Evaluation of an adapted version of the International Trauma Questionnaire for use by people with intellectual disabilities.

AIMS: The International Trauma Questionnaire (ITQ) is a novel assessment instrument that is aligned to the ICD-11 diagnoses of post-traumatic stress disorder (PTSD) and complex PTSD (CPTSD). The purpose of this study was to develop and evaluate an adapted version of the ITQ suitable for use by people with intellectual disabilities. METHODS: The ITQ-ID follows the original ITQ, using wording developed in collaboration with a focus group of people with intellectual disabilities The ITQ-ID was administered to 40 people with intellectual disabilities recruited from learning disability forensic and community settings, alongside a Trauma Information Form and the Impact of Event Scale-Intellectual Disabilities (IES-IDs). RESULTS: Most participants reported multiple traumatizing events. Around half of the participants met strict criteria for a diagnosis of PTSD, and around three quarters met looser criteria. Depending on definitions, between 66% and 93% of those who met criteria for PTSD also met criteria for a diagnosis of CPTSD. The ITQ-ID showed a single-component structure, with very good-to-excellent internal consistency, excellent test-retest reliability, and evidence of concurrent, discriminant, and content validity. SIGNIFICANCE: The results support the potential of the ITQ-ID for assessment of PTSD and CPTSD in people with intellectual disabilities in both clinical and research contexts and highlight the need for further validation work.

Models of Affective Illness: Chronic Mild Stress in the Rat.

This article describes a chronic mild stress (CMS) model for predicting antidepressant response and investigating mechanisms of antidepressant action in rats. Following exposure to a variety of mild stressors for several weeks, the rats' behavior is modified in several ways that parallel symptoms of depression. Among these is a substantial reduction in consumption of a 1% sucrose solution, which models the cardinal symptom of major depression, anhedonia. Our standard procedure employs a battery of behavioral tests, comprising weekly assessment of sucrose intake and, at the end of treatment, the elevated plus-maze and novel object recognition tests to assess the anxiogenic and dyscognitive effects of CMS. Chronic administration of antidepressant drugs reverses the decreased sucrose intake and other behavioral changes in these subjects. Also effective are second-generation antipsychotics. The CMS model can be employed in discovery programs to identify anti-anhedonic drugs (e.g., antidepressants and antipsychotics) that act more quickly than existing agents. While most antidepressants require 3 to 5 weeks to normalize behavior, some treatments provide a faster onset of action. For example, the CMS-induced deficits can be reversed by acute or sub-chronic application of treatments that act rapidly in depressed patients, such as deep brain stimulation (DBS), ketamine, and scopolamine, as well as several compounds that have yet to be tested in humans but have fast-onset antidepressant-like effects in animals, such as the 5-HT-1A biased agonists NLX-101 and GLYX-13. Application of the CMS model in Wistar-Kyoto (WKY) rats causes similar behavioral changes to those seen in Wistars, but these are not reversed by antidepressant treatment. However, WKY rats respond to DBS and ketamine, which are effective in patients who are antidepressant non-responders, establishing CMS in WKY rats as a model of treatment-resistant depression. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Induction of chronic mild stress in rats as a model of depression and treatment-resistant depression.

Optogenetic stimulation of transmission from prelimbic cortex to nucleus accumbens core overcomes resistance to venlafaxine in an animal model of treatment-resistant depression.

BACKGROUND: Our earlier study demonstrated that repeated optogenetic stimulation of afferents from ventral hippocampus (vHIP) to the prelimbic region of medial prefrontal cortex (mPFC) overcame resistance to antidepressant treatment in Wistar-Kyoto (WKY) rats. These results suggested that antidepressant resistance may result from an insufficiency of transmission from vHIP to mPFC. Here we examined whether similar effects can be elicited from major output of mPFC; the pathway from to nucleus accumbens core (NAc). METHOD: WKY rats were subjected to Chronic Mild Stress and were used in two sets of experiments: 1) they were treated acutely with optogenetic stimulation of afferents to NAc core originating from the mPFC, and 2) they were treated with chronic (5 weeks) venlafaxine (10 mg/kg) and/or repeated (once weekly) optogenetic stimulation of afferents to NAc originating from either mPFC or vHIP. RESULTS: Chronic mild stress procedure decreased sucrose intake, open arm entries on elevated plus maze, and novel object recognition test. Acute optogenetic stimulation of the mPFC-NAc and vHIP-NAc pathways had no effect in sucrose or plus maze tests, but increased object recognition. Neither venlafaxine nor mPFC-NAc optogenetic stimulation alone was effective in reversing the effects of CMS, but the combination of chronic antidepressant and repeated optogenetic stimulation improved behaviour on all three measures. CONCLUSIONS: The synergism between venlafaxine and mPFC-NAc optogenetic stimulation supports the hypothesis that the mechanisms of non-responsiveness of WKY rats involves a failure of antidepressant treatment to restore transmission in the mPFC-NAc pathway. Together with earlier results, this implicates insufficiency in a vHIP-mPFC-NAc circuit in non-responsiveness to antidepressant drugs.

Optogenetic stimulation of medial prefrontal cortex excites GABAergic cells in the nucleus accumbens and hippocampus of Wistar-Kyoto rats exposed to chronic mild stress.

BACKGROUND: High frequency optogenetic stimulation (OGS) of prelimbic cortex (PLC) has been reported to exert antidepressant-like effects in the chronic mild stress model of depression in Wistar Kyoto (WKY) rats, which are non-responsive to antidepressant drugs. Here we have examined the effect of OGS on activity in the PLC and in two other regions implicated in depression, the nucleus accumbens (NAc) and hippocampus (HPC). METHOD: OGS was applied to the PLC of WKY rats using the same stress schedule, and the identical placement, virus infection and stimulation parameters, used in the earlier behavioural experiments. Confocal microscopy was used to identify cells co-expressing the immediate early gene c-Fos and markers of GABAergic (GAD) and glutamatergic (CaMKII) neurons. RESULTS: Stress decreased sucrose intake, which was restored by OGS. Stress also caused an overall decrease in Fos expression in the structures examined. In stressed animals, but not in non-stressed controls, OGS in mPFC increased the number of Fos+ cells in both the core and shell of the NAc (where the vast majority of cells are GABAergic), and increased the number and proportion of active GABAergic, but not glutamatergic, cells in dorsal and ventral HPC and dentate gyrus. CONCLUSIONS: We conclude that OGS of PLC has a net excitatory effect on outputs from the PLC, leading to an overall inhibitory effect in structures innervated (NAc and HPC).

Perspectives for therapy of treatment-resistant depression.

A high proportion of depressed patients fail to respond to antidepressant drug treatment. Treatment-resistant depression (TRD) is a major challenge for the psychopharmacology of mood disorders. Only in the past decade have novel treatments, including deep brain stimulation (DBS) and ketamine, been discovered that provide rapid and sometimes prolonged relief to a high proportion of TRD sufferers. In this review, we consider the current status of TRD from four perspectives: the challenge of developing an appropriate regulatory framework for novel rapidly acting antidepressants; the efficacy of non-pharmacological somatic therapies; the development of an animal model of TRD and its use to understand the neural basis of antidepressant non-response; and the potential for rapid antidepressant action from targets (such as 5-HT1A receptors) beyond the glutamate receptor. LINKED ARTICLES: This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc.

Insufficiency of ventral hippocampus to medial prefrontal cortex transmission explains antidepressant non-response.

BACKGROUND: There is extensive evidence that antidepressant drugs restore normal brain function by repairing damage to ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC). While the damage is more extensive in hippocampus, the evidence of treatments, such as deep brain stimulation, suggests that functional changes in prefrontal cortex may be more critical. We hypothesized that antidepressant non-response may result from an insufficiency of transmission from vHPC to mPFC. METHOD: Antidepressant non-responsive Wistar Kyoto (WKY) rats were subjected to chronic mild stress (CMS), then treated with chronic daily administration of the antidepressant drug venlafaxine (VEN) and/or repeated weekly optogenetic stimulation (OGS) of afferents to mPFC originating from vHPC or dorsal HPC (dHPC). RESULTS: As in many previous studies, CMS decreased sucrose intake, open-arm entries on the elevated plus maze (EPM), and novel object recognition (NOR). Neither VEN nor vHPC-mPFC OGS alone was effective in reversing the effects of CMS, but the combination of chronic VEN and repeated OGS restored normal behaviour on all three measures. dHPC-mPFC OGS restored normal behaviour in the EPM and NOR test irrespective of concomitant VEN treatment, and had no effect on sucrose intake. CONCLUSIONS: The synergism between VEN and vHPC-mPFC OGS supports the hypothesis that the antidepressant non-responsiveness of WKY rats results from a failure of antidepressant treatment fully to restore transmission in the vHPC-mPFC pathway.

The Experiences of Carers of Adults With Intellectual Disabilities During the First COVID-19 Lockdown Period.

Background: The recent COVID-19 pandemic led to widespread international restrictions, severely impacting on health and social care services. For many individuals with an intellectual disability (ID) this meant reduced access to services and support for them and their carers. Aim: The aim of this study was to gain insight into the ways parents of adults with ID coped during the first 2020 lockdown period. Methods: Eight parents of adults with ID were interviewed. The recordings of these interviews were subjected to a thematic analysis. Results: Four main themes were identified: powerless and unappreciated; coping under lockdown; support; and the impact of lockdown on well-being. Conclusions: The parents of adults with ID who made up our sample reported that they received little support from services and experienced a sense of powerlessness. Nevertheless, they were open to accepting support from family and friends and showed remarkable resilience. These findings are discussed in the light of the Willner et al. (2020) survey results on parental mental health and coping, and suggestions for future service provision during pandemic conditions are proposed.

The experiences of mothers of children and young people with intellectual disabilities during the first COVID-19 lockdown period.

BACKGROUND: Recent COVID-19 lockdown restrictions resulted in reduced access to educational, professional and social support systems for children with intellectual disabilities and their carers. AIM: The aim of this study was to gain insight into the ways mothers of children with intellectual disabilities coped during the first 2020 lockdown period. METHODS: Eight mothers of children with intellectual disabilities were interviewed. The recordings of these interviews were subjected to a thematic analysis. RESULTS: Three main themes were identified: carrying the burden; a time of stress; and embracing change and looking to the future. CONCLUSIONS: All mothers experienced increased burden and stress. However, some also described some positive impact of lockdown conditions on them as well as on their child's well-being and behaviour. These findings are discussed in the light of the (Journal of Applied Research in Intellectual Disabilities, 33, 2020, 1523) survey results on parental coping and suggestions for future service provision during pandemic conditions are proposed.

AMPA receptors mediate the pro-cognitive effects of electrical and optogenetic stimulation of the medial prefrontal cortex in antidepressant non-responsive Wistar-Kyoto rats.

BACKGROUND: The chronic mild stress (CMS) procedure is a widely used animal model of depression, and its application in Wistar-Kyoto (WKY) rats has been validated as a model of antidepressant-refractory depression. While not responding to chronic treatment with antidepressant drugs, WKY rats do respond to acute deep brain stimulation (DBS) of the medial prefrontal cortex (mPFC). In antidepressant-responsive strains there is evidence suggesting a role for AMPA subtype of glutamate receptor in the action mechanism of both antidepressants and DBS. METHODS: Animals were subjected to CMS for 6 to 8 weeks; sucrose intake was monitored weekly and novel object recognition (NOR) test was conducted following recovery from CMS. Wistars were treated chronically with venlafaxine (VEN), while WKY were treated acutely with either DBS, optogenetic stimulation (OGS) of virally-transduced (AAV5-hSyn-ChR2-EYFP) mPFC or ventral hippocampus, or acute intra-mPFC injection of the AMPA receptor positive allosteric modulator CX-516. The AMPA receptor antagonist NBQX was administered, at identical sites in mPFC, immediately following the exposure trial in the NOR. RESULTS: Sucrose intake and NOR were suppressed by CMS, and restored by VEN in Wistars and by DBS, OGS, or CX-516 in WKY. However, OGS of the ventral hippocampal afferents to mPFC was ineffective. A low dose of NBQX selectively blocked the procognitive effect of VEN, DBS and OGS. CONCLUSIONS: These results suggest that activation of AMPA receptors in the mPFC represents a common pathway for the antidepressant effects of both conventional (VEN) and novel (DBS, OGS) antidepressant modalities, in both antidepressant responsive (Wistar) and antidepressant-resistant (WKY) rats.

Effect of the COVID-19 pandemic on the mental health of carers of people with intellectual disabilities.

INTRODUCTION: The measures implemented to manage the COVID-19 pandemic have been shown to impair mental health. This problem is likely to be exacerbated for carers. METHOD: Informal carers (mainly parents) of children and adults with intellectual disabilities, and a comparison group of parents of children without disabilities, completed an online questionnaire. Almost all the data were collected while strict lockdown conditions were in place. RESULTS: Relative to carers of children without intellectual disability, carers of both children and adults with intellectual disability had significantly greater levels of a wish fulfilment coping style, defeat/entrapment, anxiety, and depression. Differences were 2-3 times greater than reported in earlier pre-pandemic studies. Positive correlations were found between objective stress scores and all mental health outcomes. Despite their greater mental health needs, carers of those with intellectual disability received less social support from a variety of sources. CONCLUSIONS: The greater mental health needs of carers in the context of lesser social support raises serious concerns. We consider the policy implications of these findings.

Genomic Screening of Wistar and Wistar-Kyoto Rats Exposed to Chronic Mild Stress and Deep Brain Stimulation of Prefrontal Cortex.

Stress, a major precipitant of depression, and antidepressants have major impact on synaptic integrity and plasticity in brain areas, such as hippocampus (HPC) and prefrontal cortex (PFC). We have recently shown that, unlike Wistar rats, rats of the Wistar-Kyoto (WKY) strain fail to respond to chronic antidepressant treatment after exposure to chronic mild stress (CMS) procedure. However, deep brain stimulation (DBS) of PFC was effective in both strains. We aimed to identify genes that were affected by CMS, to determine whether their expression was normalized by DBS, and to establish whether common changes could be identified in antidepressant responsive (Wistar) and antidepressant-resistant (WKY) strains. Male Wistar and WKY rats were exposed chronically to CMS then treated acutely with DBS. A battery of behavioural tests was used to monitor recovery, followed by TaqMan screening of a panel of genes known to be involved in stress and antidepressant action. WKY showed over-expression of five genes in dorsal HPC and under-expression of seven genes in ventral HPC. Expression of three genes, Egr1, Htr7 and Mmp9 was decreased by CMS and normalized by DBS in the ventral HPC of Wistar rats. Some other changes in gene expression were identified in dorsal HPC and PFC, particularly in Wistars, that were not normalized by DBS. No effects were identified that were common to both Wistars and WKY. The difference between Wistars and WKY in the balance of overall gene expression in HPC may be relevant to the resistance of WKY rats to antidepressant drug treatment.