Discontinuation of psychotropic medication: a synthesis of evidence across medication classes.

Pharmacotherapy is an effective treatment modality across psychiatric disorders. Nevertheless, many patients discontinue their medication at some point. Evidence-based guidance for patients, clinicians, and policymakers on rational discontinuation strategies is vital to enable the best, personalized treatment for any given patient. Nonetheless, there is a scarcity of guidelines on discontinuation strategies. In this perspective, we therefore summarize and critically appraise the evidence on discontinuation of six major psychotropic medication classes: antidepressants, antipsychotics, benzodiazepines, mood stabilizers, opioids, and stimulants. For each medication class, a wide range of topics pertaining to each of the following questions are discussed: (1) Who can discontinue (e.g., what are risk factors for relapse?); (2) When to discontinue (e.g., after 1 year or several years of antidepressant use?); and (3) How to discontinue (e.g., what's the efficacy of dose reduction compared to full cessation and interventions to mitigate relapse risk?). We thus highlight how comparing the evidence across medication classes can identify knowledge gaps, which may pave the way for more integrated research on discontinuation.

The Relationship of Early Sleep Improvement With Response to Pharmacotherapy in Unipolar Psychotic Depression.

BACKGROUND: Since insomnia and depression are interrelated, improved sleep early in antidepressant pharmacotherapy may predict a positive treatment outcome. We investigated whether early insomnia improvement (EII) predicted treatment outcome in psychotic depression (PD) and examined if there was an interaction effect between EII and treatment type to assess if findings were treatment-specific. METHODS: This study is a secondary analysis of a randomized trial comparing 7 weeks treatment with the antidepressants venlafaxine, imipramine and venlafaxine plus the antipsychotic quetiapine in PD ( n = 114). Early insomnia improvement, defined as ≥20% reduced insomnia after 2 weeks, was assessed by the Hamilton Rating Scale for Depression (HAM-D-17). Associations between EII and treatment outcome were examined using logistic regressions. Subsequently, we added interaction terms between EII and treatment type to assess interaction effects. The predictive value of EII was compared with early response on overall depression (≥20% reduced HAM-D-17 score after 2 weeks). RESULTS: EII was associated with response (odds ratio [OR], 7.9; 95% confidence interval [CI], 2.7-23.4; P = <0.001), remission of depression (OR, 6.1; 95% CI, 1.6-22.3; P = 0.009), and remission of psychosis (OR, 4.1; 95% CI, 1.6-10.9; P = 0.004). We found no interaction effects between EII and treatment type on depression outcome. Early insomnia improvement and early response on overall depression had a comparable predictive ability for treatment outcome. CONCLUSIONS: Early insomnia improvement was associated with a positive outcome in pharmacotherapy of PD, regardless of the medication type. Future studies are needed to confirm our findings and to examine the generalizability of EII as predictor in treatment of depression.

Effect of Past Pharmacotherapy for Attention-Deficit/Hyperactivity Disorder on Substance Use Disorder.

BACKGROUND: Substance use disorders (SUDs) are a considerable public health problem. Attention-deficit/hyperactivity disorder (ADHD) frequently occurs in patients with SUD. Several studies demonstrated that ADHD constitutes a significant risk factor for the development of SUDs and suggest that childhood ADHD pharmacotherapy might help prevent development of SUD. OBJECTIVES: The study aimed to explore the effect of childhood ADHD pharmacotherapy on later life's functional impairment and substance use patterns. METHODS: Treatment-seeking SUD patients with ADHD (n = 52) were recruited from various rehabilitation facilities in South Africa. Adult ADHD individuals without SUD (n = 48) were recruited from clinicians, retail pharmacies, and the general public. SUD participants in rehabilitation facilities were screened for and diagnosed with ADHD. Lifetime substance use was assessed using self-report. ADHD-related functional impairment was assessed by the Weiss Functional Impairment Rating Scale (WFIRS). Information on present and lifetime use of ADHD medication was obtained. Clinical outcomes between those with and without a history of ADHD pharmacotherapy were compared. RESULTS: Medicated participants (n = 59) showed lower levels of ADHD-related impairment across all functional domains (p < 0.001), compared to non-medicated participants (n = 41). They also consumed less alcohol (p = 0.04), cannabis (p < 0.001), and illicit drugs (p = 0.006) compared to the non-medicated group. Furthermore, medicated participants had a lower frequency of tobacco use compared to non-medicated participants (p = 0.04). ADHD patients without SUD also more often received medication (100% vs. 18.6%; p < 0.001) and for a longer time (121.10 vs. 9.52 months; p < 0.001). CONCLUSION: Childhood ADHD pharmacotherapy might be associated with a decreased risk for substance use in adulthood and lower ADHD-related impairment. Despite study limitations, these findings underline the importance of early ADHD detection and treatment, which might prevent SUD.

Patients' Perspectives on the Development of Prescription Opioid Use Disorder in Patients with Chronic Non-Cancer Pain.

INTRODUCTION: In the past decade, prescription opioid use increased exponentially and concomitantly opioid use disorders (OUD) are becoming more common. Several risk factors for developing OUD have been identified, but little is known regarding the patients' perspective on developing a prescription OUD. METHODS: We recruited 25 adults undergoing treatment for prescription OUD. In-depth, semi-structured interviews focussed on experiences with long-term opioid use, knowledge and attitudes regarding opioids, and access to opioids. A directed content analysis was conducted on the transcribed interviews using NVivo. RESULTS: Participants showed that the development of an OUD is affected by various factors which could be grouped into three themes: (1) experiences driving initiation, (2) experiences driving continuation, and (3) experiences with prescription OUD. Besides the need for pain management, the dynamics of patient-provider communication, care coordination, provider vigilance, and environmental support all contributed to the way patients used their opioids. CONCLUSION: Patients' experiences illustrate that the first stage of the development of prescription OUD differs from the development of other substance addictions. Negative reinforcement might play a more prominent role in the early phase of prescription opioid use. Patients expressed a lack of guidance, both at the start of use and long-term use, easy access to new prescriptions and a lack of monitoring as main drivers of the development. Poorly controlled pain and subjective stress fuelled continuous opioid use.

Effectiveness of a group intervention to reduce sexual transmission risk behavior among MSM living with HIV: a non-randomized controlled pilot study.

ABSTRACTWith an annual incidence of about 1.5 million new infections, HIV is an ongoing public health concern. Sexual transmission risk behavior (STRB) is a main driver of the HIV epidemic in most Western countries, particularly among specific populations such as men who have sex with men (MSM). This quasi-experimental pilot study examined the effectiveness of a ten-session group intervention, aiming to reduce STRB among a high-risk subpopulation of MSM living with HIV. Self-reported STRB, impulsivity, mental health symptoms, and functional impairment were compared between the intervention group (n = 12) and a control group (n = 16). At baseline, participants in the intervention group had higher levels of STRB, impulsivity, mental health problems, and functional impairment, compared to the control group. A significant time-by-group interaction effect revealed that after the intervention, STRB, impulsivity, and functional impairment reduced in the intervention group to levels comparable to the control group. These findings suggest that a targeted behavioral intervention might be an effective strategy to reduce persistent STRB and related factors in MSM living with HIV. Future studies should confirm these findings in larger samples, using randomized designs.

Effects of substance misuse on inhibitory control in patients with attention-deficit/hyperactivity disorder.

Patients with attention-deficit/hyperactivity disorder (ADHD) are often diagnosed with comorbid substance misuse (SM), which is associated with poor treatment efficacy. Although literature indicates similar inhibitory control deficits in both conditions, it is unclear whether SM in ADHD exaggerates pre-existing deficits, with additive or distinct impairments in patients. Our aim was to examine SM effects on inhibitory control in ADHD. Behavioural and functional magnetic resonance imaging (fMRI) data from a stop-signal task were compared across ADHD patients with and without SM (ADHD + SM and ADHD-only, respectively) and controls (n = 33/group; 79 males, mean age 18.02 ± 2.45). To limit substance use disorder (SUD) trait effects, groups were matched for parental SUD. Overall, we found worse performance for ADHD-only and/or ADHD + SM compared with controls but no difference between the ADHD groups. Moreover, the ADHD groups showed decreased frontostriatal and frontoparietal activity during successful and failed stop trials. There were no differences between the ADHD groups in superior frontal nodes, but there was more decreased activation in temporal/parietal nodes in ADHD-only compared with ADHD + SM. During go-trials, ADHD + SM showed decreased activation in inferior frontal nodes compared with ADHD-only and controls. Findings during response inhibition showed deficits in inhibition and attentional processes for ADHD patients with and without SM. Despite no evidence for SM effects during response inhibition, results during go-trials suggest distinct effects on nodes that are associated with several executive functions. Future studies should investigate whether distinct deficits in ADHD + SM relate to poor treatment results and can direct development of distinct ADHD treatment strategies for these patients.

Effects of family history of substance use disorder on reward processing in adolescents with and without attention-deficit/hyperactivity disorder.

Patients with attention-deficit/hyperactivity disorder (ADHD) often develop early onset substance use disorder (SUD) and show poor treatment outcomes. Both disorders show similar reward-processing alterations, but it is unclear whether these are associated with familial vulnerability to SUD. Our aim was to investigate effects of family history of SUD (FH) on reward processing in individuals with and without ADHD, without substance misuse. Behavioural and functional magnetic resonance imaging (fMRI) data from a modified monetary incentive delay task were compared between participants with and without FH (FH positive [FH+]: n = 76 and FH negative [FH-]: n = 69; 76 with ADHD, aged 16.74 ± 3.14, 82 males), while accounting for continuous ADHD scores. The main analysis showed distinct positive association between ADHD scores and reaction times during neutral versus reward condition. ADHD scores were also positively associated with anticipatory responses of dorsolateral prefrontal cortex, independent of FH. There were no main FH effects on brain activation. Yet, FH+ participants showed distinct neural alterations in ventrolateral prefrontal cortex (VLPFC), dependent on ADHD. This was driven by positive association between ADHD scores and VLPFC activation during reward outcome, only in FH+. Sensitivity analysis with stricter SUD index showed hyperactivation of anterior cingulate cortex for FH+, independent of ADHD, during reward anticipation. There were no FH or ADHD effects on activation of ventral striatum in any analysis. Findings suggest both FH and ADHD effects in circuits of reward and attention/memory during reward processing. Future studies should examine whether these relate to early substance use initiation in ADHD and explore the need for adjusted SUD prevention strategies.

Cognitive Functioning in Long-Term Benzodiazepine Users.

BACKGROUND: Benzodiazepines are widely used in the treatment of anxiety disorders and sleep disturbances, but negative cognitive side effects have been reported after long-term use. Studies on the cognitive effects of long-term benzodiazepine use to date have typically included small samples and limited cognitive assessments. OBJECTIVES: This study examined cognitive performance on four cognitive domains in long-term benzodiazepine users, compared to normative data. Furthermore, it was examined whether sex, age, benzodiazepine dose, and state and trait anxiety moderated cognitive functioning in long-term benzodiazepine users. METHODS: Neuropsychological tests targeting different cognitive domains were administered to 92 patients with long-term benzodiazepine use who were accepted for enrolment into a benzodiazepine discontinuation programme in an academic hospital. Test scores were compared to a large normative data sample. RESULTS: Of the long-term benzodiazepine users, 20.7% could be classified as cognitively impaired across all domains, with the largest effects found in the domains processing speed and sustained attention, and an overall worse performance in women, an effect which appears to be moderated by state anxiety. No effects of age or benzodiazepine dose were found. CONCLUSIONS: These results extend those of earlier studies on benzodiazepine effects on specific cognitive domains. This study implies an overall detrimental cognitive effect in long-term benzodiazepine users rather than specific effects. Therefore, long-term benzodiazepine use should be avoided, and once present, tailored interventions aimed at tapering benzodiazepines are warranted.

Cognitive Impairments in Patients with GHB Use Disorder Predict Relapse in GHB Use.

BACKGROUND: The recreational use of gamma hydroxybutyrate (GHB) is associated with frequent overdoses, coma and the risk of developing GHB use disorder (GUD). Several studies suggest negative effects of GHB use or related comas on cognition. Since relapse rates are high in GUD and cognitive impairment has been associated with relapse in other substance use disorders, we aimed to (1) investigate the prevalence of cognitive impairment before and after detoxification, (2) analyse the relationship between GHB use, comas, and cognitive impairment, and (3) explore the association between cognitive impairment and relapse after detoxification in GUD patients. METHODS: In these secondary analyses of a prospective cohort study, a consecutive series of patients with GUD (n = 103) admitted for detoxification were recruited at six addiction care facilities in the Netherlands. The Montreal Cognitive Assessment (MoCA) was used to screen for cognitive impairments before and after detoxification. The follow-up duration for the assessment of relapse in GHB use was 3 months. RESULTS: A substantial number of patients with GUD screened positive for cognitive impairment before (56.3%) and after (30.6%) detoxification. Impairment on the MoCA memory domain was most frequent (58.8%). Cognitive impairment was not related to the severity of GUD or number of GHB-induced comas. Logistic regression analysis showed that only the memory score independently predicted relapse. DISCUSSION: Cognitive impairment seems highly prevalent among patients with GUD, possibly related to the risk of relapse. The absence of a relationship between the severity of GUD, level of GHB use, the number of GHB-induced comas, and cognitive impairment suggest that other factors may also contribute to the observed cognitive impairment.

Monitoring Opioids in Europe: The Need for Shared Definitions and Measuring Drivers of Opioid Use and Related Harms.

The past 20 years, the USA is facing a serious opioid crisis initiated by an increase in prescription opioid use. Europe has also seen an increase in prescription opioid use, but the extent of related harm is still largely unknown. Given the impact of the US opioid epidemic, it is important to closely monitor signs of emerging opioid-related problems to guarantee early warnings and timely actions. Shared and meaningful definitions for opioid use and related harms, and relevant information about specific drivers for opioid use and related problems are needed for an adequate policy response. In this commentary, we discuss these definitions, the need to know more about the specific drivers for increased opioid use, its related harm, and proposals for strategies to move forward. Policy recommendations include making a distinction between licit and illicit opioids when monitoring and reporting on opioid-related harm, and using oral morphine equivalents to quantify prescription opioid use in a clinically relevant and comparable manner. A major topic of further research is exploring unique and universal drivers of prescription opioid (mis)use across Europe, in particular the role of opioid diversion.

Barriers and Facilitators to Seek Help for Substance Use Disorder among Dutch Physicians: A Qualitative Study.

INTRODUCTION: Substance use disorders (SUDs) among physicians affect their health, quality of life, but potentially also their quality of care. Despite the availability of effective specific Physician Health Programs (PHPs), physicians with SUD often experience barriers when seeking professional help. Therefore, we studied barriers and facilitators when seeking help for SUD among physicians from a multiple perspective approach. METHODS: A qualitative design was adopted for 2 sub-studies. First, answers of 2 open-ended questions (about anticipated barriers and facilitators) of an existing questionnaire were analyzed. This questionnaire was filled out by 1,685 general physicians (response rate = 47%). The answers of these open-ended questions were coded inductively. Second, 21 semi-structured interviews (about experienced barriers and facilitators) were performed with physician SUD-patients, significant others, and PHP employees. Themes identified in the first sub-study were used to deductively code the interview transcripts. Results were reported in accordance with the Consolidated Criteria for Reporting Qualitative Research guidelines. RESULTS: Barriers were found at the level of the individual physician (negative feelings and lack of disease awareness), whereas facilitators were found at the level of social relationships (confrontation with SUD and social support) and health services (supportive approach, good accessibility, and positive image of services). The interviews emphasized the importance of nonjudgmental confrontation by social relationships in the process of seeking help for SUD. CONCLUSION: Physicians with SUD face barriers when seeking help for SUD mostly at the level of the individual physician. Health services and people around physicians with SUD could facilitate the help-seeking process by offering confidential and nonpunitive support. Future studies should explore whether the barriers and facilitators identified in this study also hold for other mental health issues.

Associations between the CADM2 gene, substance use, risky sexual behavior, and self-control: A phenome-wide association study.

Risky behaviors, such as substance use and unprotected sex, are associated with various physical and mental health problems. Recent genome-wide association studies indicated that variation in the cell adhesion molecule 2 (CADM2) gene plays a role in risky behaviors and self-control. In this phenome-wide scan for risky behavior, it was tested if underlying common vulnerability could be (partly) explained by pleiotropic effects of this gene and how large the effects were. Single nucleotide polymorphism (SNP)-level and gene-level association tests within four samples (25 and Up, Spit for Science, Netherlands Twin Register, and UK Biobank and meta-analyses over all samples (combined sample of 362,018 participants) were conducted to test associations between CADM2, substance- and sex-related risk behaviors, and various measures related to self-control. We found significant associations between the CADM2 gene, various risky behaviors, and different measures of self-control. The largest effect sizes were found for cannabis use, sensation seeking, and disinhibition. Effect sizes ranged from 0.01% to 0.26% for single top SNPs and from 0.07% to 3.02% for independent top SNPs together, with sufficient power observed only in the larger samples and meta-analyses. In the largest cohort, we found indications that risk-taking proneness mediated the association between CADM2 and latent factors for lifetime smoking and regular alcohol use. This study extends earlier findings that CADM2 plays a role in risky behaviors and self-control. It also provides insight into gene-level effect sizes and demonstrates the feasibility of testing mediation. These findings present a good starting point for investigating biological etiological pathways underlying risky behaviors.

Successful treatment of severe, treatment resistant GHB withdrawal through thiopental-coma.

BACKGROUND: In patients with gamma-hydroxybutyrate (GHB) use disorder (GUD), withdrawal can have a fulminant course with rapid progression of severe, potentially life-threatening complications. Case: We present a 45-year old man with severe GHB withdrawal, resistant to conventional treatment with pharmaceutical GHB, high doses of benzodiazepines and baclofen. GHB withdrawal finally responded to thiopental-induced coma therapy, with burst suppression pattern on electroencephalography (EEG). The patient fully recovered, without withdrawal or residual neuropsychiatric symptoms. Discussion: To our knowledge, this is the first case report in which barbiturates were used to induce a coma to treat severe, treatment resistant GHB withdrawal. This case suggests barbiturate coma therapy might be considered in severe GHB withdrawal which does not respond to conventional treatment.

The relationship between depressive symptoms, general psychopathology, and well-being in patients with major depressive disorder.

OBJECTIVE: In mental health care, treatment effects are commonly monitored by symptom severity measures. This study aimed to investigate the relationship between symptom severity and well-being in the treatment of patients with major depressive disorder (MDD). METHODS: Adult MDD outpatients (n = 77) were administered the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR), the Outcome Questionnaire (OQ-45), and the Mental Health Continuum-Short Form (MHC-SF) before treatment and 6 months later. RESULTS: Symptom severity correlated moderately with well-being at baseline and strongly at follow-up. Reliable change index scores showed improvement on the QIDS-SR, OQ-45, and MHC-SF in 65%, 59%, and 40%, respectively. A quarter of patients improved in symptom severity but not well-being (Inventory of Depressive Symptomatology-Self-Report [IDS-SR]: 25%; OQ-45: 24%). CONCLUSION: Findings suggest that symptom severity and subjective well-being are related, but distinct concepts. Several reasons for the stronger improvements in symptoms than in well-being are discussed.

Brain responses to anticipating and receiving beer: Comparing light, at-risk, and dependent alcohol users.

Impaired brain processing of alcohol-related rewards has been suggested to play a central role in alcohol use disorder. Yet, evidence remains inconsistent and mainly originates from studies in which participants passively observe alcohol cues or taste alcohol. Here, we designed a protocol in which beer consumption was predicted by incentive cues and contingent on instrumental action closer to real life situations. We predicted that anticipating and receiving beer (compared with water) would elicit activity in the brain reward network and that this activity would correlate with drinking level across participants. The sample consisted of 150 beer-drinking males, aged 18 to 25 years. Three groups were defined based on alcohol use disorders identification test (AUDIT) scores: light drinkers (n = 39), at-risk drinkers (n = 64), and dependent drinkers (n = 47). fMRI measures were obtained while participants engaged in the beer incentive delay task involving beer- and water-predicting cues followed by real sips of beer or water. During anticipation, outcome notification and delivery of beer compared with water, higher activity was found in a reward-related brain network including the dorsal medial prefrontal cortex, orbitofrontal cortex, and amygdala. Yet, no activity was observed in the striatum, and no differences were found between the groups. Our results reveal that anticipating, obtaining, and tasting beer activates parts of the brain reward network, but that these brain responses do not differentiate between different drinking levels.

Effects of Substance Misuse and Family History of Substance Use Disorder on Delay Discounting in Adolescents and Young Adults with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and substance use disorder (SUD) often co-occur. Both disorders are characterized by impulsive choice. However, little is known about the effects of substance misuse (SM) and family history of SUD (FH) on impulsive choice in ADHD-SUD comorbidity. Impulsive choice is also linked to callous-unemotional (CU) traits, which are suggested to play a role in ADHD-SUD comorbidity. Our aim was to examine the effects of (1) FH and (2) SM on impulsive choice, while exploring the role of CU traits. METHODS: Impulsive choice was assessed with the delay discounting (DD) task. We compared task performance across (1) ADHD patients and controls with or without FH of SUD (ADHD FH+: n = 86; ADHD FH-: n = 63; control FH+: n = 49; control FH-: n = 72; mean age of the whole sample [n = 270]: 16.39, SD: 3.43) and (2) family history-matched ADHD groups with and without SM and controls (ADHD + SM: n = 62; ADHD-only: n = 62; controls: n = 62; mean age of the whole sample [n = 186]: 18.01, SD: 2.71). Effects of CU traits were explored by adding this as a covariate in all analyses. RESULTS: (1) There was no main effect of FH on DD. (2) We found increased DD in ADHD + SM compared to ADHD-only and no difference between ADHD-only and controls. Finally, increased DD was associated with increased callous traits only in ADHD FH+ and control FH+. CONCLUSIONS: In adolescents and young adults with ADHD, high impulsive choice might only be present in those with comorbid SM and in an FH+ subgroup with high callous traits. This suggests that impulsive choice in ADHD might result from (1) effects of SM and (2) a combined effect of SUD vulnerability and high callousness. Future studies should investigate efficacy of early interventions, targeting CU traits.

Establishing the dopamine dependency of human striatal signals during reward and punishment reversal learning.

Drugs that alter dopamine transmission have opposite effects on reward and punishment learning. These opposite effects have been suggested to depend on dopamine in the striatum. Here, we establish for the first time the neurochemical specificity of such drug effects, during reward and punishment learning in humans, by adopting a coadministration design. Participants (N = 22) were scanned on 4 occasions using functional magnetic resonance imaging, following intake of placebo, bromocriptine (dopamine-receptor agonist), sulpiride (dopamine-receptor antagonist), or a combination of both drugs. A reversal-learning task was employed, in which both unexpected rewards and punishments signaled reversals. Drug effects were stratified with baseline working memory to take into account individual variations in drug response. Sulpiride induced parallel span-dependent changes on striatal blood oxygen level-dependent (BOLD) signal during unexpected rewards and punishments. These drug effects were found to be partially dopamine-dependent, as they were blocked by coadministration with bromocriptine. In contrast, sulpiride elicited opposite effects on behavioral measures of reward and punishment learning. Moreover, sulpiride-induced increases in striatal BOLD signal during both outcomes were associated with behavioral improvement in reward versus punishment learning. These results provide a strong support for current theories, suggesting that drug effects on reward and punishment learning are mediated via striatal dopamine.