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The Cochrane Database of Systematic... Sep 2020Antisocial personality disorder (AsPD) is associated with rule-breaking, criminality, substance use, unemployment, relationship difficulties, and premature death.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Antisocial personality disorder (AsPD) is associated with rule-breaking, criminality, substance use, unemployment, relationship difficulties, and premature death. Certain types of medication (drugs) may help people with AsPD. This review updates a previous Cochrane review, published in 2010.
OBJECTIVES
To assess the benefits and adverse effects of pharmacological interventions for adults with AsPD.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, 13 other databases and two trials registers up to 5 September 2019. We also checked reference lists and contacted study authors to identify studies.
SELECTION CRITERIA
Randomised controlled trials in which adults (age 18 years and over) with a diagnosis of AsPD or dissocial personality disorder were allocated to a pharmacological intervention or placebo control condition.
DATA COLLECTION AND ANALYSIS
Four authors independently selected studies and extracted data. We assessed risk of bias and created 'Summary of findings tables' and assessed the certainty of the evidence using the GRADE framework. The primary outcomes were: aggression; reconviction; global state/global functioning; social functioning; and adverse events.
MAIN RESULTS
We included 11 studies (three new to this update), involving 416 participants with AsPD. Most studies (10/11) were conducted in North America. Seven studies were conducted exclusively in an outpatient setting, one in an inpatient setting, and one in prison; two studies used multiple settings. The average age of participants ranged from 28.6 years to 45.1 years (overall mean age 39.6 years). Participants were predominantly (90%) male. Study duration ranged from 6 to 24 weeks, with no follow-up period. Data were available from only four studies involving 274 participants with AsPD. All the available data came from unreplicated, single reports, and did not allow independent statistical analysis to be conducted. Many review findings were limited to descriptive summaries based on analyses carried out and reported by the trial investigators. No study set out to recruit participants on the basis of having AsPD; many participants presented primarily with substance abuse problems. The studies reported on four primary outcomes and six secondary outcomes. Primary outcomes were aggression (six studies) global/state functioning (three studies), social functioning (one study), and adverse events (seven studies). Secondary outcomes were leaving the study early (eight studies), substance misuse (five studies), employment status (one study), impulsivity (one study), anger (three studies), and mental state (three studies). No study reported data on the primary outcome of reconviction or the secondary outcomes of quality of life, engagement with services, satisfaction with treatment, housing/accommodation status, economic outcomes or prison/service outcomes. Eleven different drugs were compared with placebo, but data for AsPD participants were only available for five comparisons. Three classes of drug were represented: antiepileptic; antidepressant; and dopamine agonist (anti-Parkinsonian) drugs. We considered selection bias to be unclear in 8/11 studies, attrition bias to be high in 7/11 studies, and performance bias to be low in 7/11 studies. Using GRADE, we rated the certainty of evidence for each outcome in this review as very low, meaning that we have very little confidence in the effect estimates reported. Phenytoin (antiepileptic) versus placebo One study (60 participants) reported very low-certainty evidence that phenytoin (300 mg/day), compared to placebo, may reduce the mean frequency of aggressive acts per week (phenytoin mean = 0.33, no standard deviation (SD) reported; placebo mean = 0.51, no SD reported) in male prisoners with aggression (skewed data) at endpoint (six weeks). The same study (60 participants) reported no evidence of difference between phenytoin and placebo in the number of participants reporting the adverse event of nausea during week one (odds ratio (OR) 1.00, 95% confidence interval (CI) 0.06 to 16.76; very low-certainty evidence). The study authors also reported that no important side effects were detectable via blood cell counts or liver enzyme tests (very low-certainty evidence). The study did not measure reconviction, global/state functioning or social functioning. Desipramine (antidepressant) versus placebo One study (29 participants) reported no evidence of a difference between desipramine (250 to 300 mg/day) and placebo on mean social functioning scores (desipramine = 0.19; placebo = 0.21), assessed with the family-social domain of the Addiction Severity Index (scores range from zero to one, with higher values indicating worse social functioning), at endpoint (12 weeks) (very low-certainty evidence). Neither of the studies included in this comparison measured the other primary outcomes: aggression; reconviction; global/state functioning; or adverse events. Nortriptyline (antidepressant) versus placebo One study (20 participants) reported no evidence of a difference between nortriptyline (25 to 75 mg/day) and placebo on mean global state/functioning scores (nortriptyline = 0.3; placebo = 0.7), assessed with the Symptom Check List-90 (SCL-90) Global Severity Index (GSI; mean of subscale scores, ranging from zero to four, with higher scores indicating greater severity of symptoms), at endpoint (six months) in men with alcohol dependency (very low-certainty evidence). The study measured side effects but did not report data on adverse events for the AsPD subgroup. The study did not measure aggression, reconviction or social functioning. Bromocriptine (dopamine agonist) versus placebo One study (18 participants) reported no evidence of difference between bromocriptine (15 mg/day) and placebo on mean global state/functioning scores (bromocriptine = 0.4; placebo = 0.7), measured with the GSI of the SCL-90 at endpoint (six months) (very low-certainty evidence). The study did not provide data on adverse effects, but reported that 12 patients randomised to the bromocriptine group experienced severe side effects, five of whom dropped out of the study in the first two days due to nausea and severe flu-like symptoms (very low-certainty evidence). The study did not measure aggression, reconviction and social functioning. Amantadine (dopamine agonist) versus placebo The study in this comparison did not measure any of the primary outcomes.
AUTHORS' CONCLUSIONS
The evidence summarised in this review is insufficient to draw any conclusion about the use of pharmacological interventions in the treatment of antisocial personality disorder. The evidence comes from single, unreplicated studies of mostly older medications. The studies also have methodological issues that severely limit the confidence we can draw from their results. Future studies should recruit participants on the basis of having AsPD, and use relevant outcome measures, including reconviction.
Topics: Adult; Aggression; Alcohol-Related Disorders; Amantadine; Antisocial Personality Disorder; Anxiety; Bromocriptine; Desipramine; Female; Humans; Male; Middle Aged; Nortriptyline; Phenytoin; Placebos; Psychotropic Drugs; Randomized Controlled Trials as Topic
PubMed: 32880105
DOI: 10.1002/14651858.CD007667.pub3 -
Nuclear Medicine and Biology 2022Meta-[At]astato-benzylguanidine ([At]MABG) accumulates in pheochromocytoma via norepinephrine transporter (NET) and leads to a strong antitumor effect, but it also...
INTRODUCTION
Meta-[At]astato-benzylguanidine ([At]MABG) accumulates in pheochromocytoma via norepinephrine transporter (NET) and leads to a strong antitumor effect, but it also distributed in normal tissues non-specifically. Meta-[I]iodo-benzylguanidine ([I]MIBG), an iodine-labeled analog of [At]MABG, is known to be transported by not only NET but also organic cation transporter (OCT). The involvement of OCT in [At]MABG uptake is still largely unknown. We investigated the involvement of OCT in the non-NET-driven uptake of [At]MABG both in vitro and in vivo.
METHODS
[I]MIBG and [At]MABG uptake was investigated in PC-12 (rat pheochromocytoma cell line), NIH/3T3 (mouse fibroblasts cell line), ACHN (human renal cancer cell line), and BxPC-3 (human pancreatic cancer cell line). Herein, we used desipramine and dl-norepinephrine to inhibit NET, and we used steroids (hydrocortisone and prednisolone) to inhibit OCT3. The [At]MABG uptake in OCT3-knockdown cells established with OCT3-selective siRNA was also investigated. We investigated the biodistribution of [At]MABG in PC-12 tumor-bearing mice after a preloading of phosphate-buffered saline (PBS) or hydrocortisone solution.
RESULTS
The uptake of both [I]MIBG and [At]MABG was significantly inhibited by desipramine in PC-12 cells but not the other cell lines. The expression of OCT3 was relatively higher than those of the other OCT subtypes in ACHN and BxPC-3 cells. The expression of OCTs was not observed in NIH/3T3 cells. The uptake of both [I]MIBG and [At]MABG in ACHN and BxPC-3 cells was significantly inhibited by the steroid treatments. The [At]MABG uptake was also reduced in OCT3-knockdown cells (p < 0.001). The radioactivity of [At]MABG was significantly reduced in normal tissues by the preloading of hydrocortisone. In contrast, there was an increasing trend of [At]MABG uptake in the PC-12 tumors. The tumor-to-normal tissue ratio was significantly increased by the preloading of hydrocortisone compared to that of PBS.
CONCLUSION
Our results suggest that OCT3 is involved in non-NET-driven [At]MABG uptake. The preloading of hydrocortisone selectively reduced [At]MABG accumulation in normal organs in vivo. OCT3 inhibition may therefore be beneficial for a reduction of the radiation risk in healthy organs in the treatment of malignant pheochromocytomas.
Topics: 3-Iodobenzylguanidine; Adrenal Gland Neoplasms; Animals; Cations; Desipramine; Guanidines; Humans; Hydrocortisone; Iodine Radioisotopes; Mice; Norepinephrine Plasma Membrane Transport Proteins; Pheochromocytoma; Phosphates; Prednisolone; RNA, Small Interfering; Rats; Tissue Distribution
PubMed: 35802985
DOI: 10.1016/j.nucmedbio.2022.06.005 -
Journal of Psychiatric Research Jun 2022Tricyclic antidepressants (TCAs) are frequently prescribed in case of non-response to first-line antidepressants in Major Depressive Disorder (MDD). Treatment of MDD... (Review)
Review
Tricyclic antidepressants (TCAs) are frequently prescribed in case of non-response to first-line antidepressants in Major Depressive Disorder (MDD). Treatment of MDD often entails a trial-and-error process of finding a suitable antidepressant and its appropriate dose. Nowadays, a shift is seen towards a more personalized treatment strategy in MDD to increase treatment efficacy. One of these strategies involves the use of biomarkers for the prediction of antidepressant treatment response. We aimed to summarize biomarkers for prediction of TCA specific (i.e. per agent, not for the TCA as a drug class) treatment response in unipolar nonpsychotic MDD. We performed a systematic search in PubMed and MEDLINE. After full-text screening, 36 papers were included. Seven genetic biomarkers were identified for nortriptyline treatment response. For desipramine, we identified two biomarkers; one genetic and one nongenetic. Three nongenetic biomarkers were identified for imipramine. None of these biomarkers were replicated. Quality assessment demonstrated that biomarker studies vary in endpoint definitions and frequently lack power calculations. None of the biomarkers can be confirmed as a predictor for TCA treatment response. Despite the necessity for TCA treatment optimization, biomarker studies reporting drug-specific results for TCAs are limited and adequate replication studies are lacking. Moreover, biomarker studies generally use small sample sizes. To move forward, larger cohorts, pooled data or biomarkers combined with other clinical characteristics should be used to improve predictive power.
Topics: Antidepressive Agents; Antidepressive Agents, Tricyclic; Biomarkers; Depressive Disorder, Major; Humans; Nortriptyline
PubMed: 35397333
DOI: 10.1016/j.jpsychires.2022.03.057 -
The Medical Letter on Drugs and... Mar 2020
Topics: Constipation; Diarrhea; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome
PubMed: 32324172
DOI: No ID Found -
Frontiers in Cellular Neuroscience 2022It is known that overexpression of -methyl-D-aspartate receptors (NMDARs) contributes to central sensitization and development of neuropathic pain. Tricyclic...
It is known that overexpression of -methyl-D-aspartate receptors (NMDARs) contributes to central sensitization and development of neuropathic pain. Tricyclic antidepressants (TCAs), amitriptyline (ATL), and desipramine (DES) exhibit analgetic anti-NMDAR activity and are commonly utilized for pain therapy. This property is determined by their ability to enhance the calcium-dependent desensitization (CDD) of NMDARs. Coincidently ethanol and cholesterol, the ubiquitous food supplements, also modulate NMDAR CDD. The convergence of the effects of these compounds on a similar calcium-dependent process allows to assume their interaction on NMDARs. Since there is no information on whether ethanol supplementation and cholesterol deficit interfere with TCA inhibition of NMDARs at a cellular level, here we investigated this issue. Whole-cell NMDA-activated currents were recorded in rat cortical neurons of primary cultures to study how the IC values for TCA inhibition of NMDARs are influenced by ethanol and cholesterol extraction from the plasma membrane with methyl-β-cyclodextrin. Ethanol at 0.03% did not reliably affect the steady-state NMDA-activated currents. At this threshold concentration ethanol, however, increased ICs for ATL and DES abolishing their calcium-dependent inhibition of NMDARs but did not change IC for clomipramine (CLO), which is calcium-independent. Whereas the ethanol effects on ATL-induced NMDAR inhibition reached a maximum at 2 mM external [Ca], for DES the maximum was achieved already at 1 mM external [Ca], that correlates with the manifestation of the calcium-dependent inhibition of NMDARs by these agents. Cholesterol depletion also increased ICs for both ATL and DES abolishing the calcium-dependent inhibition of NMDARs. The restitution of cholesterol in the plasma membrane reversed the ATL IC back to the low values, by a restoration of calcium-dependence of ATL. These observations are consistent with the explanation that either 0.03% ethanol or cholesterol extraction may interrupt some intermediate step of CDD transduction or augment NMDAR CDD to the maximal level so that ATL and DES could not further enhance CDD. It is likely that anti-NMDAR action of ATL and DES against neuropathic pain could demonstrate peculiarities in therapeutic profiles during cholesterol decline in aging or medical treatments and ethanol supplementations even in quantities that are insufficient to cause the symptoms of intoxication.
PubMed: 35860312
DOI: 10.3389/fncel.2022.946426 -
Therapeutic Advances in... 2024Tricyclic antidepressants (TCAs) remain widely prescribed for depression and many other conditions. There may be important differences between individual TCA in regard... (Review)
Review
Tricyclic antidepressants (TCAs) remain widely prescribed for depression and many other conditions. There may be important differences between individual TCA in regard to their overdose toxicity and their cardiac toxicity in clinical use. We conducted a systematic review to compare the toxicity of individual TCA in overdose and the risk of serious adverse cardiac events occurring with therapeutic doses. We used the fatal toxicity index (FTI) and case fatality ratio as markers of fatality in overdose, and hazard ratios or odds ratios for the risk of cardiovascular adverse events during normal clinical use. In all, 30 reports of mortality in overdose and 14 observational studies assessing the risk of cardiovascular adverse events in clinical use were included. FTI values were of the same order of magnitude (10-10) for all TCAs except lofepramine. Desipramine appears to be somewhat more likely than other TCAs to lead to death in overdose. Amitriptyline, clomipramine, dothiepin/dosulepin, doxepin, trimipramine and imipramine showed broadly similar toxicity and were usually reported to be less toxic than desipramine. Data on nortriptyline were contradictory. Lofepramine had the lowest risk of death in overdose. The rank order of overdose toxicity was broadly consistent between different FTI definitions and between markers used. With respect to the risk of cardiovascular events at clinically relevant exposure, amitriptyline, nortriptyline and lofepramine were associated with a greater risk of in-use cardiotoxicity. All measures of overdose toxicity were subject to external influences and confounding. The continued use of TCAs in depression and other conditions should be minimized when considering their undoubted toxicity in overdose and possible toxicity in normal clinical use.
PubMed: 38827015
DOI: 10.1177/20451253241243297 -
Journal of Separation Science Nov 2023This study introduces a reliable and inexpensive magnetic dispersive solid phase extraction to extract imipramine and its primary metabolite (desipramine) from urine...
This study introduces a reliable and inexpensive magnetic dispersive solid phase extraction to extract imipramine and its primary metabolite (desipramine) from urine samples. To accomplish this aim, Fe O magnetic nanoparticles were synthesized by sonication, subsequently, polycarbonate was precipitated gradually onto the surface of them to form the adsorbent. Extraction recoveries of 85% and 76%, enrichment factors of 57 and 51, limits of detection of 2.5 and 2.8 μg/L, and limits of quantification of 8.3 and 9.3 μg/L were obtained for imipramine and desipramine under the optimal conditions, respectively. In addition, relative standard deviations for intra- (n = 6) and inter-day (n = 5) precisions at two concentrations (50 and 100 μg/L of each analyte) were less than or equal to 4%. Short extraction time, good repeatability, high enrichment factors, and simplicity are the main advantages of the proposed method.
Topics: Imipramine; Desipramine; Magnetite Nanoparticles; Solid Phase Extraction; Chromatography, High Pressure Liquid; Magnetic Phenomena
PubMed: 37691072
DOI: 10.1002/jssc.202300323 -
Journal of Clinical Pharmacology May 2024This study investigated the differences in the pharmacokinetics (PK) of dextromethorphan and desipramine in healthy African volunteers to understand the effect of...
Investigation of the Differences in the Pharmacokinetics of CYP2D6 Substrates, Desipramine, and Dextromethorphan in Healthy African Subjects Carrying the Allelic Variants CYP2D6*17 and CYP2D6*29, When Compared with Normal Metabolizers.
This study investigated the differences in the pharmacokinetics (PK) of dextromethorphan and desipramine in healthy African volunteers to understand the effect of allelic variants of the human cytochrome P450 2D6 (CYP2D6) enzyme, namely the diplotypes of CYP2D6*1/*2 (*1*1, *1*2, *2*2) and the genotypes of CYP2D6*17*17 and CYP2D6*29*29. Overall, 28 adults were included and split into 3 cohorts after genotype screening: CYP2D6*1/*2 (n = 12), CYP2D6*17*17 (n = 12), and CYP2D6*29*29 (n = 4). Each subject received a single oral dose of dextromethorphan 30 mg syrup on day 1 and desipramine 50 mg tablet on day 8. The PK parameters of area under the plasma concentration-time curve from time of dosing to time of last quantifiable concentration (AUC), and extrapolated to infinity (AUC), and the maximum plasma concentration (C) were determined. For both dextromethorphan and desipramine, AUC and C were higher in subjects of the CYP2D6*29*29 and CYP2D6*17*17 cohorts, as compared with subjects in the CYP2D6*1/*2 diplotype cohort and with normal metabolizers from the literature. All PK parameters, including AUC, C, and the elimination half-life, followed a similar trend: CYP2D6*17*17 > CYP2D6*29*29 > CYP2D6*1/*2. The plasma and urinary drug/metabolite exposure ratios of both drugs were higher in subjects of the CYP2D6*17*17 and CYP2D6*29*29 cohorts, when compared with subjects in the CYP2D6*1/*2 diplotype cohort. All adverse events were mild, except in 1 subject with CYP2D6*17*17 who had moderately severe headache with desipramine. These results indicate that subjects with CYP2D6*17*17 and CYP2D6*29*29 genotypes were 5-10 times slower metabolizers than those with CYP2D6*1/*2 diplotypes. These findings suggest that dose optimization may be required when administering CYP2D6 substrate drugs in African patients. Larger studies can further validate these findings.
Topics: Humans; Dextromethorphan; Desipramine; Cytochrome P-450 CYP2D6; Adult; Male; Female; Genotype; Young Adult; Alleles; Healthy Volunteers; Area Under Curve; Black People; Middle Aged; Half-Life; Antidepressive Agents, Tricyclic
PubMed: 37803948
DOI: 10.1002/jcph.2366 -
Sleep Medicine Mar 2024The hippocampus (HPC) plays a pivotal role in fear learning and memory. Our two recent studies suggest that rapid eye movement (REM) sleep via the HPC downregulates fear...
The hippocampus (HPC) plays a pivotal role in fear learning and memory. Our two recent studies suggest that rapid eye movement (REM) sleep via the HPC downregulates fear memory consolidation and promotes fear extinction. However, it is not clear whether and how the dorsal and the ventral HPC regulates fear memory differently; and how the HPC in wake regulates fear memory. By chemogenetic stimulating in the HPC directly and its afferent entorhinal cortex that selectively activated the HPC in REM sleep for 3-6 h post-fear-acquisition, we found that HPC activation in REM sleep consolidated fear extinction memory. In particular, dorsal HPC (dHPC) stimulation in REM sleep virtually eliminated fear memory by enhancing fear extinction and reducing fear memory consolidation. By contrast, chemogenetic stimulating HPC afferent the supramammillary nucleus (SUM) induced 3-hr wake with HPC activation impaired fear extinction. Finally, desipramine (DMI) injection that selectively eliminated REM sleep for >6 h impaired fear extinction. Our results demonstrate that the HPC is critical for fear memory regulation; and wake HPC and REM sleep HPC have an opposite role in fear extinction of respective impairment and consolidation.
Topics: Humans; Fear; Extinction, Psychological; Sleep; Learning; Hippocampus; Memory Consolidation
PubMed: 38367358
DOI: 10.1016/j.sleep.2024.02.022 -
Pharmacological Reports : PR Aug 2022The preclinical antidepressant-like characterization of desipramine relied almost exclusively in male rodents, with only a few contradictory reports done in females....
BACKGROUND
The preclinical antidepressant-like characterization of desipramine relied almost exclusively in male rodents, with only a few contradictory reports done in females. Given that most experiments assessed a single dose and/or timepoint of analysis after-treatment, this study evaluated potential sex-differences in the length of the antidepressant-like response induced by different doses of desipramine as well as the molecular underpinnings driving the different responses by sex.
METHODS
Male and female Sprague-Dawley rats were treated (i.p.) with 3 pulses of desipramine (5, 10 or 20 mg/kg) or vehicle (0.9% NaCl) within 24 h. The antidepressant-like effects were evaluated in the forced-swim test 1-h, 1- and 3-day post-treatment. The rate of cell proliferation and the regulation of key neuroplasticity markers (FADD, Cdk5, p35, p25) involved in antidepressant-like responses in the hippocampus were evaluated 1-h, 1-day and 5-day post-treatment.
RESULTS
Desipramine induced similar antidepressant-like effects in male and female rats (effective doses of 10 and 20 mg/kg, with effects that lasted up to 1-day post-treatment), without altering the rate of cell proliferation. However, some sex-differences emerged when evaluating neuroplasticity markers in the hippocampus, while no changes were observed for female rats, desipramine regulated FADD, Cdk-5 and p25 in males in a way that suggested neuroprotective actions.
CONCLUSIONS
Our findings imply that while desipramine induced similar antidepressant-like responses for male and female rats, some differences emerged in the regulation of certain neuroplasticity markers, suggesting that distinctive molecular mechanisms might be participating in the therapeutic response of desipramine for both sexes.
Topics: Animals; Antidepressive Agents; Desipramine; Female; Hippocampus; Male; Rats; Rats, Sprague-Dawley; Swimming
PubMed: 35653030
DOI: 10.1007/s43440-022-00372-1