Publications by authors named "Nicola J Kalk"

25 Publications

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Synthetic Cannabinoid-Related Deaths in England, 2012-2019.

Cannabis Cannabinoid Res 2021 Feb 24. Epub 2021 Feb 24.

Population Health Research Institute, St George's, University of London, London, United Kingdom.

To identify drug-related death trends associated with synthetic cannabinoid receptor agonists (SCRAs) reported to the National Programme on Substance Abuse Deaths (NPSAD) from England. Case reports from NPSAD (England) where a SCRA was detected in post-mortem tissue(s) and/or implicated in the death were extracted, analyzed, and compared against non-SCRA-related deaths that occurred over the same time period (2012-2019). One hundred sixty-five death SCRA-related reports were extracted, with 18 different SCRAs detected. Following the first death in 2012, a subsequent sharp increase in reporting is evident. Acute SCRA use was the underlying cause of death in the majority of cases (75.8%) with cardiorespiratory complications the most frequently cited underlying physiological cause (13.4%). SCRA users were predominantly found dead (68.6%), with a large proportion of those witnessed becoming unresponsive described as suddenly collapsing (81.6%). Psychoactive polydrug use was detected in 90.3% of cases, with alcohol the most commonly co-detected (50.3%), followed by opioids (42.2%), benzodiazepines/Z-drugs (32.1%), stimulants (32.1%, [28.5% cocaine]), and cannabis (24.8%). Compared to all non-SCRA-related NPSAD deaths occurring over the same time period, SCRA-related decedents were more predominantly male (90.3% vs. 72.0%; <0.01), and lived in more deprived areas (<0.01). While a comparatively significant proportion of decedents were homeless (19.4% vs. 4.1%), living in a hostel (13.3% vs. 2.3%) or in prison (4.9% vs. 0.2%) at time of death (all <0.01), the greatest majority of SCRA-related decedents were living in private residential accommodations (57.6%). This is the largest dataset regarding SCRA-related mortalities reported to date. Reporting of SCRA-related deaths in England have increased considerably, with polydrug use a specific concern. Lack of effective deterrents to SCRA use under current UK legislation, compounded by limited knowledge regarding the physiological impacts of SCRA consumption and their interaction with other co-administered substances are contributory factors to the occurrence of SCRA-related mortalities in an increasingly deprived demographic.
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http://dx.doi.org/10.1089/can.2020.0161DOI Listing
February 2021

Synthetic Cannabinoid-Related Deaths in England, 2012-2019.

Cannabis Cannabinoid Res 2021 Feb 24. Epub 2021 Feb 24.

Population Health Research Institute, St George's, University of London, London, United Kingdom.

To identify drug-related death trends associated with synthetic cannabinoid receptor agonists (SCRAs) reported to the National Programme on Substance Abuse Deaths (NPSAD) from England. Case reports from NPSAD (England) where a SCRA was detected in post-mortem tissue(s) and/or implicated in the death were extracted, analyzed, and compared against non-SCRA-related deaths that occurred over the same time period (2012-2019). One hundred sixty-five death SCRA-related reports were extracted, with 18 different SCRAs detected. Following the first death in 2012, a subsequent sharp increase in reporting is evident. Acute SCRA use was the underlying cause of death in the majority of cases (75.8%) with cardiorespiratory complications the most frequently cited underlying physiological cause (13.4%). SCRA users were predominantly found dead (68.6%), with a large proportion of those witnessed becoming unresponsive described as suddenly collapsing (81.6%). Psychoactive polydrug use was detected in 90.3% of cases, with alcohol the most commonly co-detected (50.3%), followed by opioids (42.2%), benzodiazepines/Z-drugs (32.1%), stimulants (32.1%, [28.5% cocaine]), and cannabis (24.8%). Compared to all non-SCRA-related NPSAD deaths occurring over the same time period, SCRA-related decedents were more predominantly male (90.3% vs. 72.0%; <0.01), and lived in more deprived areas (<0.01). While a comparatively significant proportion of decedents were homeless (19.4% vs. 4.1%), living in a hostel (13.3% vs. 2.3%) or in prison (4.9% vs. 0.2%) at time of death (all <0.01), the greatest majority of SCRA-related decedents were living in private residential accommodations (57.6%). This is the largest dataset regarding SCRA-related mortalities reported to date. Reporting of SCRA-related deaths in England have increased considerably, with polydrug use a specific concern. Lack of effective deterrents to SCRA use under current UK legislation, compounded by limited knowledge regarding the physiological impacts of SCRA consumption and their interaction with other co-administered substances are contributory factors to the occurrence of SCRA-related mortalities in an increasingly deprived demographic.
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http://dx.doi.org/10.1089/can.2020.0161DOI Listing
February 2021

The Association Between Smartphone Addiction and Sleep: A UK Cross-Sectional Study of Young Adults.

Front Psychiatry 2021 2;12:629407. Epub 2021 Mar 2.

Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

In a large UK study we investigated the relationship between smartphone addiction and sleep quality in a young adult population. We undertook a large UK cross-sectional observational study of 1,043 participants aged 18 to 30 between January 21st and February 30th 2019. Participants completed the Smartphone Addiction Scale Short Version, an adapted Pittsburgh Sleep Quality Score Index and reported smartphone use reduction strategies using both in-person ( = 968) and online ( = 75) questionnaires. A crude and adjusted logistic regression was fitted to assess risk factors for smartphone addiction, and the association between smartphone addiction and poor sleep. One thousand seventy one questionnaires were returned, of which 1,043 participants were included, with median age 21.1 [interquartile range (IQR) 19-22]. Seven hundred and sixty three (73.2%) were female, and 406 reported smartphone addiction (38.9%). A large proportion of participants disclosed poor sleep (61.6%), and in those with smartphone addiction, 68.7% had poor sleep quality, compared to 57.1% of those without. Smartphone addiction was associated with poor sleep (aOR = 1.41, 95%CI: 1.06-1.87, = 0.018). Using a validated instrument, 39% young adults reported smartphone addiction. Smartphone addiction was associated with poor sleep, independent of duration of usage, indicating that length of time should not be used as a proxy for harmful usage.
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http://dx.doi.org/10.3389/fpsyt.2021.629407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961071PMC
March 2021

The Association Between Smartphone Addiction and Sleep: A UK Cross-Sectional Study of Young Adults.

Front Psychiatry 2021 2;12:629407. Epub 2021 Mar 2.

Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

In a large UK study we investigated the relationship between smartphone addiction and sleep quality in a young adult population. We undertook a large UK cross-sectional observational study of 1,043 participants aged 18 to 30 between January 21st and February 30th 2019. Participants completed the Smartphone Addiction Scale Short Version, an adapted Pittsburgh Sleep Quality Score Index and reported smartphone use reduction strategies using both in-person ( = 968) and online ( = 75) questionnaires. A crude and adjusted logistic regression was fitted to assess risk factors for smartphone addiction, and the association between smartphone addiction and poor sleep. One thousand seventy one questionnaires were returned, of which 1,043 participants were included, with median age 21.1 [interquartile range (IQR) 19-22]. Seven hundred and sixty three (73.2%) were female, and 406 reported smartphone addiction (38.9%). A large proportion of participants disclosed poor sleep (61.6%), and in those with smartphone addiction, 68.7% had poor sleep quality, compared to 57.1% of those without. Smartphone addiction was associated with poor sleep (aOR = 1.41, 95%CI: 1.06-1.87, = 0.018). Using a validated instrument, 39% young adults reported smartphone addiction. Smartphone addiction was associated with poor sleep, independent of duration of usage, indicating that length of time should not be used as a proxy for harmful usage.
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http://dx.doi.org/10.3389/fpsyt.2021.629407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961071PMC
March 2021

The Association Between Smartphone Addiction and Sleep: A UK Cross-Sectional Study of Young Adults.

Front Psychiatry 2021 2;12:629407. Epub 2021 Mar 2.

Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

In a large UK study we investigated the relationship between smartphone addiction and sleep quality in a young adult population. We undertook a large UK cross-sectional observational study of 1,043 participants aged 18 to 30 between January 21st and February 30th 2019. Participants completed the Smartphone Addiction Scale Short Version, an adapted Pittsburgh Sleep Quality Score Index and reported smartphone use reduction strategies using both in-person ( = 968) and online ( = 75) questionnaires. A crude and adjusted logistic regression was fitted to assess risk factors for smartphone addiction, and the association between smartphone addiction and poor sleep. One thousand seventy one questionnaires were returned, of which 1,043 participants were included, with median age 21.1 [interquartile range (IQR) 19-22]. Seven hundred and sixty three (73.2%) were female, and 406 reported smartphone addiction (38.9%). A large proportion of participants disclosed poor sleep (61.6%), and in those with smartphone addiction, 68.7% had poor sleep quality, compared to 57.1% of those without. Smartphone addiction was associated with poor sleep (aOR = 1.41, 95%CI: 1.06-1.87, = 0.018). Using a validated instrument, 39% young adults reported smartphone addiction. Smartphone addiction was associated with poor sleep, independent of duration of usage, indicating that length of time should not be used as a proxy for harmful usage.
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http://dx.doi.org/10.3389/fpsyt.2021.629407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961071PMC
March 2021

Correction to: Prevalence of problematic smartphone usage and associated mental health outcomes amongst children and young people: a systematic review, meta-analysis and GRADE of the evidence.

BMC Psychiatry 2021 Jan 22;21(1):52. Epub 2021 Jan 22.

Department of Biostatistics, and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Denmark Hill, De Crespigny Park, London, SE5 8AF, UK.

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http://dx.doi.org/10.1186/s12888-020-02986-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821539PMC
January 2021

Substance use in psychiatric crisis: relationship to violence.

Psychol Med 2020 Nov 5:1-7. Epub 2020 Nov 5.

South London and Maudsley NHS Foundation Trust, London, UK.

Background: Substance use and psychiatric illness, particularly psychotic disorders, contribute to violence in emergency healthcare settings. However, there is limited research regarding the relationship between specific substances, psychotic symptoms and violent behaviour in such settings. We investigated the interaction between recent cannabinoid and stimulant use, and acute psychotic symptoms, in relation to violent behaviour in a British emergency healthcare setting.

Methods: We used electronic medical records from detentions of 1089 individuals under Section 136 of the UK Mental Health Act (1983 amended 2007), an emergency police power used to detain people for 24-36 h for psychiatric assessment. The relationship between recent cannabinoids and/or stimulant use, psychotic symptoms, and violent behaviour, was estimated using logistic regression.

Findings: There was evidence of recent alcohol or drug use in 64.5% of detentions. Violent incidents occurred in 12.6% of detentions. Psychotic symptoms increased the odds of violence by 4.0 [95% confidence intervals (CI) 2.2-7.4; p < 0.0001]. Cannabinoid use combined with psychotic symptoms increased the odds of violence further [odds ratios (OR) 7.1, 95% CI 3.7-13.6; p < 0.0001]. Recent use of cannabinoids with stimulants but without psychotic symptoms was also associated with increased odds of violence (OR 3.3, 95% CI 1.4-7.9; p < 0.0001).

Interpretation: In the emergency setting, patients who have recently used cannabinoids and exhibit psychotic symptoms are at higher risk of violent behaviour. Those who have used both stimulants and cannabinoids without psychotic symptoms may also be at increased risk. De-escalation protocols in emergency healthcare settings should account explicitly for substance use.
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http://dx.doi.org/10.1017/S0033291720003451DOI Listing
November 2020

Factors associated with withdrawal symptoms and anger among people resuscitated from an opioid overdose by take-home naloxone: Exploratory mixed methods analysis.

J Subst Abuse Treat 2020 10 5;117:108099. Epub 2020 Aug 5.

Division on Substance Use Disorders, Columbia University Irving Medical Center and New York State Psychiatric Institute, 1051 Riverside Drive, Unit 120, New York, NY 10032, United States. Electronic address:

Introduction: Take-home naloxone (THN) is a clinically effective and cost-effective means of reducing opioid overdose fatality. Nonetheless, naloxone administration that successfully saves a person's life can still produce undesirable and harmful effects.

Aim: To better understand factors associated with two widely reported adverse outcomes following naloxone administration; namely the person resuscitated displays: i. withdrawal symptoms and ii. anger.

Methods: A mixed methods study combining a randomized controlled trial of overdose education and naloxone prescribing to people with opioid use disorder and semi-structured qualitative interviews with trial participants who had responded to an overdose whilst in the trial. All data were collected in New York City (2014-2019). A dataset (comprising demographic, pharmacological, situational, interpersonal, and overdose training related variables) was generated by transforming qualitative interview data from 47 overdose events into dichotomous variables and then combining these with quantitative demographic and overdose training related data from the main trial. Associations between variables within the dataset and reports of: i. withdrawal symptoms and ii. anger were explored using chi-squared tests, t-tests, and logistic regressions.

Results: A multivariate logistic regression found that people who had overdosed were significantly more likely to display anger if the person resuscitating them criticized, berated or chastised them during resuscitation (adjusted OR = 27 [95% CI = 4.0-295]). In contrast, they were significantly less likely to display anger if the person resuscitating them communicated positively with them (OR = 0.10 [95% CI = 0.01-0.78]). Both positive and negative communication styles were independently associated with anger, and communication was associated with 59% of the variance in anger. There was no evidence that people who displayed withdrawal symptoms were more likely to display anger than those not displaying withdrawal symptoms, and neither displaying withdrawal symptoms nor displaying anger were associated with using more drugs after resuscitation.

Conclusions: Contrary to common assumptions, withdrawal symptoms and anger following naloxone administration may be unrelated phenomena. Findings are consistent with previous research that has suggested that a lay responder's positive or reassuring communication style may lessen anger post overdose. Implications for improving THN programmes and naloxone administration are discussed.
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http://dx.doi.org/10.1016/j.jsat.2020.108099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491601PMC
October 2020

Synthetic cannabinoids and potential cardiac arrhythmia risk: an important message for drug users.

Ther Adv Drug Saf 2020 24;11:2042098620913416. Epub 2020 Mar 24.

The School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK.

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http://dx.doi.org/10.1177/2042098620913416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093686PMC
March 2020

Heroin-induced respiratory depression and the influence of dose variation: within-subject between-session changes following dose reduction.

Addiction 2020 10 11;115(10):1954-1959. Epub 2020 Mar 11.

King's College London, National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, London, UK.

Background And Aims: Globally, more than 100 000 people die annually from opioid overdose. Opportunities to study physiological events in at-risk individuals are limited. This study examined variation of opioid dose and impact on respiratory depression in a chronic injecting heroin user at separate time-points during his long-term diamorphine maintenance treatment.

Design: A single-subject study over 5 years during which participant underwent experimental studies on diamorphine-induced respiratory depression, at changing maintenance doses.

Setting: A clinical research facility. Participant Male subject on long-term injectable diamorphine (pharmaceutical heroin) maintenance treatment for heroin addiction.

Measurements: Physiological measures of oxygen saturation (SpO ), end-tidal carbon dioxide (ETCO ) and respiratory rate (RR) were used to indicate severity of respiratory depression.

Findings: (1) After diamorphine injection, respiratory regulation became abnormal, with prolonged apnoea exceeding 20 sec (maximum 56 sec), elevated ETCO (maximum 6.9%) and hypoxaemia (minimum SpO 80%). (2) Abnormalities were greater with highest diamorphine dose: average SpO was 89.3% after 100 mg diamorphine versus 93.6% and 92.8% for the two 30-mg doses. (3) However, long apnoeic pauses and high levels of ETCO % were also present after lower doses.

Conclusions: With marked inter-session variability, these findings corroborate observations of inconsistent relationships between opioid dose and overdose risk.
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http://dx.doi.org/10.1111/add.15014DOI Listing
October 2020

Correction to: Prevalence of problematic smartphone usage and associated mental health outcomes amongst children and young people: a systematic review, meta-analysis and GRADE of the evidence.

BMC Psychiatry 2019 Dec 16;19(1):397. Epub 2019 Dec 16.

Department of Biostatistics, and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Denmark Hill, De Crespigny Park, London, SE5 8AF, UK.

After publication of our article [1] we were notified that one of the author names was misspelled.
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http://dx.doi.org/10.1186/s12888-019-2393-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912990PMC
December 2019

Prevalence of problematic smartphone usage and associated mental health outcomes amongst children and young people: a systematic review, meta-analysis and GRADE of the evidence.

BMC Psychiatry 2019 11 29;19(1):356. Epub 2019 Nov 29.

Department of Biostatistics, and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Denmark Hill, De Crespigny Park, London, SE5 8AF, UK.

Background: Over the past decade, smartphone use has become widespread amongst today's children and young people (CYP) which parallels increases in poor mental health in this group. Simultaneously, media concern abounds about the existence of 'smartphone addiction' or problematic smartphone use. There has been much recent research concerning the prevalence of problematic smartphone use is in children and young people who use smartphones, and how this syndrome relates to mental health outcomes, but this has not been synthesized and critically evaluated.

Aims: To conduct a systematic review and meta-analysis to examine the prevalence of PSU and quantify the association with mental health harms.

Methods: A search strategy using Medical Subject Headings was developed and adapted for eight databases between January 1, 1st 2011 to October 15th 2017. No language restriction was applied. Of 924 studies identified, 41 were included in this review, three of which were cohort studies and 38 were cross sectional studies. The mental health outcomes were self-reported: depression; anxiety; stress; poor sleep quality; and decreased educational attainment, which were synthesized according to an a priori protocol.

Results: The studies included 41,871 CYP, and 55% were female. The median prevalence of PSU amongst CYP was 23.3% (14.0-31.2%). PSU was associated with an increased odds of depression (OR = 3.17;95%CI 2.30-4.37;I = 78%); increased anxiety (OR = 3.05 95%CI 2.64-3.53;I = 0%); higher perceived stress (OR = 1.86;95%CI 1.24-2.77;I = 65%); and poorer sleep quality (OR = 2.60; 95%CI; 1.39-4.85, I = 78%).

Conclusions: PSU was reported in approximately one in every four CYP and accompanied by an increased odds of poorer mental health. PSU is an evolving public health concern that requires greater study to determine the boundary between helpful and harmful technology use. Policy guidance is needed to outline harm reduction strategies.
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http://dx.doi.org/10.1186/s12888-019-2350-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883663PMC
November 2019

Spicing it up - synthetic cannabinoid receptor agonists and psychosis - a systematic review.

Eur Neuropsychopharmacol 2018 12 16;28(12):1289-1304. Epub 2018 Nov 16.

King's College London Institute of Psychiatry, Psychology and Neuroscience, United Kingdom. Electronic address:

Synthetic cannabinoid receptor agonists (SCRAs) are suggested to have increased potential to induce psychosis compared to natural cannabis (NC). In this review we synthesise current knowledge about the association of SCRA use with psychotic symptoms. Following a literature search we identified 2 toxicology reports, 4 case-control studies, 3 cross-sectional studies and 15 case reports. In each of the case reports, we identified the presence or absence of symptoms based on the items of the Postitive and Negative Syndrome Scele (PANSS). The toxicology reports highlighted the main presenting features as being toxic psychosis and delirium (40%), agitation (10%) and hallucinations (4-7%). The median age was 25 years, and around 80% cases were male. Cross-sectional studies reported that SCRA use was present in approximately 10-13% patients presenting to acute psychiatric services, and was often the cause of their presentation, and that psychotic symptoms were present in 15% patients attending emergency departments following SCRA use. Case-control studies reported that SCRA use was significantly associated with psychotic symptoms and that SCRA users had higher levels of positive psychotic symptoms than NC users. The case reports supported the association of SCRA use with a wide range of positive and negative psychotic symptoms as well as with self-harm, agitation and aggressive behaviour. SCRA use is relatively prevalent in patients with psychosis and may lead to psychotic symptoms in individuals with no past psychiatric history. Further work is required to understand the long term risks of SCRA use and optimal management strategies.
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http://dx.doi.org/10.1016/j.euroneuro.2018.10.004DOI Listing
December 2018

Harm reduction in opioid treatment: an established idea under threat.

Authors:
Nicola J Kalk

Addiction 2019 01 16;114(1):20-21. Epub 2018 Nov 16.

South London and Maudsley NHS Foundation Trust/Clinical Lecturer, IOPPN, King's College London, London, UK.

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http://dx.doi.org/10.1111/add.14468DOI Listing
January 2019

Harm reduction in opioid treatment: an established idea under threat.

Authors:
Nicola J Kalk

Addiction 2019 01 16;114(1):20-21. Epub 2018 Nov 16.

South London and Maudsley NHS Foundation Trust/Clinical Lecturer, IOPPN, King's College London, London, UK.

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http://dx.doi.org/10.1111/add.14468DOI Listing
January 2019

Bipolar disorder and addictions: the elephant in the room.

Br J Psychiatry 2017 Sep;211(3):132-134

Paul R. A. Stokes, PhD, Nicola J. Kalk, PhD, Allan H. Young, FRCPsych, Centre far Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Addictions are highly prevalent in bipolar disorder and greatly affect clinical outcomes. In this editorial, we review the evidence that addictions are a key challenge in bipolar disorder, examine putative neurobiological mechanisms, and reflect on the limited clinical trial evidence base with suggestions for treatment strategies and further developments.
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http://dx.doi.org/10.1192/bjp.bp.116.193912DOI Listing
September 2017

Footnotes to Kraepelin: changes in the classification of mood disorders with DSM-5.

BJPsych Open 2017 May 11;3(3):e1-e3. Epub 2017 May 11.

, MBChB, MPhil, PhD, FRCPsych, FRCPC, South London and Maudsley NHS Foundation Trust, London, UK, and Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Summary: Reliable diagnosis of mood disorders continues to pose a challenge. This is surprising because they have been recognised clinically since classical times. Mood disorders are also common: major depressive disorder affects nearly 300 million people worldwide and bipolar affective disorder nearly 60 million and they are a major cause of disability. Nonetheless, the reliability trials of the updated Diagnostic and Statistical Manual, Fifth Edition (DSM-5) found that the reliability of the diagnosis of major depressive disorder was in the 'questionable' range. Although the reliability of the diagnosis of bipolar I disorder in the same trials was 'good', the sample size of the individuals recruited to validate bipolar II disorder was insufficient to confirm reliability. As the epidemiological prevalences of bipolar I and bipolar II disorders are the same, this alone implies problems in its recognition. Here, we critically evaluate the most recent iteration of DSM mood disorder diagnoses in a historical light and set out the implications for clinical practice and research.

Declaration Of Interest: N.J.K. has attended educational activities funded by GlaxoSmithKline (GSK) and by Lundbeck and has worked on data from a study funded by Wyeth; her PhD was jointly funded by the Wellcome Trust and GSK. A.H.Y. has given paid lectures and is on advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Janssen, Lundeck, Sunovion, Servier, Livanova. He is Lead Investigator for the Embolden Study (Astrazenaca), BCI Neuroplasticity study and Aripiprazole Mania Study, which are investigator-initiated studies from Astrazenaca, Eli Lilly, Lundbeck, and Wyeth.

Copyright And Usage: © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.
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http://dx.doi.org/10.1192/bjpo.bp.117.004739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425931PMC
May 2017

Spice and all things nasty: the challenge of synthetic cannabinoids.

BMJ 2016 Oct 24;355:i5639. Epub 2016 Oct 24.

South London and Maudsley NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1136/bmj.i5639DOI Listing
October 2016

The Imperial College Cambridge Manchester (ICCAM) platform study: An experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part A: Study description.

J Psychopharmacol 2015 Sep 5;29(9):943-60. Epub 2015 Aug 5.

Centre for Neuropsychopharmacology, Imperial College London, London, UK.

Drug and alcohol dependence are global problems with substantial societal costs. There are few treatments for relapse prevention and therefore a pressing need for further study of brain mechanisms underpinning relapse circuitry. The Imperial College Cambridge Manchester (ICCAM) platform study is an experimental medicine approach to this problem: using functional magnetic resonance imaging (fMRI) techniques and selective pharmacological tools, it aims to explore the neuropharmacology of putative relapse pathways in cocaine, alcohol, opiate dependent, and healthy individuals to inform future drug development. Addiction studies typically involve small samples because of recruitment difficulties and attrition. We established the platform in three centres to assess the feasibility of a multisite approach to address these issues. Pharmacological modulation of reward, impulsivity and emotional reactivity were investigated in a monetary incentive delay task, an inhibitory control task, and an evocative images task, using selective antagonists for µ-opioid, dopamine D3 receptor (DRD3) and neurokinin 1 (NK1) receptors (naltrexone, GSK598809, vofopitant/aprepitant), in a placebo-controlled, randomised, crossover design. In two years, 609 scans were performed, with 155 individuals scanned at baseline. Attrition was low and the majority of individuals were sufficiently motivated to complete all five sessions (n=87). We describe herein the study design, main aims, recruitment numbers, sample characteristics, and explain the test hypotheses and anticipated study outputs.
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http://dx.doi.org/10.1177/0269881115596155DOI Listing
September 2015

Acute increases in synaptic GABA detectable in the living human brain: a [¹¹C]Ro15-4513 PET study.

Neuroimage 2014 Oct 17;99:158-65. Epub 2014 May 17.

Centre for Neuropsychopharmacology, Division of Brain Sciences, Burlington Danes Building, Imperial College London, W12 0NN, UK.

The inhibitory γ-aminobutyric acid (GABA) neurotransmitter system is associated with the regulation of normal cognitive functions and dysregulation has been reported in a number of neuropsychiatric disorders including anxiety disorders, schizophrenia and addictions. Investigating the role of GABA in both health and disease has been constrained by difficulties in measuring acute changes in synaptic GABA using neurochemical imaging. The aim of this study was to investigate whether acute increases in synaptic GABA are detectable in the living human brain using the inverse agonist GABA-benzodiazepine receptor (GABA-BZR) positron emission tomography (PET) tracer, [(11)C]Ro15-4513. We examined the effect of 15 mg oral tiagabine, which increases synaptic GABA by inhibiting the GAT1 GABA uptake transporter, on [(11)C]Ro15-4513 binding in 12 male participants using a paired, double blind, placebo-controlled protocol. Spectral analysis was used to examine synaptic α1 and extrasynaptic α5 GABA-BZR subtype availability in brain regions with high levels of [(11)C]Ro15-4513 binding. We also examined the test-retest reliability of α1 and a5-specific [(11)C]Ro15-4513 binding in a separate cohort of 4 participants using the same spectral analysis protocol. Tiagabine administration produced significant reductions in hippocampal, parahippocampal, amygdala and anterior cingulate synaptic α1 [(11)C]Ro15-4513 binding, and a trend significance reduction in the nucleus accumbens. These reductions were greater than test-retest reliability, indicating that they are not the result of chance observations. Our results suggest that acute increases in endogenous synaptic GABA are detectable in the living human brain using [(11)C]Ro15-4513 PET. These findings have potentially major implications for the investigation of GABA function in brain disorders and in the development of new treatments targeting this neurotransmitter system.
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http://dx.doi.org/10.1016/j.neuroimage.2014.05.035DOI Listing
October 2014

Measurement of GABA using J-difference edited 1H-MRS following modulation of synaptic GABA concentration with tiagabine.

Synapse 2014 Aug 2;68(8):355-62. Epub 2014 May 2.

Division of Brain Sciences, Centre for Neuropsychopharmacology, Imperial College London, London, W12 0NN, United Kingdom; Psychopharmacology Unit, University of Bristol, Bristol, BS8 2BN, United Kingdom.

Though GABA is the major inhibitory neurotransmitter in the brain, involved in a wide variety of brain functions and many neuropsychiatric disorders, its intracellular and metabolic presence provides uncertainty in the interpretation of the GABA signal measured by (1)H-MRS. Previous studies demonstrating the sensitivity of this technique to pharmacological manipulations of GABA have used nonspecific challenges that make it difficult to infer the exact source of the changes. In this study, the synaptic GABA reuptake inhibitor tiagabine, which selectively blocks GAT1, was used to test the sensitivity of J-difference edited (1)H-MRS to changes in extracellular GABA concentrations. MEGA-PRESS was used to obtain GABA-edited spectra in 10 male individuals, before and after a 15-mg oral dose of tiagabine. In the three voxels measured, no significant changes were found in GABA+ concentration after the challenge compared to baseline. This dose of tiagabine is known to modulate synaptic GABA and neurotransmission through studies using other imaging modalities, and significant increases in self-reported sleepiness scales were observed. Therefore, it is concluded that recompartmentalization of GABA through transport block does not have a significant impact on total GABA concentration. Furthermore, it is likely that the majority of the magnetic resonance spectroscopy (MRS)-derived GABA signal is intracellular. It should be considered, in individual interpretation of GABA MRS studies, whether it is appropriate to attribute observed effects to changes in neurotransmission.
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http://dx.doi.org/10.1002/syn.21747DOI Listing
August 2014

Determination of [(11)C]PBR28 binding potential in vivo: a first human TSPO blocking study.

J Cereb Blood Flow Metab 2014 Jun 19;34(6):989-94. Epub 2014 Mar 19.

1] Centre for Neuroimaging Sciences, Institute of Psychiatry, King's College London, London, UK [2] Imanova, Centre for Imaging Sciences, London, UK.

Positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) is used to quantify neuroinflammation. Translocator protein is expressed throughout the brain, and therefore a classical reference region approach cannot be used to estimate binding potential (BPND). Here, we used blockade of the TSPO radioligand [(11)C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution (VND), and hence estimate the BPND. A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [(11)C]PBR28 PET scan with arterial sampling. Six of the HABs received oral XBD173 (10 to 90 mg), 2 hours before a repeat scan. In XBD173-dosed subjects, VND was estimated via the occupancy plot. Values of BPND for all subjects were calculated using this VND estimate. Total volume of distribution (VT) of MABs (2.94±0.31) was lower than VT of HABs (4.33±0.29) (P<0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50=0.34±0.13 mg/kg). The occupancy plot provided a VND estimate of 1.98 (1.69, 2.26). Based on these VND estimates, BPND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [(11)C]PBR28 VND and hence BPND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating VND for TSPO targeting radioligands.
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http://dx.doi.org/10.1038/jcbfm.2014.46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050243PMC
June 2014

Resting state synchrony in anxiety-related circuits of abstinent alcohol-dependent patients.

Am J Drug Alcohol Abuse 2013 Nov;39(6):433-40

Centre for Neuropsychopharmacology, Imperial College London , London , UK .

Background: Anxiety has been linked to initiation, maintenance and relapse of alcohol dependence. Neurobiological models of anxiety have proposed important roles for amygdala-insula and amygdala-medial prefrontal cortex interactions in the generation and regulation of anxiety states, respectively.

Objectives: This study tested the hypotheses that abstinent alcohol-dependent patients would show a disruption of synchrony in these circuits as measured by resting state functional MRI.

Methods: The study examined recently abstinent (n = 13), longer-term abstinent (n = 16) alcohol-dependent patients and healthy controls (n = 22). Resting-state synchrony (RSS) was examined in specific circuits, where degree of synchrony has been found to correlate with state anxiety levels in previous studies.

Results: Alcohol-dependent patients showed significantly elevated scores on anxiety and depression inventories compared with controls. No significant group differences in synchrony were observed between right amygdala and right ventromedial prefrontal cortex (vmPFC), between left amygdala and left vmPFC, or, after correction for multiple comparisons, right amygdala and dorsomedial prefrontal cortex (dmPFC). However, significantly decreased positive synchrony was found between left basolateral amygdala and left anterior insula, in patients relative to controls.

Conclusion: Both early and longer-term abstinent alcohol-dependent patients showed increased anxiety levels relative to controls and altered resting state synchrony in circuits previously linked to state anxiety. Notably, the significant group differences in synchrony were in the opposite direction to our predictions based on the literature. These results may point to a lack of generalizability of models derived from young healthy homogeneous samples.
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http://dx.doi.org/10.3109/00952990.2013.846348DOI Listing
November 2013

The clinical pharmacology of acamprosate.

Br J Clin Pharmacol 2014 Feb;77(2):315-23

Centre for Neuropsychopharmacology, Imperial College London, London, W12 0NN, UK.

Acamprosate is one of the few medications licensed for prevention of relapse in alcohol dependence, and over time it has proved to be significantly, if moderately, effective, safe and tolerable. Its use is now being extended into other addictions and neurodevelopmental disorders. The mechanism of action of acamprosate has been less clear, but in the decade or more that has elapsed since its licensing, a body of translational evidence has accumulated, in which preclinical findings are replicated in clinical populations. Acamprosate modulates N-methyl-d-aspartic acid receptor transmission and may have indirect effects on γ-aminobutyric acid type A receptor transmission. It is known to decrease brain glutamate and increase β-endorphins in rodents and man. Acamprosate diminishes reinstatement in ethanolized rodents and promotes abstinence in humans. Although acamprosate has been called an anticraving drug, its subjective effects are subtle and relate to diminished arousal, anxiety and insomnia, which parallel preclinical findings of decreased withdrawal symptoms in animals treated with acamprosate. Further understanding of the pharmacology of acamprosate will allow appropriate targeting of therapy in individuals with alcohol dependence and extension of its use to other addictions.
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http://dx.doi.org/10.1111/bcp.12070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014018PMC
February 2014

Characterisation of the contribution of the GABA-benzodiazepine α1 receptor subtype to [(11)C]Ro15-4513 PET images.

J Cereb Blood Flow Metab 2012 Apr 4;32(4):731-44. Epub 2012 Jan 4.

Psychopharmacology Unit, University of Bristol, Bristol, UK.

This positron emission tomography (PET) study aimed to further define selectivity of [(11)C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [(11)C]Ro15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand [(11)C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [(11)C]Ro15-4513 time-activity curves was used to describe distribution volume (V(T)) differences in regions populated by different GABA receptor subtypes. Those with low α5 were best fitted by one-tissue compartment models; and those with high α5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that zolpidem caused a significant V(T) decrease (~10%) in [(11)C]flumazenil, but no decrease in [(11)C]Ro15-4513 binding. Further analysis of [(11)C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both α1 and α5 subtypes compared with those containing only α1. Zolpidem reduced one component (mean±s.d.: 71%±41%), presumed to reflect α1-subtype binding, but not another (13%±22%), presumed to reflect α5. The proposed method for [(11)C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands.
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http://dx.doi.org/10.1038/jcbfm.2011.177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318150PMC
April 2012
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