulation of the anterior cingulate via TMS applied to the overlaying scalp region would result in a beneficial effect.
Baseline brain scans were used to ensure accurate coil positioning at each treatment. TMS treatments were administered at 115% of motor threshold at 1 Hz continuous pulsation given that these settings were within safety guidelines and consistent with previous research. Using this method, we hypothesized that the dissociative effects of ketamine along with TMS activation of the anterior cingulate would help reestablish normal oscillatory rhythms in this region, leading to a decrease in depression symptoms.
After the treatment on week three, Patient X reported a substantial improvement in mood and energy levels. Patient X noted that these gains were maintained over the duration of treatment with some fluctuation in mood due to relationship difficulties. Soon after the last combined treatment, Patient X reported a nondepressed mood with increased motivation and diminished attention difficulties. Combined treatment was followed by regular psychiatric visits 1–2× /month for 14 months. Gains were generally maintained over this span, with Patient X reporting that she was able to begin graduate studies and sustain an intimate relationship. Four hundred and eighty three days after her initial assessment, Patient X was again systematically assessed for psychopathology by an independent licensed psychologist. Results showed substantial decreases in depression (BDI-II = 0, PAI DEP T = 41), suicidal ideation (PAI SUI T = 45), alcohol use (PAI ALC T = 49), and concentration difficulties (PAI SCZ T = 49), along with increased sense of self-purpose (PAI BOR-I T = 56).
Discussion. This case report adds to the literature on improving the efficacy of brain electromagnetic stimulation by administering pharmacological agents that modulate glutamatergic transmission. Whereas previous research suggests that rTMS is somewhat effective in treating depression , and that subanesthetic doses of ketamine are temporarily helpful with depression [5–9]; the present case report is the first to suggest that a combined ketamine/rTMS treatment may be a more efficacious treatment for refractory depression than either infused ketamine or rTMS alone. Future research should examine combined ketamine/TMS treatment in a randomized controlled trial.
Declaration of Interest
Dr. Best reports no biomedical financial interests or potential conflicts of interest. Brian Griffin reports no biomedical financial interests or potential conflicts of interest. The authors alone are responsible for the content and writing of this paper.
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The fast-acting nasal spray esketamine, marketed as SpravatoTM, was recently approved by the Food and Drug Administration (FDA) to treat depression in individuals whose depression has been resistant to at least two medications. Structurally, esketamine is an enantiomer, or mirror image, of ketamine and works by a similar mechanism.1 The antidepressant response is evident within a few days of administration, unlike traditional antidepressants that often take weeks for the patient to feel any improvement in mood. This is particularly advantageous for patients who have suicidal thoughts and need quick resolution of depression symptoms.
While an old anesthetic drug, this new formulation has yet to be explored extensively through clinical studies in the pregnant and breastfeeding population. Interestingly, animal studies conducted don’t seem to produce promising results. A new study conducted in 2017 found that offspring of pregnant rats treated with ketamine had impaired learning and memory.2 Another study found that offspring of rats treated with ketamine during the second trimester had long-term neurocognitive dysfunction.3 A study in 2016 found that ketamine exposure during pregnancy in rats resulted in reduced development of certain brain regions in the offspring.4 Thus, at this time, ketamine’s effects in pregnancy are concerning and it is not recommended for use during pregnancy. Although the FDA has not assigned a pregnancy category to esketamine, the pharmaceutical provider suggests that SpravatoTM may cause fetal toxicity and should be avoided in pregnant and breastfeeding women.5
This is not to say that women shouldn’t seek treatment for depression during pregnancy, however. It is instead recommended that pregnant or potentially soon-to-be pregnant women turn to older antidepressants, such as select serotonin reuptake inhibitors (SSRIs). The more popular antidepressants used during pregnancy include sertraline, escitalopram, or fluoxetine.6 Paroxetine has been associated with an increased risk of cardiac defects in exposed infants with exposure in the 1st trimester.6 Bupropion is another alternative treatment for depression in pregnant mothers. Treatment should be initiated on a case-by-case basis depending on severity of symptoms and personal history. All of these aspects should be discussed with a physician before initiating therapy. Medication changes should ideally be made prior to pregnancy.6
Common antidepressants in pregnancy:
|Bupropion||Animal studies revealed no evidence of harm6|
|Citalopram||Possible SSRI withdrawal syndrome6|
|Esketamine||New to the market|
|Escitalopram||Possible SSRI withdrawal syndrome6|
|Fluoxetine||Possible SSRI withdrawal syndrome6|
|Paroxetine||Studies in pregnant women suggested some risk to fetus6|
- Esketamine has not been studied extensively in pregnant women, but has shown negative effects on exposed offspring in rats.
- Esketamine is not currently recommended for pregnant women.
- Other antidepressants, such as an SSRI or bupropion, should be considered for depression in pregnancy.
- Medication changes should ideally be made before pregnancy and should be initiated on case-by-case basis with individualized treatment.
- An appropriate dose for an adult is 56 mg (2 sprays total intranasally) administered on day 1 of treatment, then 56-84 mg (2-3 sprays total) twice weekly for 4 weeks.5
- It is important to remember that untreated depression during pregnancy is very risky and mothers should seek treatment for depression during pregnancy.
Erika Anderson MS4
Thomas W. Hale, Ph.D.
Teresa Baker MD
- Paddock, Catharine. “The FDA Approve Esketamine Nasal Spray for Severe Depression.” Medical News Today, MediLexicon International, 8 Mar. 2019, www.medicalnewstoday.com/articles/324656.php.
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- Li, Yanan, et al. “Long-Term Neurocognitive Dysfunction in Offspring via NGF/ ERK/CREB Signaling Pathway Caused by Ketamine Exposure during the Second Trimester of Pregnancy in Rats.” Oncotarget, vol. 8, no. 19, 2017, doi:10.18632/oncotarget.16042.
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- “SPRAVATO™ Treatment Center.” Spravato Esketomine, www.spravatotreatmentcenter.com/.
- Payne, Jennifer L., and Samantha Meltzer-Brody. “Antidepressant Use During Pregnancy: Current Controversies and Treatment Strategies.” Clinical Obstetrics and Gynecology, vol. 52, no. 3, 2009, pp. 469–482., doi:10.1097/grf.0b013e3181b52e20.
Lesen Sie die Studie auf: Neurosciencenews.com
Adriana Feder M.D., Sara Costi, M.D., Sarah B. Rutter, M.A., Abigail B. Collins, B.S., Usha Govindarajulu, Ph.D., Manish K. Jha, M.D., Sarah R. Horn, M.A., Marin Kautz, M.A., Morgan Corniquel, M.A., Katherine A. Collins, Ph.D., M.S.W., Laura Bevilacqua, M.D., Ph.D., Andrew M. Glasgow, M.D., Jess Brallier, M.D., Robert H. Pietrzak, Ph.D., M.P.H., James W. Murrough, M.D., Ph.D.,Dennis S. Charney, M.D.
Published Online: American Journal of Psychiatry, 5 Jan 2021 https://doi.org/10.1176/appi.ajp.2020.20050596
Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors’ previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD.
Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale–Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures.
The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events.
This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine’s full potential as a treatment for chronic PTSD.
Deborah Brauser, 18. Januar 2021
Wiederholte intravenöse Ketamin-Infusionen verschaffen Patienten mit posttraumatischer Belastungsstörung (PTBS) schnelle Linderung, so neue Forschungsergebnisse.
In der ersten randomisierten kontrollierten Studie zur wiederholten Verabreichung von Ketamin bei chronischer PTBS erhielten 30 Patienten sechs Infusionen mit Ketamin oder Midazolam (als psychoaktives Placebo) über zwei aufeinanderfolgende Wochen.
Es wurden keine ernsthaften TRAE berichtet. Während der Ketamin-Infusion kam es zu einigen dissoziativen Symptomen mit den höchsten Werten gegen Ende der Infusion, die jedoch bis zur nächsten Bewertung 2 Stunden nach der Infusion wieder verschwunden waren.
Die am häufigsten berichtete Nebenwirkung in der Ketamin-Gruppe im Vergleich zu Midazolam waren nach Beginn der Infusion verschwommenes Sehen (53% vs. 0%), gefolgt von Schwindel (33% vs. 13%), Müdigkeit (33% vs. 87%), Kopfschmerzen (27% vs. 13%) und Übelkeit oder Erbrechen (20% vs. 7%).
„Die Ergebnisse in dieser Patientenpopulation zeigen insgesamt, dass wiederholte Ketamin-Infusionen über 2 Wochen mit einer deutlichen, klinisch signifikanten Verbesserung der PTBS-Symptomatik verbunden sind“, schreiben die Untersucher und Feder empfand sie als „sehr zufriedenstellend“.
„Es war auch ermutigend zu hören, was einige der Teilnehmer zu sagen hatten. So berichteten manche davon, wie sich ihre Symptome und Gefühle im Laufe der Ketamin-Behandlung verändert hatten, wobei sie sich stärker fühlten und besser mit ihrem Trauma und ihren Erinnerungen umgehen konnten.“
Sie fügte jedoch hinzu, dass die Studie nicht speziell zur Bewertung von Ketamin bei therapieresistenter PTBS angelegt war. „Einige Patienten hatten bereits mehrere erfolglose Behandlungen hinter sich, während andere noch nie behandelt worden waren. Die Wirksamkeit bei therapieresistenter PTBS ist eine wichtige Frage für zukünftige Untersuchungen“, sagte Feder.
Weitere Bereiche, die es wert seien, in Zukunft erforscht zu werden, wären die Wirksamkeit der Behandlung bei Patienten mit verschiedenen Traumaformen und die Frage, ob die Ergebnisse bei Patienten, die Ketamin plus Psychotherapie erhalten, länger anhielten, merkte sie an.
„Ich möchte nicht die Tatsache ignorieren, dass die derzeit verfügbaren Behandlungen bei einer Reihe von Menschen mit chronischer PTBS funktionieren. Da es aber noch viel mehr Menschen gibt, bei denen diese Behandlungen nicht oder nicht ausreichend helfen, ist dies sicherlich ein potenziell sehr vielversprechender Ansatz, der in das Behandlungsrepertoire eines Klinikers aufgenommen werden kann“, sagt Feder.
Link zur Studie auf Elsevier:
Igor Kungurtsev, M. D.
The recent changes in the former Soviet Union have allowed Russian and American researchers to
communicate freely for the first time since the October Revolution. Prior to these changes, the story of
Russian psychedelic research had remained a mystery in the West. The following article is one of the first
reports of psychedelic research to emerge from Russia as well as the first published outcome study of
Igor Kungurtsev, M.D. is a research associate at the Bekhterev Psychoneurological Research Institute in
St. Petersburg, Russia, and a psychiatrist in private practice. Kungurtsev is also Vice Chairman of the St.
Petersburg Transpersonal Association, and a member of the Board of Advisors of the Albert Hofmann
About five years ago, our research team obtained permission from the Central Pharmacological
Committee in Moscow to use ketamine as an adjunct to psychotherapy with alcoholics. Ketamine is an
anesthetic used in modern medicine which can also be used in subanesthetic doses to safely and reliably
induce transpersonal states with profound healing potential. This paper will review the phenomenology of
the ketamine state, the procedure for ketamine-assisted psychotherapy, and the preliminary results of our
study with alcoholic and neurotic patients.
Ketamine, 2-(o-chlorophenyl)-2-(methyl-amino) cyclohexanone HCL, has several advantages over other
psychedelics as an adjunct to psychotherapy. It is short acting, the psychoactive effects lasting about an
hour. In addition, ketamine is not scheduled like other psychedelics. In lower doses (about one sixth to
one tenth of that usually used in surgery), it induces profound transpersonal states. My colleagues and I
adopted the transpersonal paradigm as a result of our personal and clinical experience with ketamine
before we had become acquainted with the literature on psychedelics and altered states of consciousness.
At first, we attempted to use ketamine solely as a means of increasing the patient’s suggestibility. The
psychotherapist could then place suggestions of sobriety more deeply into the patient’s subconscious.
Anesthesiologists have reported that ketamine frequently induces states of confusion, feelings of death
and dying, and unpleasant hallucinations. This is known as the “emergence reaction”, and is considered to
be a negative side effect of ketamine in surgical patients who are unprepared for these psychological
Subsequently, we had the idea that we could associate these feelings of death and dying with the smell and
taste of alcohol (an aversive conditioning model). Not long after we started our research, however, we
came across situations which were incompatible with this paradigm. After ketamine injections, many of
our patients reported very strange experiences. They began to report that they felt disconnected from their
bodies, and that they were “floating” in strange worlds. Some of them, for the first time in their lives,
spoke about God, the meaning of life, and their relationships. Although we tried to help our patients form
negative associations and develop an aversion to alcohol, their experience was more profound and
mystical, sometimes with no relationship to our suggestions or psychotherapy.
At this point, I undertook a series of self-administrations which completely changed my conception of the
ketamine experience. I tried various dosages in order to choose the level most appropriate for our patients.
Three or four minutes after the first injection, I felt this world begin to disappear, and I experienced
myself as a point of consciousness which was floating in strange worlds. The most unusual feeling was
that I had no body, yet somehow “I” existed. The next development was indescribable. During the first
stage, I seemed to exist only as a point of consciousness, but still, “I” existed. Then there was a stage
where even this disembodied sense of self began to disappear, and I felt a real terror of dying. At that
moment I managed to surrender and let go. All that remained was awareness; there was no “I” as me, as
an individual point of consciousness. It was as if there existed only that which was aware of itself.
This experience profoundly changed my view of ketamine, and gave me new insight into some esoteric
concepts of Buddhism and other Eastern philosophies. It profoundly changed my understanding of death
and dying as well.
For several days after this session, I had a feeling of inner surrender, as if my life was a game that I was
playing very easily. While I performed my daily activities, I was very calm and centered inside. It was a
remarkable feeling. After this self-experimentation, we changed our paradigm and adopted a transpersonal
approach. We now refer to this treatment as “Death-Rebirth” Psychotherapy.
The research is done in a comparatively large hospital for the treatment of alcoholics near St. Petersburg.
The patients in this hospital are all voluntary. The psychotherapy is usually limited to the area of alcohol
abuse, and the goal of treatment is overcoming their so-called “alcohol denial.”
A typical patient in our ketamine program stays in the hospital about one month. During the first phase of
therapy, we treat their alcohol withdrawal syndrome and any related anxiety or affective disorders. Then,
we start rational, cognitive psychotherapy in order to establish a mental set of sobriety and a negative
attitude toward alcohol. However, we go beyond the problem of alcohol abuse to explore broader issues
including the patient’s life history, relationships, and world view.
Later in the program, we tell them that they will undergo a new treatment which will allow them to see
and feel the subconscious roots of their problems. We help our patients understand that their alcohol
problem is only a superficial symptom – the manifestation of more deeply rooted problems.
On the day of the session, we give the patient an intragluteal injection of about 150 mg. of ketamine
(approx. 2 mg. per kg.). We prefer the intramuscular route because the effect is more gradual, and the
transpersonal state lasts longer. With an intravenous injection, the effect lasts only about fifteen to twenty
minutes, but after an intramuscular injection, it lasts from about forty-five minutes to an hour.
We tell the patient that they will enter some unusual states of consciousness and that they may feel
detached from their body. We also instruct them to surrender fully to the experience. I gave up our original
approach of trying to induce something specific in the patient during the session. Under the influence of
ketamine, especially in these doses, one has no direct contact with ordinary reality. The psychotherapist
can try to influence the experience, but it will be in vain. We are available, however, to give emotional
support if the patient requests it.
As with other psychedelics, music also enhances the ketamine experience. We have found composers
whose music is particularly conducive for ketamine sessions, such as Jean Michael Jarre or Kitaro. After
forty-five minutes to an hour, the patient slowly comes back from the experience. During the recovery
period, which takes about an hour and a half or two hours, the patient begins to feel ordinary reality
returning, but part of their consciousness is still in another world, another dimension. At this point in the
session, the patient usually begins to describe their experience, and we begin some interpretation. After
the session, the patient goes to rest, and we ask them to write down a detailed report of their experience
that evening. The next day, we have a follow-up session which includes an in-depth discussion of their
experience. When several patients have ketamine sessions on the same day, we do it as group therapy. We
gather these patients in a group the day before treatment and the day after, because when they all share the
experience, it is usually more powerful.
Regarding spiritual experiences induced by ketamine, it is interesting that many people who never thought
about spirituality or the meaning of life reported having experiences that one might read about only in
spiritual texts or Eastern teachings. At the beginning of ketamine sessions, people often experience the
separation of consciousness from the body and the dissolving of the body ego. For many patients, it is a
profound insight that they can exist without their bodies as pure consciousness or pure spirit. Many of
them said that as a result of their experience, they understood the Christian notion of the separation of the
soul and the body, and that they now believe some part of them will continue to exist after death. There
were several cases where people reported contact with God, but this is usually not an anthropomorphic
figure. They describe an ocean of brilliant white light, sometimes a golden white light, which is filled with
love, bliss and energy. After coming back to ordinary consciousness, they feel sure that they have had
contact with a higher power. There were also several cases where people saw Jesus Christ approaching
them. It seems ironic that so many of our patients, through their own experience, were converted to a
more spiritual approach to life, despite living in a country where people have been brought up for
generations with atheism.
A second observation is that many patients report the existence of other dimensions or other worlds that
are parallel to ours. They usually report that these other dimensions seem as real or more real than our
own. Some patients experience this “ego death”, or the dissolving of the individual sense of self, which 1
had experienced. Of course they do not use these terms. They might say, “I ceased to exist, I disappeared,
yet still something existed. It was like I became the whole universe or the whole cosmos”. In my
experience, I also got the feeling of the collapse of space and time, and I really felt that space and time
were illusions. It was as if I had collapsed into a single point with no space and no time, and it was from
this point that the whole universe seemed to be manifesting.
Another interesting observation, although not a topic of our research, is the correlation between the type
of personality and the type of experience under the influence of ketamine. People who are very controlled
and have difficulties letting go, or who have problems with relationships, often have negative experiences
with ketamine. For them, the dissolving of the individual sense of self is horrible. For other patients who
are more relaxed and able to surrender, who have a deep capacity to love, the experience is usually
blissful, even ecstatic.
The action of ketamine is somewhat unique in comparison with other psychoactive substances. Stanislav
Grof has divided the psychedelic experience and other experiences of altered states of consciousness into
three main categories; the psychodynamic level, where people recall the past events of their lives,
especially childhood memories; the perinatal level, or the recollection of the birth experience; and the
transpersonal level, which includes the mystical experience. “Transpersonal” refers to experiences which
go beyond one’s individual personality and involve the transcendence of the spatial or temporal
boundaries of ordinary consciousness. One might also experience mythological themes or archetypal
figures like the god or goddess, or the expansion of consciousness to encompass the whole cosmos, etc.
Ketamine differs from other psychedelics in that in medium doses, it usually it does not engage the
psychodynamic level. Instead, it almost “throws” one into the transpersonal realm. The other major
psychedelics, such as LSD or mescaline, are more gradual and gentle, and in medium doses they usually
engage the psychodynamic level. To induce transpersonal states, higher doses of these substances are
Of course, the effects of ketamine are also a function of dosage. In low doses, one remains in contact with
ordinary reality, but with eyes closed one can see some strange images. They are not human forms, but
usually geometric shapes like spheres or triangles, or simply open spaces.
Following treatment, the patient is released from the hospital. Every two or three months, we see them for
follow-up visits. We have collected data on patients who have undergone ketamine-assisted
psychotherapy after spending one month in the hospital. About sixty eight per cent of these patients
remain sober for one year following treatment. This is a very high success rate in comparison with other
programs for alcoholism. In the control group, which was composed of patients who were in the same
hospital, who were the same average age, and who were in the same stage of the development of
alcoholism, the percentage who remained sober for one year was about forty-five to fifty per cent. So we
have proven statistically that the ketamine experience is very useful. We believe that these positive results
in maintaining sobriety were not achieved simply because we were more successful in establishing a set
of sobriety and a deeper negative attitude toward alcohol, but rather because of changes in the values,
relationships, and world view of these patients. They began to see other goals, other values, other
pleasures in their lives, and this was the main reason for their sobriety. For us, this was much more
interesting than the limited issue of keeping sober.
We also administered several psychological tests before and after the ketamine treatment. We gave
patients the MMPI, and after the session the scales which indicated anxiety and depression decreased
statistically, even though these patients were not primarily neurotic or depressive. The same results were
also confirmed by the Zung anxiety and depression scales, but we were interested in more than these
clinical symptoms. We also tried to measure changes in values and world view after treatment. It was
difficult to find an instrument to measure these changes, but the two scales we found most useful were the
Omega Life Changes Questionnaire by Kenneth Ring, and the Self-Assessment Spirituality Scale by
Charles Whitfield. Kenneth Ring is a professor of psychology at the University of Connecticut who has
done extensive research on near-death experiences, and he created The Life Changes Questionnaire. It
consists of some thirty questions that assess the individual’s values, goals, and attitudes toward material
things, etc. Our patients showed the most significant changes in exactly this scale. According to the results
of this questionnaire, they shifted to a more spiritual world view. We also used the Self-Assessment
Spirituality Scale by Charles Whitfield, an American researcher who has tried to introduce spirituality into
recovery from alcoholism. In addition, we developed our own instrument, called the “repertory grid”,
which measures psychosemantic fields. It measures the meanings of key words such as life, love, death,
despair, Jesus Christ, etc. Through this tool, we can measure changes in the patient’s attitude toward
various aspects of life. This scale also showed that our patients shifted to a wider, more spiritual world
Our anecdotal observations also confirmed these changes. Some patients began to write poems after their
ketamine sessions, while others began to paint. Many of them began to feel more connected with nature
and reported, for example, that after treatment they went to the countryside more often. When some
patients went back to their families, they noticed problems in their relationships, or certain idiosyncrasies
of their spouses and relatives which they were unaware of before treatment. Ketamine seems to increase
the capacity for detached observation.
I would also like to relate some unusual anecdotes connected with our research. About one year after we
began our study, a group composed of two men and one woman appeared at our hospital who were very
strange looking, wore strange clothes, and had strange, shiny eyes that seemed out of focus. They called
themselves “magicians”, and said that they sensed in their meditations and magic practice that in this
hospital, some people were throwing other souls into the “astral plane”. They had come to see what we
were doing, like “astral police”. Prior to this, we had not published the results of our work, and only a few
professionals knew about it. Also, this hospital is situated in the suburbs of St. Petersburg, and is not
widely known. So we described our work and showed them our hospital. They approved! They also told
us that they themselves used ketamine for their underground magic practice. As far as I understood from
our conversations, their practice to some extent imitates or closely parallels the practice of Carlos
Casteneda. They had gone into the forest and found power spots and power plants, and practiced
meditation there. This acquaintance was useful for us because, as it turned out, they had a tremendous
volume of underground psychedelic literature, translated into Russian. When we shifted to the
transpersonal paradigm, we began a literature search, and we sent requests to several libraries, including
the main state library in Moscow. Although they probably had this literature, it was two or three years
ago, before the changes in Russia, and they didn’t send it to us. So the magicians gave us, for example,
Peter Stafford’s Psychedelics Encyclopedia. Later, there was another interesting episode with these
magicians. One of the men told me that they also used mushrooms growing in the forest near the region of
St. Petersburg to induce psychedelic states. At first I didn’t believe him, but he gave me a dried specimen,
and I identified it in the Psychedelics Encyclopedia as Psilocybe semilanceata.
To date, the total number of patients treated with this method is about four hundred. Our results show that
ketamine-assisted psychotherapy is significantly more effective in treating alcoholism than standard nondrug
psychotherapy. In addition, ketamine-assisted psychotherapy results in positive life changes which
go beyond the limited goal of maintaining sobriety, including profound changes in values, relationships,
and world view. In the near future, we plan to continue our work with alcoholic patients and to develop
this approach further with neurotic patients using repeated ketamine sessions.
Note: The author would like to thank Robert Zanger and Blackbird Willow for their assistance in the
preparation of this article.
Reprinted from the Fall 1991 issue of the Albert Hofmann Foundation bulletin.
This study aimed to develop a method that objectively measures the clinical benefits of ketamine infusions to treat complex regional pain syndrome (CRPS), thus making it possible, for the first time, to determine the optimal dosing of ketamine and duration of treatment to treat CRPS.
Materials and Methods:
All patients were diagnosed with hyperalgesia associated with CRPS. Patients underwent an outpatient, 4-day, escalating dose ketamine infusion. Hyperalgesia was measured using pain thresholds. Clinical outcome was determined without knowledge of the patient’s pain thresholds throughout treatment.
We found a correlation between pain thresholds and the intensity of pain reported by the patient at various sites of the body. We found that clinical outcomes correlated with improvement in pain thresholds. There was a plateau in pain thresholds between days 3 and 4 for the lower extremities. There was no plateau in pain thresholds observed for the upper extremities.
Our findings suggest that 4 days of treatment are sufficient for the treatment of CRPS of the lower extremities. For the upper extremities, >4 days may be required. Our study is the first to utilize quantitative sensory testing to direct the treatment of a chronic pain disorder.
Objective: Pharmacotherapy and behavioral treatments for alcohol use disorder are limited in their effectiveness, and new treatments with innovative mechanisms would be valuable. In this pilot study, the authors tested whether a single subanesthetic infusion of ketamine administered to adults with alcohol dependence and engaged in motiva- tional enhancement therapy affects drinking outcomes.
Methods: Participants were randomly assigned to a 52- minute intravenous administration of ketamine (0.71 mg/kg, N=17) or the active control midazolam (0.025 mg/kg, N=23), provided during the second week of a 5-week outpatient regimen of motivational enhancement therapy. Alcohol use following the infusion was assessed with timeline followback method, with abstinence confirmed by urine ethyl glucuro- nide testing. A longitudinal logistic mixed-effects model was used to model daily abstinence from alcohol over the 21 days after ketamine infusion.
Results: Participants (N=40) were mostly middle-aged (mean age=53 years [SD=9.8]), predominantly white (70.3%), and largely employed (71.8%) and consumed an average of five drinks per day prior to entering the study. Ketamine significantly increased the likelihood of abstinence, delayed the time to re- lapse, and reduced the likelihood of heavy drinking days com- pared with midazolam. Infusions were well tolerated, with no participants removed from the study as a result of adverse events.
Conclusions: A single ketamine infusion was found to im- prove measures of drinking in persons with alcohol de- pendence engaged in motivational enhancement therapy. These preliminary data suggest new directions in integrated pharmacotherapy-behavioral treatments for alcohol use dis- order. Further research is needed to replicate these promis- ing results in a larger sample.
Am J Psychiatry 2020; 177:125–133; doi: 10.1176/appi.ajp.2019.19070684
Sub-anesthetic ketamine infusions may benefit a range of psychiatric conditions, including alcohol and cocaine use disorders. Currently, there are no effective pharmacological treatments for cannabis use disorder.
The objective of this uncontrolled proof of concept trial was to test the feasibility, tolerability, and potential therapeutic effects of integrating ketamine infusions with a behavioral platform of motivational enhancement therapy and mindfulness-based relapse prevention in treating cannabis use disorder (CUD).
Eight cannabis-dependent individuals (four female, four male) receiving motivational enhancement therapy and mindfulness-based relapse prevention behavioral treatments completed this single-blind outpatient 6-week study. Participants received either one or two infusions of ketamine (0.71 mg/kg [infusion 1]; 1.41 mg/kg [infusion 2] for non-responders) during the study. Participants self-reported cannabis use (Timeline Follow-Back) and underwent an assessment of confidence in abstaining from using cannabis (Drug-Taking Confidence Questionnaire) at predetermined time points throughout the study.
Ketamine infusions were well-tolerated and there were no adverse events. Frequency of cannabis use decreased significantly from baseline (B = 5.1, s.e = 0.7) to the week following the first infusion (B = 0.8, s.e = 0.412), and remained reduced at the end of the study (B = 0.5, s.e = 0.3). Participants’ confidence in their ability to abstain from cannabis in potentially triggering situations increased significantly from baseline to the end of study.
These findings suggest that combining ketamine with behavioral therapy is feasible,tolerable, and potentially helpful, in treating cannabis-dependent individuals.
Studien zu Neurofeedback
- Ashlie N. Bell, PhDSaybrook University / NeuroGrove, P.C. / Integrative Neurotherapy Center of Colorad
- Donald Moss, PhDSaybrook University
- Robert J. Kallmeyer, PhDSaybrook University
1- Mousavi Hospital, Zanjan University of Medical Sciences, Zanjan, Iran.
2- Department of Clinical Psychology, Social Determinants of Health Research Center, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
3- Department of Neurology, Faculty of Medicine, Vali Asr Hospital, Zanjan University of Medical Sciences, Zanjan, Iran.
4- Department of Physiology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
Basic and Clinical Neuroscience, 2020
Introduction: Migraine is considered one of the most common primary headache disorders. Migraine attacks may occur due to a lack of sleep. Furthermore, sleep is regarded as one of the smoothing factors of migraine pain. Patients with sleep disorders often suffer from headaches when they wake up compared with healthy individuals.
Methods: This research was a quasi-experimental study with a pretest-posttest design and a 2-month follow-up. The samples included 20 migraine patients within the age range of 15 to 55 years who were selected as volunteers for treatment by the neurologists and psychiatrists during 2017. The initial evaluation was then conducted based on the inclusion and exclusion criteria and using the Ahvaz migraine questionnaire, and Pittsburgh sleep quality index. The patients were randomly assigned to two neurofeedback (n=10) and transcranial direct current stimulation (tDCS) (n=10) groups and evaluated three times. The obtained data were analyzed by the repeated measures ANCOVA and Chi-square test in SPSS.
Results: Based on the scores of both groups, no significant difference was observed between neurofeedback and tDCS groups. However, based on the results, neurofeedback decreased sleep latency, whereas tDCS increased sleep efficiency. Overall, these two treatments were effective in improving subjective sleep quality and sleep quality.
Conclusion: Both neurofeedback and tDCS treatments could significantly enhance sleep quality of the patients in the posttest and 2-month follow-up. Given the effectiveness of both treatments, neurofeedback and tDCS are recommended to be used for improving the sleep status of patients with migraine.
Martijn Arns · C. Richard Clark · Mark Trullinger · Roger deBeus · Martha Mack · Michelle Aniftos
© The Author(s) 2020
Stimulant medication and behaviour therapy are the most often applied and accepted treatments for Attention-Deficit/ Hyperactivity-Disorder (ADHD). Here we explore where the non-pharmacological clinical intervention known as neuro- feedback (NFB), fits on the continuum of empirically supported treatments, using standard protocols. In this quantitative review we utilized an updated and stricter version of the APA guidelines for rating ‘well-established’ treatments and focused on efficacy and effectiveness using effect-sizes (ES) and remission, with a focus on long-term effects. Efficacy and effec- tiveness are compared to medication and behaviour therapy using benchmark studies. Only recent systematic reviews and meta-analyses as well as multi-centre randomized controlled trials (RCT’s) will be included. Two meta-analyses confirmed significant efficacy of standard neurofeedback protocols for parent and teacher rated symptoms with a medium effect size, and sustained effects after 6–12 months. Four multicenter RCT’s demonstrated significant superiority to semi-active control groups, with medium-large effect sizes end of treatment or follow-up and remission rates of 32–47%. Effectiveness in open- label studies was confirmed, no signs of publication bias were found and no significant neurofeedback-specific side effects have been reported. Standard neurofeedback protocols in the treatment of ADHD can be concluded to be a well-established treatment with medium to large effect sizes and 32–47% remission rates and sustained effects as assessed after 6–12 months.
Studien über repetitive transkranielle Magnetstimulation (rTMS)
Amin et al. The Egyptian Journal of Neurology, Psychiatry and Neurosurgery (2020) 56:19
The Egyptian Journal of Neurology, https://doi.org/10.1186/s41983-019-0140-5 Psychiatry and Neurosurgery
Randa Amin1, Tamer Emara1*, Samia Ashour1, Mahmoud Hemeda1, Nahed Salah Eldin1, Salma Hamed1, Sara Shouman2 and Mohamed Shouman3
Objective: The aim of the study was to examine the prophylactic role of repetitive transcranial magnetic stimulation (rTMS) on the frequency, and severity of migraine attacks in episodic migraineurs who failed medical treatment.
Methods: A randomized double-blinded placebo-controlled study was designed to assess the effect of 5 Hz rTMS applied over the left dorsolateral prefrontal cortex (LDLPFC ) in 33 migraineurs. Patients were followed up for 1 month before receiving rTMS, and for another month after the sessions by a headache diary. The primary outcome measure was the achievement of 50% reduction in the number of migraine attacks. Secondary outcome measures included migraine days, assessment of migraine attack severity, disability by HIT-6, and side-effects to the procedure.
Results: The study revealed that 69.2% of the active treatment group achieved 50% or more reduction in the number of migraine attacks versus 25% of cases in the control group (p = 0.02). The absolute number of migraine attacks was reduced by 3.1 vs 1.5 in the active and control group, respectively. The number of cases with severe HIT-6 scores was reduced by 46.2% in active treatment group versus a 7.1% reduction in the control group (p = 0.02).
Conclusion: High-frequency rTMS applied to LDLPFC can reduce the number of migraine attacks by 50% or more in almost 70% of a sample of episodic migraineurs with a concomitant decrease in functional disability.
Trial registration: ClinicalTrials.gov, Identifier: NCT04031781. Registered 23 July 2019—retrospectively registered at https://clinicaltrials.gov/ct2/show/NCT04031781?term=Migraine+Prophylaxis&recrs=ce&type=Intr&cond=Migraine&rank=9
Repetitive transcranial magnetic stimulation (rTMS), a noninvasive brain stimulation technique, has emerged as a promising treatment for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Currently, however, the effectiveness of this therapy is unclear because of the low statistical power and heterogeneity of previous trials. The purpose of the meta-analysis was to systematically characterize the effectiveness of various combinations of rTMS parameters on different cognitive domains in patients with MCI and AD. Thirteen studies comprising 293 patients with MCI or AD were included in this analysis. Random-effects analysis revealed an overall medium-to-large effect size (0.77) favoring active rTMS over sham rTMS in the improvement of cognitive functions. Subgroup analyses revealed that (1) high-frequency rTMS over the left dorsolateral prefrontal cortex and low-frequency rTMS at the right dorsolateral prefrontal cortex significantly improved memory functions; (2) high-frequency rTMS targeting the right inferior frontal gyrus significantly enhanced executive performance; and (3) the effects of 5–30 consecutive rTMS sessions could last for 4–12 weeks. Potential mechanisms of rTMS effects on cognitive functions are discussed.
Jean-Pascal Lefaucheur et al (2020)
A group of European experts reappraised the guidelines on the therapeutic efficacy of repetitive transcra- nial magnetic stimulation (rTMS) previously published in 2014 [Lefaucheur et al., Clin Neurophysiol 2014;125:2150–206]. These updated recommendations take into account all rTMS publications, includ- ing data prior to 2014, as well as currently reviewed literature until the end of 2018. Level A evidence (definite efficacy) was reached for: high-frequency (HF) rTMS of the primary motor cortex (M1) contralat- eral to the painful side for neuropathic pain; HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC) using a figure-of-8 or a H1-coil for depression; low-frequency (LF) rTMS of contralesional M1 for hand motor recovery in the post-acute stage of stroke. Level B evidence (probable efficacy) was reached for: HF-rTMS of the left M1 or DLPFC for improving quality of life or pain, respectively, in fibromyalgia; HF-rTMS of bilateral M1 regions or the left DLPFC for improving motor impairment or depression, respec- tively, in Parkinson’s disease; HF-rTMS of ipsilesional M1 for promoting motor recovery at the post-acute stage of stroke; intermittent theta burst stimulation targeted to the leg motor cortex for lower limb spas- ticity in multiple sclerosis; HF-rTMS of the right DLPFC in posttraumatic stress disorder; LF-rTMS of the right inferior frontal gyrus in chronic post-stroke non-fluent aphasia; LF-rTMS of the right DLPFC in depression; and bihemispheric stimulation of the DLPFC combining right-sided LF-rTMS (or continuous theta burst stimulation) and left-sided HF-rTMS (or intermittent theta burst stimulation) in depression. Level A/B evidence is not reached concerning efficacy of rTMS in any other condition. The current recom- mendations are based on the differences reached in therapeutic efficacy of real vs. sham rTMS protocols, replicated in a sufficient number of independent studies. This does not mean that the benefit produced by rTMS inevitably reaches a level of clinical relevance.
! 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Nervenheilkunde 2020; 39(04): 213-221
© Georg Thieme Verlag KG Stuttgart · New York
Transkranielle Magnetstimulation zur Behandlung von Depressionen bei Schwangeren Eine Übersicht
Transcranial magnetic stimulation in the treatment of depression during pregnancy A review
Tobias Hebel, Martin Schecklmann, Berthold Langguth
Gegenstand und Ziel In dieser Übersichtsarbeit sollen die Wirksamkeit und Sicherheit der repetitiven transkraniellen Magnetstimulation (rTMS) für die Patientengruppe depressiv erkrankter Schwangerer evaluiert werden.
Material und Methoden Es wurde eine Datenbankrecherche auf Pubmed durchgeführt, um alle relevanten Original- und Übersichtsarbeiten zu dem Thema zu identifizieren und zu analysieren
Ergebnisse Zusätzlich zu einer Reihe von Fallberichten existieren 3 kontrollierte Studien zur Behandlung depressiver Schwangerer mittels rTMS. Der Datenlage nach scheint die rTMS sowohl für die schwangeren Patientinnen als auch ihre ungeborenen Kinder sicher zu sein. Es wurden keine postnatalen negativen Wirkungen auf die Kindesentwicklung berichtet.
Schlussfolgerung rTMS stellt eine vielversprechende Behandlungsoption dar. Weitere Studien mit größeren Teilnehmerzahlen sind notwendig, um den Stellenwert der rTMS in einer multimodalen Depressionsbehandlung in der Schwangerschaft zu klären.
Arch Womens Ment Health. 2014 Aug;17(4):311-5. doi: 10.1007/s00737-013-0397-0. Epub 2013 Nov 20.
The aim of the present study was to assess the safety and effectiveness of high-frequency repetitive transcranial magnetic stimulation (rTMS) in pregnant patients with depression. Thirty depressed pregnant patients received rTMS over the left prefrontal cortex for 6 days in a week, from Monday to Saturday for 3 weeks. The rTMS intensity was set at 100% of the motor threshold. A 25-Hz stimulation with a duration of 2 s was delivered 20 times with 30-s intervals. A session comprised 1,000 magnetic pulses. Depression was rated using the 17-item Hamilton depression rating scale (HAMD) before and after treatment. Response was defined as a 50% reduction of the HAMD score. Patients with HAMD scores less than 8 were considered to be in remission. The mean HAMD score for the study group decreased from 26.77 ± 5.58 to 13.03 ± 6.93 (p < 0.001) after 18 sessions of rTMS. After the treatment period, 41.4% of the study group demonstrated significant mood improvements as indexed by a reduction of more than 50% on the HAMD score. In addition, 20.7% attained remission (HAMD score < 8), 34.5% achieved a partial response, and 3.4% had worsening in HAMD scores at the end of treatment. Treatment was well tolerated, and no significant adverse effects were reported. rTMS was well tolerated and found to be statistically and clinically effective in pregnant patients with treatment-resistant depression. This study contributed to the existing evidence of the antidepressant effect of rTMS in the treatment of depression in pregnancy.
The aim of this paper is to present the clinical data analysis results from a service delivering repetitive transcranial magnetic stimulation (rTMS) for people with cocaine-use disorder (CUD).
The study was a retrospective investigation of routinely collected data on patients receiving rTMS between 2018 and 2019. Measures used were a cocaine craving Visual Analogue Scale (VAS), Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire (PHQ-9) self-rated depression measures.
The outcome data of 10 patients with CUD were analysed. There was a statistically significant reduction and a large effect size on CUD and depression scales. Conclusions: Reductions in craving and depression indicate the potential benefits to patients and to society of rTMS in treating CUD. Further sufficiently powered RCTs are warranted with studies focusing on the optimization of rTMS treatment and exploring the underlying mechanisms.
Studien über den Einsatz von Virtual Reality
Der Nervenarzt volume 89, pages 1227 – 1231 (2018)
Angststörungen zählen zu den häufigsten psychischen Störungen in Deutschland. Mit der Expositionstherapie steht eine effektive Methode zur Behandlung von Angststörungen zur Verfügung. Im Rahmen der Expositionstherapie werden Patienten systematisch mit dem gefürchteten Objekt bzw. der gefürchteten Situation konfrontiert. Die Expositionstherapie kann dabei in vivo oder in sensu erfolgen. In den letzten Jahren wurde zudem vermehrt der Einsatz der Expositionstherapie in virtuo zur Behandlung von Angststörungen – insbesondere Phobien – untersucht. Bei der Expositionstherapie in virtuo werden Patienten mit einer virtuellen Version des gefürchteten Objekts bzw. der gefürchteten Situation konfrontiert. Eine Vielzahl an Studien belegt die Wirksamkeit der Expositionstherapie in virtuo, insbesondere im Hinblick auf die Behandlung spezifischer Phobien. Vorteile der Expositionstherapie in virtuo liegen in der Kontrollierbarkeit des gefürchteten Stimulus bzw. der gefürchteten Situation und in einem – im Vergleich zur Exposition in vivo – geringeren organisatorischen Aufwand bei der Durchführung der Konfrontation. Nachteile der Expositionstherapie in virtueller Realität liegen vor allem in der Gefahr der Simulatorkrankheit. Mit der Entwicklung kostengünstiger benutzerfreundlicher Systeme kann die virtuelle Expositionstherapie zunehmend Einzug in die psychotherapeutische Praxis finden. Hinsichtlich der weiteren Entwicklung der virtuellen Expositionstherapie ist insbesondere der Einsatz der erweiterten Realität als vielversprechende Behandlungsalternative zu erwähnen. Eindeutige Wirksamkeitsnachweise für diese Art der Konfrontationstherapie stehen noch aus.
Zeitschrift für Klinische Psychologie und Psychotherapie (2017), 46, pp. 236-247. https://doi.org/10.1026/1616-3443/a000444. © 2017 Hogrefe Verlag.
Institut für Psychologie, Lehrstuhl für Klinische Psychologie und Psychotherapie, Universität Regensburg, Julia Diemer
Institut für Psychologie, Lehrstuhl für Klinische Psychologie und Psychotherapie, Universität Regensburg
kbo-Inn-Salzach-Klinikum, Wasserburg am Inn, Peter Zwanzger
kbo-Inn-Salzach-Klinikum, Wasserburg am Inn
Lehrstuhl für Psychiatrie und Psychotherapie, Ludwig-Maximilians-Universität München, Swantje Notzon
Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Münster, Andreas Mühlberger
Institut für Psychologie, Lehrstuhl für Klinische Psychologie und Psychotherapie, Universität Regensburg
Published online: April 10, 2018
Theoretischer Hintergrund: Soziale Kompetenztrainings sind wichtige Werkzeuge bei der Psychotherapie der Sozialen Angststörung. Die Durchführung in Virtueller Realität (VR) könnte die Verfügbarkeit und Effektivität erhöhen, allerdings besteht ein Bedarf an validierten VR-Szenarien. Fragestellung: Geprüft wird die Validität von zwei in Anlehnung an das Gruppentraining sozialer Kompetenzen von Hinsch und Pfingsten (2015) entwickelten VR-Szenarien. Es wird angenommen, dass die durch das Szenario ausgelösten Komponenten sozialer Angst auf subjektiver, psychophysiologischer und kognitiver Ebene signifikant zwischen höher (HSA) und niedriger (NSA) sozial ängstlichen Personen differenzieren. Methode: Insgesamt durchliefen N = 55 HSA und NSA Studierende zwei VR-Szenarien vom Typ „Recht durchsetzen“. Zusätzlich wurde experimentell die Blickkontaktdauer des virtuellen Gesprächspartners variiert. Hauptoutcome war die erlebte Angst in den Rollenspielen. Zusätzlich wurden Herzschlagfrequenz, Hautleitfähigkeit sowie die Einschätzung der eigenen Kompetenz erfasst. Ergebnisse: HSA im Vergleich zu NSA berichteten für beide Szenarien signifikant höhere Angst sowie negative Verzerrungen in Bezug auf die Einschätzung der eigenen Kompetenz. Zusätzlich zeigte sich eine physiologische Aktivierung während der Rollenspiele, aber keine Differenzierung zwischen beiden Gruppen. Beide VR-Szenarien wurden als realistisch empfunden. Schlussfolgerungen: Virtuelle Interaktionsszenarien können zu Trainingszwecken genutzt werden und Soziale Kompetenztrainings in VR haben ein großes Potential für den Einsatz als psychotherapeutisches Verfahren bei Sozialer Angststörung.
Studien über HRV Biofeedback
Applied Psychophysiology and Biofeedback
Marcos Economides · Paul Lehrer · Kristian Ranta · Albert Nazander · Outi Hilgert · Anu Raevuori · Richard Gevirtz · Inna Khazan · Valerie L. Forman‐Hoffman
© The Author(s) 2020
A rise in the prevalence of depression underscores the need for accessible and effective interventions. The objectives of this study were to determine if the addition of a treatment component showing promise in treating depression, heart rate variability-biofeedback (HRV-B), to our original smartphone-based, 8-week digital intervention was feasible and whether patients in the HRV-B (“enhanced”) intervention were more likely to experience clinically significant improvements in depressive symptoms than patients in our original (“standard”) intervention. We used a quasi-experimental, non-equivalent (matched) groups design to compare changes in symptoms of depression in the enhanced group (n = 48) to historical out- come data from the standard group (n = 48). Patients in the enhanced group completed a total average of 3.86 h of HRV-B practice across 25.8 sessions, and were more likely to report a clinically significant improvement in depressive symptom score post-intervention than participants in the standard group, even after adjusting for differences in demographics and engagement between groups (adjusted OR 3.44, 95% CI [1.28–9.26], P = .015). Our findings suggest that adding HRV-B to an app-based, smartphone-delivered, remote intervention for depression is feasible and may enhance treatment outcomes.
Clin Psychopharmacol Neurosci. 2019 Mar; 17(2): 222–232.
Published online 2019 Apr 30. doi: 10.9758/cpn.2019.17.2.222
I-Mei Lin,1,* Sheng-Yu Fan,,* Cheng-Fang Yen, Yi-Chun Yeh, Tze-Chun Tang, Mei-Feng Huang, Tai-Ling Liu, Peng-Wei Wang, Huang-Chi Lin, Hsin-Yi Tsai, and Yu-Che Tsai” src=”blob:https://www.psychosomatik.com/61724f14-b840-4c3c-bf1c-de47cbec0d0e” alt=”corresponding author” border=”0″ class=”Apple-web-attachment Singleton” style=”width: 0.0729in; height: 0.0937in; opacity: 1;”>
Autonomic imbalance is considered a psychopathological mechanism underlying major depressive disorder (MDD). Heart rate variability (HRV) is an index for autonomic activation. Poor sleep quality is common among patients with MDD. HRV biofeedback (BF) has been used for regulating autonomic balance among patients with physical illness and mental disorders. The purpose of present study was to examine the effects of HRV-BF on depressive symptoms, sleep quality, pre-sleep arousal, and HRV indices, in patients with MDD and insomnia.
In this case-controlled study, patients with MDD and Pittsburgh Sleep Quality Index (PSQI) score higher than 6 were recruited. The HRV-BF group received weekly 60-minute protocol for 6 weeks, and the control group who have matched the age and sex received medical care only. All participants were assessed on Beck Depression Inventory-II, Back Anxiety Inventory, PSQI, and Pre-Sleep Arousal Scale. Breathing rates and electrocardiography were also performed under resting state at pre-testing, and post-testing conditions and for the HRV-BF group, also at 1-month follow-up.
In the HRV-BF group, symptoms of depression and anxiety, sleep quality, and pre-sleep arousal were significantly improved, and increased HRV indices, compared with the control group. Moreover, in the HRV-BF group, significantly improved symptoms of depression and anxiety, decreased breathing rates, and increased HRV indices were detected at post-testing and at 1-month follow-up, compared with pre-testing values.
We performed a systematic and meta analytic review of heart rate variability biofeedback (HRVB) for various symptoms and human functioning. We analyzed all problems addressed by HRVB and all outcome measures in all studies, whether or not relevant to the studied population, among randomly controlled studies. Targets included various biological and psychological problems and issues with athletic, cognitive, and artistic performance. Our initial review yielded 1868 papers, from which 58 met inclusion criteria. A significant small to moderate effect size was found favoring HRVB, which does not differ from that of other effective treatments. With a small number of studies for each, HRVB has the largest effect sizes for anxiety, depression, anger and athletic/artistic performance and the smallest effect sizes on PTSD, sleep and quality of life. We found no significant differences for number of treatment sessions or weeks between pretest and post-test, whether the outcome measure was targeted to the population, or year of publication. Effect sizes are larger in comparison to inactive than active control conditions although significant for both. HRVB improves symptoms and and functioning in many areas, both in the normal and pathological ranges. It appears useful as a complementary treatment. Further research is needed to confirm its efficacy for particular applications.
Studien über transkranielle Gleichstromsimulation (tDCS)
Eman M. Khedr, MD, Ragaa H. Salama, MD, Mohamed Abdel Hameed, MD, …
First Published April 3, 2019
To explore the neuropsychological effects and levels of tau protein (TAU), amyloid β 1-42 (Aβ 1-42), and lipid peroxidase after 10 sessions of anodal transcranial direct current stimulation (tDCS) in patients with mild to moderate Alzheimer disease (AD). Patients and methods. A total of 46 consecutive patients with probable AD participated in this study. They were classified randomly into 2 equal groups: active versus sham. Each patient received 10 sessions of anodal tDCS over the left and right temporoparietal region for 20 minutes for each side with the cathode on the left arm. Patients were assessed using the Modified Mini Mental State Examination (MMMSE), clock drawing test, Montreal Cognitive Scale (MoCA), and the Cornell Scale for depression. Serum TAU, Aβ 1-42, and lipid peroxidase were measured before and after the 10th session. Results. There was a significant improvement in the total score of each cognitive rating scale (MMMSE, clock drawing test, and MoCA) in the real group, whereas no such change was observed in the sham group. The Cornell depression score improved significantly in both groups. There was a significant increase in serum Aβ 1-42 (P = .02) in the real but not in the sham group, with a significant Treatment condition × Time interaction (P = .009). There was no significant effect on tau or lipid peroxidase in either group but a significant positive correlation between changes of Aβ1-42 and MMMSE (P = .005) and MoCA (P= .02). Conclusion. The observed cognitive improvements were complemented by parallel changes in serum levels of Aβ 1-42.
Lais B. Razza
Adriano H. Moffa
Andre F. Carvalho
Colleen K. Loo
Andre Russowsky Brunoni
First published: 26 February 2020
Transcranial direct current stimulation (tDCS) has shown mixed results for depression treatment.
To perform a systematic review and meta‐analysis of trials using tDCS to improve depressive symptoms.
A systematic review was performed from the first date available to January 06, 2020 in PubMed, EMBASE, Cochrane Library, and additional sources. We included randomized, sham‐controlled clinical trials (RCTs) enrolling participants with an acute depressive episode and compared the efficacy of active versus sham tDCS, including association with other interventions. The primary outcome was the Hedges’ g for continuous depression scores; secondary outcomes included odds ratios (ORs) and number needed to treat (NNT) for response, remission, and acceptability. Random effects models were employed. Sources of heterogeneity were explored via metaregression, sensitivity analyses, subgroup analyses, and bias assessment.
We included 23 RCTs (25 datasets, 1,092 participants), most (57%) presenting a low risk of bias. Active tDCS was superior to sham regarding endpoint depression scores (k = 25, g = 0.46, 95% confidence interval [CI]: 0.22–0.70), and also achieved superior response (k = 18, 33.3% vs. 16.56%, OR = 2.28 [1.52–3.42], NNT = 6) and remission (k = 18, 19.12% vs. 9.78%, OR = 2.12 [1.42–3.16], NNT = 10.7) rates. Moreover, active tDCS was as acceptable as sham. No risk of publication bias was identified. Cumulative meta‐analysis showed that effect sizes are basically unchanged since total sample reached 439 participants.
TDCS is modestly effective in treating depressive episodes. Further well‐designed, large‐scale RCTs are warranted.
Volumes 17–18, November–December 2019, Pages 17-22
Mayank V.Jogab Danny J.J.Wangb Katherine L.Narrac
- TDCS of the left dorsolateral prefrontal cortex can reduce depressive symptoms.
- TDCS may be less suited for treatment-resistant depression.
- Combining tDCS with pharmaco- or psychotherapies may enhance therapeutic outcomes.
- Optimizing tDCS parameters to individual patients can improve physiological response.
Transcranial direct current stimulation (tDCS) is a low intensity neuromodulation technique shown to elicit therapeutic effects in a number of neuropsychological conditions. Independent randomized sham-controlled trials and meta- and mega-analyses demonstrate that tDCS targeted to the left dorsolateral prefrontal cortex can produce a clinically meaningful response in patients with major depressive disorder (MDD), but effects are small to moderate in size. However, the heterogeneous presentation, and the neurobiology underlying particular features of depression suggest clinical outcomes might benefit from empirically informed patient selection. In this review, we summarize the status of tDCS research in MDD with focus on the clinical, biological, and intrinsic and extrinsic factors shown to enhance or predict antidepressant response. We also discuss research strategies for optimizing tDCS to improve patient-specific clinical outcomes. TDCS appears suited for both bipolar and unipolar depression, but is less effective in treatment resistant depression. TDCS may also better target core aspects of depressed mood over vegetative symptoms, while pretreatment patient characteristics might inform subsequent response. Peripheral blood markers of gene and immune system function have not yet proven useful as predictors or correlates of tDCS response. Though further research is needed, several lines of evidence suggest that tDCS administered in combination with pharmacological and cognitive behavioral interventions can improve outcomes. Tailoring stimulation to the functional and structural anatomy and/or connectivity of individual patients can maximize physiological response in targeted networks, which in turn could translate to therapeutic benefits.
Studien zu EMDR
Patricia Novo Navarroa,b,c, Ramón Landin-Romerod,e,f,g, Rocio Guardiola-Wanden-Bergheb,c, Ana Moreno-Alcázarc,d, Alicia Valiente-Gómezc,d, Walter Lupoh, Francisca Garcíai, Isabel Fernándezj, Víctor Pérezb,c
y Benedikt L. Amannc,d,∗
Eye movement desensitization and reprocessing (EMDR) is a relatively new psychot- herapy that has gradually gained popularity for the treatment of post-traumatic stress disorder. In the present work, the standardised EMDR protocol is introduced, along with current hypot- heses of its mechanism of action, as well as a critical review of the available literature on its clinical effectiveness in adult post-traumatic stress disorder. A systematic review of the published literature was performed using PubMed and PsycINFO databases with the keywords «eye movement desensitization and reprocessing» and «post-traumatic stress disorder» and its abbreviations «EMDR» and «PTSD». Fifteen randomised controlled trials of good methodologi- cal quality were selected. These studies compared EMDR with unspecific interventions, waiting lists, or specific therapies. Overall, the results of these studies suggest that EMDR is a useful, evidence-based tool for the treatment of post-traumatic stress disorder, in line with recent recommendations from different international health organisations.
© 2016 SEP y SEPB. Published by Elsevier España, S.L.U. All rights reserved.
- de Jongh, Ad
- Amann, Benedikt L.
- Hofmann, Arne
- Farrell, Derek
- Lee, Christopher W.
Journal of EMDR Practice and Research
Vol 13Issue 4
Given that 2019 marks the 30th anniversary of eye movement desensitization and reprocessing (EMDR) therapy, the purpose of this article is to summarize the current empirical evidence in support of EMDR therapy as an effective treatment intervention for posttraumatic stress disorder (PTSD). Currently, there are more than 30 randomized controlled trials (RCT) demonstrating the effectiveness in patients with this debilitating mental health condition, thus providing a robust evidence base for EMDR therapy as a first-choice treatment for PTSD. Results from several meta-analyses further suggest that EMDR therapy is equally effective as its most important trauma-focused comparator, that is, trauma-focused cognitive behavioral therapy, albeit there are indications from some studies that EMDR therapy might be more efficient and cost-effective. There is emerging evidence showing that EMDR treatment of patients with psychiatric disorders, such as psychosis, in which PTSD is comorbid, is also safe, effective, and efficacious. In addition to future well-crafted RCTs in areas such as combat-related PTSD and psychiatric disorders with comorbid PTSD, RCTs with PTSD as the primary diagnosis remain pivotal in further demonstrating EMDR therapy as a robust treatment intervention.
- Tesarz, Jonas
- Wicking, Manon
- Bernardy, Kathrin
- Seidler, Günter H.
Journal of EMDR Practice and Research Vol 13 Issue 4 DOI:
Chronic pain is the most common global cause of functional and quality of life limitations. Although there are many effective therapies for the treatment of acute pain, chronic pain is often unsatisfactory. Against this background, there is currently an urgent need to develop innovative therapies that enable more efficient pain relief. Psychosocial factors play an important role in the development and persistence of chronic pain. Especially in patients with high levels of emotional stress, significant anxiety, or relevant psychological comorbidity, classical pain therapy approaches often fail. This is in line with the results of recent pain research, which has shown that dysfunctions in emotion processing have a significant influence on the persistence of pain symptoms. The recognition that pain can become chronic through maladaptive emotional processing forms the pathophysiological basis for the application of eye movement desensitization and reprocessing (EMDR) in the treatment of chronic pain. In this sense, EMDR can be used as an established method for desensitizing and processing of emotional distress from trauma therapy specifically for processing emotional stress in patients with chronic pain. Against this background, it is not surprising that the implementation of EMDR for patients with chronic pain is expanding. However, the increasing clinical use of EMDR in the treatment of chronic pain has also led to a reputation to test the efficacy of EMDR in pain management through randomized clinical trials. In addition to numerous case control studies, there are now also six randomized controlled clinical trials available that demonstrate the efficacy and safety of EMDR in the treatment of different pain conditions. However, in order to overcome several methodological limitations, large multicenter studies are needed to confirm the results.
Marianne Littel* , Marcel A. van den Hout and Iris M. Engelhard
Clinical Psychology, Utrecht University, Utrecht, Netherlands
Eye movement desensitization and reprocessing (EMDR) is an effective treatment for posttraumatic stress disorder. During this treatment, patients recall traumatic memo- ries while making horizontal eye movements (EM). Studies have shown that EM not only desensitize negative memories but also positive memories and imagined events. Substance use behavior and craving are maintained by maladaptive memory associa- tions and visual imagery. Preliminary findings have indicated that these mental images can be desensitized by EMDR techniques. We conducted two proof-of-principle studies to investigate whether EM can reduce the sensory richness of substance-related mental representations and accompanying craving levels. We investigated the effects of EM on (1) vividness of food-related mental imagery and food craving in dieting and non-dieting students and (2) vividness of recent smoking-related memories and cigarette craving in daily smokers. In both experiments, participants recalled the images while making EM or keeping eyes stationary. Image vividness and emotionality, image-specific craving and general craving were measured before and after the intervention. As a behavioral outcome measure, participants in study 1 were offered a snack choice at the end of the experiment. Results of both experiments showed that image vividness and crav- ing increased in the control condition but remained stable or decreased after the EM intervention. EM additionally reduced image emotionality (experiment 2) and affected behavior (experiment 1): participants in the EM condition were more inclined to choose healthy over unhealthy snack options. In conclusion, these data suggest that EM can be used to reduce intensity of substance-related imagery and craving. Although long-term effects are yet to be demonstrated, the current studies suggest that EM might be a useful technique in addiction treatment.
Front. Psychiatry 7:14. doi: 10.3389/fpsyt.2016.00014
Hwallip Bae • Changwoo Han • Daeho Kim
Ó Springer Science+Business Media New York 2013
This case series introduces the desensitization of triggers and urge reprocessing (DeTUR), as a promising adjunctive therapy in addition to comprehensive treatment package for pathological gambling. This addiction protocol of eye movement desensiti- zation and reprocessing was delivered to four male inpatients admitted to a 10-week inpatient program for pathological gambling. The therapist gave three 60-min weekly sessions of the DeTUR using bilateral stimulation (horizontal eye movements or alterna- tive tactile stimuli) focusing on the hierarchy of triggering situations and the urge to initiate gambling behaviors. After treatment, self-reported gambling symptoms, depression, anx- iety, and impulsiveness were all improved, and all the participants reported satisfaction with the therapy. They were followed up for 6 months and all maintained their abstinence from gambling and their symptomatic improvements. Given the efficiency (i.e., brevity and efficacy) of the treatment, a controlled study to confirm the effects of the DeTUR on pathological gambling would be justified.
Open Access Original
Article DOI: 10.7759/cureus.3250
Review began 08/31/2018
Review ended 08/31/2018
Ali M. Khan 1 , Sabrina Dar 2 , Rizwan Ahmed 3 , Ramya Bachu 4 , Mahwish Adnan 5 , Vijaya Padma Kotapati 6
1. Psychiatry Resident, University of Texas Rio Grande Valley, Harlingen, Texas, USA 2. Psychiatry, Saint Elizabeth’s Medical Center, Boston, MA, USA 3. Psychiatry, Liaquat College, Karachi, PAK 4. Psychiatry, Northwell Zucker Hillside Hospital, New York, USA 5. Center for Addiction and Mental Health, University of Toronto, Toronto, CAN 6. Psychiatry, Manhattan Psychiatric Center, New York, USA
Corresponding author: Vijaya Padma Kotapati, email@example.com Disclosures can be found in Additional Information at the end of the article
Post-traumatic stress disorder (PTSD) is prevalent in children, adolescents and adults. It can occur alone or in comorbidity with other disorders. A broad range of psychotherapies such as cognitive behavioral therapy (CBT) and eye movement desensitization and reprocessing (EMDR) have been developed for the treatment of PTSD.
Through quantitative meta-analysis, we aimed to compare the efficacy of CBT and EMDR: (i) relieving the post-traumatic symptoms, and (ii) alleviating anxiety and depression, in patients with PTSD.
We systematically searched EMBASE, Medline and Cochrane central register of controlled trials (CENTRAL) for articles published between 1999 and December 2017. Randomized clinical trials (RCTs) that compare CBT and EMDR in PTSD patients were included for quantitative meta- analysis using RevMan Version 5.
Fourteen studies out of 714 were finally eligible. Meta-analysis of 11 studies (n = 547) showed that EMDR is better than CBT in reducing post-traumatic symptoms [SDM (95% CI) = -0.43 (- 0.73 – -0.12), p = 0.006]. However, meta-analysis of four studies (n = 186) at three-
month follow-up revealed no statistically significant difference [SDM (95% CI) = -0.21 (-0.50 – 0.08), p = 0.15]. The EMDR was also better than CBT in reducing anxiety [SDM (95% CI) = -0.71 (-1.21 – -0.21), p =0.005]. Unfortunately, there was no difference between CBT and EMDR in reducing depression [SDM (95% CI) = -0.21 (-0.44 – 0.02), p = 0.08].
The results of this meta-analysis suggested that EMDR is better than CBT in reducing post- traumatic symptoms and anxiety. However, there was no difference reported in reducing depression. Large population randomized trials with longer follow-up are recommended to build conclusive evidence.