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A Randomized, Placebo-Controlled Trial of Citicoline Add-On Therapy in Outpatients With Bipolar Disorder and Cocaine Dependence
Abstract
Bipolar disorder is associated with the highest rates of substance abuse of any psychiatric disorder. Cocaine use is particularly common in patients with bipolar disorder. Both cocaine use and bipolar disorder are associated with mood symptoms and cognitive impairment. Therefore, treatments that stabilize mood, improve cognition, and reduce cocaine use would be useful. Citicoline modulates phospholipids metabolism and neurotransmitter levels and appears to improve cognition in some central nervous system disorders. A 12-week, randomized, placebo-controlled, parallel-group, add-on, proof-of-concept trial of citicoline was conducted in 44 outpatients with a history of mania or hypomania and cocaine dependence. The primary aim was to examine memory, but mood and cocaine use were also assessed.
Participants were evaluated with a structured diagnostic interview; Inventory of Depressive Symptomatology-Self-Report, Young Mania Rating Scale, and Rey Auditory Verbal Learning Test. Cocaine use was assessed with urine drug screens. Data were analyzed using mixed-model analysis of covariance, generalized estimating equations, and logistic regression analyses that used all of the available data.
A significant group effect (P = 0.006) favoring citicoline was observed on the Rey Auditory Verbal Learning Test alternative word list. No significant between-group differences were found on the Inventory of Depressive Symptomatology-Self-Report or Young Mania Rating Scale. The citicoline group had a significantly lower probability of a cocaine-positive urine at exit (P = 0.026). The covariate-adjusted odds ratio estimate was 6.41, suggesting that those who took placebo had 6.41-times higher odds of testing positive for cocaine at exit than those who took citicoline. Citicoline was well tolerated, with no participants to our knowledge discontinuing because of medication side effects.
The use of citicoline was associated with improvement relative to placebo in some aspects of declarative memory and cocaine use, but not mood. The findings are promising and suggest that larger trials of citicoline are warranted.
... Eight clinical trials met the selection criteria and were included in this review [44][45][46][47][48][49][50][51]. The details of these studies are presented in Table 1. ...
... Two randomized, placebo-controlled, proof-of-concept trials have evaluated the cognitive efficacy of citicoline in BD comorbid with substance use disorders, e.g. dual diagnosis [45,46]. Brown et al. (2007) conducted a 12-week RCT in outpatients with either BD or schizoaffective disorder, bipolar type, who were in early recovery from cocaine dependence [45]. ...
... dual diagnosis [45,46]. Brown et al. (2007) conducted a 12-week RCT in outpatients with either BD or schizoaffective disorder, bipolar type, who were in early recovery from cocaine dependence [45]. At baseline, patients were in different mood states, mostly depressed and mixed. ...
Bipolar disorder and major depression are associated with significant disability, morbidity, and reduced life expectancy. People with mood disorders have shown higher ratios of unhealthy lifestyle choices, including poor diet quality and suboptimal nutrition. Diet and nutrition impact on brain /mental health, but cognitive outcomes have been less researched in psychiatric disorders. Neurocognitive dysfunction is a major driver of social dysfunction and a therapeutic target in mood disorders, although effective cognitive-enhancers are currently lacking. This narrative review aimed to assess the potential cognitive benefits of dietary and nutritional interventions in subjects diagnosed with mood disorders. Eight clinical trials with nutrients were identified, whereas none involved dietary interventions. Efficacy to improve select cognitive deficits has been reported, but results are either preliminary or inconsistent. Methodological recommendations for future cognition trials in the field are advanced. Current evidence and future views are discussed from the perspectives of precision medicine, clinical staging, and nutritional psychiatry.
... Most of them induce their effect by increasing the serotonin levels in the brain [2,4,11] so that > 50% of depressed patients respond better to selective serotonin reuptake inhibitors (SSRIs), such as citalopram, sertraline, and fluoxetine [12][13][14]. Nowadays, depression treatment is usually performed by administering a combination of several drugs with a variety of mechanisms of action instead of using a single-drug [15,16]. Therefore, applications of new drugs and substances that can increase the effectiveness of antidepressants drug lead to a decrease in their administered dosages resulting in reduced side effects of their long-term use. ...
... In the present study, we used citicoline which has been found to be a supplemental drug with neuroprotective effects that reduces neuronal degeneration and increases the level of various neurotransmitters, such as acetylcholine, dopamine, norepinephrine, and serotonin, which improve management of some disorders and neurodegenerative diseases, such as stroke, traumatic brain damage, hypoxia, cerebrovascular disease, cerebral edema, Alzheimer, Parkinson as well as learning and memory disorders [15,17,18,21,23,[55][56][57]. Based on some of the studies, administration of citicoline in some patients with bipolar depression who were also addicted to stimulant drugs improved their mood disorder in addition to reducing their drug carving [15,21,23,55]. ...
... In the present study, we used citicoline which has been found to be a supplemental drug with neuroprotective effects that reduces neuronal degeneration and increases the level of various neurotransmitters, such as acetylcholine, dopamine, norepinephrine, and serotonin, which improve management of some disorders and neurodegenerative diseases, such as stroke, traumatic brain damage, hypoxia, cerebrovascular disease, cerebral edema, Alzheimer, Parkinson as well as learning and memory disorders [15,17,18,21,23,[55][56][57]. Based on some of the studies, administration of citicoline in some patients with bipolar depression who were also addicted to stimulant drugs improved their mood disorder in addition to reducing their drug carving [15,21,23,55]. Base on the present research, the citicoline in the higher doses (10 and 50 mg/kg) could reduce depression-like behavior induced by CUMS in mice. ...
... Nevertheless, Citicoline has been shown to treat these symptoms while also favouring better adhesion to the treatment, 26 although these results are not confirmed by other work groups. 33 In studies of rapid cycling BD patients Lamotrigine was not found to be effective, 27 and the classic treatment with lithium was shown to be effective in the treatment of psychiatric symptoms. 33 These studies base their conclusions on the use of a control group and the use of similar tests or instruments to measure the dependent variables, although their samples are sometimes small and suffer high rates of abandonment. ...
... 33 In studies of rapid cycling BD patients Lamotrigine was not found to be effective, 27 and the classic treatment with lithium was shown to be effective in the treatment of psychiatric symptoms. 33 These studies base their conclusions on the use of a control group and the use of similar tests or instruments to measure the dependent variables, although their samples are sometimes small and suffer high rates of abandonment. ...
... They often lack a control group and use small samples with major experimental death. When different interventions are compared, 33 ( community friendly integrated group therapy was found to be more effective than advisory groups on drugs, helping to reduce substance consumption and psychiatric symptoms, while giving a better clinical result in general. 46 Nevertheless, the drug advisory group and integrated group therapy were apparently effective in treating BD. 47 The management of contingencies was also found suitable for reducing the consumption of alcohol and stimulants, and it also increased the improvement in manic and depressive symptoms. ...
The aim of this study was to provide a descriptive overview of different psychological and pharmacological interventions used in the treatment of patients with bipolar disorder and substance abuse, in order to determine their efficacy. A review of the current literature was performed using the databases Medline and PsycINFO (2005–2015). A total of 30 experimental studies were grouped according to the type of therapeutic modality described (pharmacological 19; psychological 11). Quetiapine and valproate have demonstrated superiority on psychiatric symptoms and a reduction in alcohol consumption, respectively. Group psychological therapies with education, relapse prevention and family inclusion have also been shown to reduce the symptomatology and prevent alcohol consumption and dropouts. Although there seems to be some recommended interventions, the multicomponent base, the lack of information related to participants during treatment, experimental control or the number of dropouts of these studies suggest that it would be irresponsible to assume that there are well established treatments.
... This neuroprotective role leaded the clinician to perform clinical trials aimed to ascertain the efficacy of citicoline on stroke [8][9][10][11][12][13] and other neurodegenerative diseases (8,14,15). However, the effect of citicoline on stroke is elusive (for literary reviews see (16)(17)(18)(19), even more if take into account data from the latest clinical trials that failed to show beneficial results (20,21). ...
... In table II, we have summarized the eight clinical trials, including 1890 patients, which evaluated citicoline effects on memory function (9,10,13,15,23,37,38). ...
... but not in RAVLT total Word (p=0.439) or RAVLT delayed recall (p=0.105) (15). In addition, two more trials described a positive but not statistically significant tendency to improve memory in volunteering patients with relatively inefficient memory (9) or Alzheimer disease (10). ...
Background: Citicoline is considered an ingredient in particular foods in the USA and is available in pharmaceutical form in Europe and Japan. It has been postulated to render positive effects on the nervous system, either by increasing levels of neurotransmitters, or by affording neuroprotection. Methods: Several clinical trials have shown the efficacy and safety of this biomolecule in several neurodegenerative diseases and in acute ischemic stroke. Here, we have performed a systematic review to validate the effect of citicoline on MMSE, memory, attention, and basic activity of daily living. In electronic database searches, we found 14 randomized clinical trials reporting citicoline effects on cognitive function. Findings: A positive effect of citicoline on MMSE in acute ischemic stroke was found, which was not evidenced for Alzheimer disease or vascular dementia. On activities of daily living, citicoline failed to exert beneficial effects in patients with acute ischemic stroke or progressive cognitive impairment. Conclusions: Given the present data there is no evidence that supports advising patients with cognitive alterations to take chronic citicoline supplements.
... The lamotrigine group reported significantly fewer dollars spent on cocaine than the placebo group, with a trend in the same direction for days of cocaine use. We recently reported on a placebo-controlled pilot study of citicoline in 44 outpatients with bipolar disorder and cocaine dependence (19). The citicoline group was significantly less likely to have a cocaine-positive urine sample at study exit than the placebo group (odds ratio=6.41). ...
... Secondary aims included evaluating the impact of citicoline on depressive and manic symptoms and study retention. Citicoline was selected for this study because of our promising pilot data in this population (19) and the literature suggesting that cholinergic systems are critical to cocaine dependence (28). In addition, citicoline's favorable side effect profile and lack of known drug-drug interactions make it a potentially useful treatment option in dual-diagnosis patients. ...
... The sample size estimate was based on comparing the slopes for the two groups on the primary outcome measure and urine drug screens in an earlier pilot study (19). Group sample sizes of 65 in each group achieved 80% power to detect a standardized difference between the slopes of 0.44 (medium effect size), assuming that the standardized regression slope is 20.10 for the placebo group and 20.54 for the treatment group using a two-sided test with a significance threshold of 0.05. ...
Although drug dependence is common in patients with bipolar disorder, minimal data are available on the treatment of drug dependence in this patient population. The authors previously reported a decreased risk of relapse to cocaine use in a pilot study of citicoline in patients with bipolar disorder and cocaine dependence. The primary aim of the present study was to determine whether citicoline reduces cocaine use in outpatients with bipolar I disorder and current cocaine dependence and active cocaine use.
A total of 130 outpatients with bipolar I disorder (depressed or mixed mood state) and cocaine dependence received citicoline or placebo add-on therapy for 12 weeks. Results of thrice-weekly urine drug screens were analyzed using a generalized linear mixed model that was fitted to the binary outcome of cocaine-positive screens at each measurement occasion for 12 weeks. Mood was assessed with the Inventory of Depressive Symptomatology-Self Report, the Hamilton Depression Rating Scale, and the Young Mania Rating Scale.
In the intent-to-treat sample (N=61 in both groups), significant treatment group and group-by-time effects were observed, whether or not missing urine screens were imputed as cocaine positive. The group effect was greatest early in the study and tended to decline with time. No between-group differences in mood symptoms or side effects were observed.
Citicoline was well tolerated for treatment of cocaine dependence in patients with bipolar disorder. Cocaine use was significantly reduced with citicoline initially, although treatment effects diminished over time, suggesting the need for augmentation strategies to optimize long-term benefit.
... [1b,3] It has been postulated that CDP-choline restores the neuronal membrane integrity and functions by increasing the production of both PC and ACh and attenuating the formation of reactive oxygen species (ROS) at the nerve damage site. [3a] Clinical studies have established that administration of CDP-choline has beneficial effects on central nerve system disorders (memory impairment, Alzheimer's disease, and Parkinson's disease) [4] and injuries (stroke and brain/spinal cord trauma), [5] substance abuse, [6] and eye conditions (glaucoma and amblyopia). [7] Deoxycytidine diphosphate choline (dCDP-choline) has also been isolated from both human cells and sea urchin eggs, but its biological functions are still elusive. ...
... Ethanol precipitation of the sodium salts followed by ion exchange chromatography afforded 6-10 in high isolated yields ranging from 78-84%. SCHEME 1 The P(V)-N activation method for the synthesis of CDP-choline and related nucleotide analogs (6)(7)(8)(9)(10). a Isolated yield. ...
... Hz, 1P), -11.9 (d, J P-α,P-β = 20.8 Hz, 1P) ppm; IR: ν max 3671, 2988, 2899, 1645, 1488, 1392, 1234, 1063, 782, 634, 609, 552 cm 6,141.1,102.2,88.0,82.8,73.3,69.2,65.4,64.5,59.4,53.5 ppm;31 P NMR (162 MHz,D 2 O): δ -11.6 (d, J P-α,P-β = 21.0 Hz, 1P), -12.3 (d, J P-α,P-β = 21.0 ...
An efficient P(V)-N activation approach for the synthesis of cytidine diphosphate choline (CDP-choline) and related ribo- and deoxyribonucleotide analogs has been established.
... All studies used nonactive placebo comparators. For the BD studies, 7 studies investigated treatment effects in alcohol addiction comorbidity, 25-31 5 in stimulant addiction comorbidity, [32][33][34][35][36] and 1 in gambling disorder comorbidity (see Table 1). 37 For the MDD studies, 13 studies investigated treatment effects in alcohol addiction comorbidity 24,38-49 and 6 investigated treatment effects in other addiction comorbidities including cocaine, opiates, and nicotine addictions 50-55 (see Table 2). ...
... Quality assessment results are summarized in Supplemental Table 1. Ten studies were assessed as having a strong quality rating, 25,28,31,38,40,43,48,[53][54][55] 15 were assessed as having a moderate quality rating, 24,26,27,29,30,33,[35][36][37]44,46,49,50,52,56 and 7 were assessed as having a weak quality rating. 34,39,41,42,45,47,51 The Funnel plot (see Supplemental Figure 1) was asymmetrical suggesting that studies without statistically significant effects remain unpublished, particularly those with small participant sample sizes and those that investigated Yes Naltrexone associated at trend significance level with an improvement in alcohol consumption and craving but no effect on mood scores. ...
Objective:
Addiction comorbidity is an important clinical challenge in mood disorders, but the best way of pharmacologically treating people with mood disorders and addictions remains unclear. The aim of this study was to assess the efficacy of pharmacological treatments for mood and addiction symptoms in people with mood disorders and addiction comorbidity.
Methods:
A systematic search of placebo-controlled randomized controlled trials investigating the effects of pharmacological treatments in people with bipolar disorder (BD) or major depressive disorder (MDD), and comorbid addictions was performed. Treatment-related effects on mood and addiction measures were assessed in a meta-analysis, which also estimated risks of participant dropout and adverse effects.
Results:
A total of 32 studies met systematic review inclusion criteria. Pharmacological therapy was more effective than placebo for improving manic symptoms (standardized mean difference [SMD] = -0.15; 95% confidence interval [95% CI], -0.29 to -0.02; P = 0.03) but not BD depressive symptoms (SMD = -0.09; 95% CI, -0.22 to 0.03; P = 0.15). Quetiapine significantly improved manic symptoms (SMD = -0.23; 95% CI, -0.39 to -0.06; P = 0.008) but not BD depressive symptoms (SMD = -0.07; 95% CI, -0.23 to 0.10; P = 0.42). Pharmacological therapy was more effective than placebo for improving depressive symptoms in MDD (SMD = -0.16; 95% CI, -0.30 to -0.03; P = 0.02). Imipramine improved MDD depressive symptoms (SMD = -0.58; 95% CI, -1.03 to -0.13; P = 0.01) but Selective serotonin reuptake Inhibitors (SSRI)-based treatments had no effect (SMD = -0.06; 95% CI, -0.30 to 0.17; P = 0.60). Pharmacological treatment improved the odds of alcohol abstinence in MDD but had no effects on opiate abstinence.
Conclusions:
Pharmacological treatments were significantly better than placebo in improving manic symptoms, MDD depressive symptoms, and alcohol abstinence but were not better for bipolar depression symptoms. Importantly, quetiapine was not more effective than placebo in improving bipolar depression symptoms nor were SSRI's for the treatment of MDD depression. Our findings highlight the need for further high-quality clinical trials of treatments for mood disorders and comorbid addictions.
... There have been a modicum of studies in bipolar disorder comorbid with anxiety disorders (Gao et al. 2014;Sheehan et al. 2009Sheehan et al. , 2013Suppes et al. 2014) and SUDs (Brown et al. 2007(Brown et al. , 2008(Brown et al. , 2009(Brown et al. , 2014(Brown et al. , 2015Geller et al. 1998;Kemp et al. 2009;Salloum et al. 2005;Stedman et al. 2010;Tolliver et al. 2012;Wang et al. 2010). However, the sample sizes of these studies were small to moderate and subjects in these studies were limited to small numbers of patients with bipolar disorder. ...
... For most studies on comorbid anxiety, patients with SUDs have been excluded (Sheehan et al. , 2013Suppes et al. 2014). For studies on a SUD, only patients with substance dependence were eligible in most previous studies and symptom severity of a substance was the primary inclusion criterion (Brown et al. 2007(Brown et al. , 2008(Brown et al. , 2009(Brown et al. , 2014(Brown et al. , 2015Salloum et al. 2005;Stedman et al. 2010;Tolliver et al. 2012). Only a few studies have included patients with more than one SUD (Geller et al. 1998;Kemp et al. 2009;Wang et al. 2010;Gao et al. 2014). ...
Objective:
This study aims to compare treatment response in bipolar I or II depression and generalized anxiety disorder (GAD) with and without recent alcohol and/or cannabis use disorder (ALC/CAN) to quetiapine-XR (extended release) or placebo.
Methods:
A randomized, double-blind, 8-week study of quetiapine-XR versus placebo in patients with bipolar I or II depression and GAD with or without a recent ALC/CAN was used to compare changes in Hamilton Depression Rating Scale-17, Hamilton Anxiety Rating Scale, the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16), Clinical Global Impression for Bipolar Disorder-Severity (CGI-BP-S), and Timeline Follow Back within and between groups.
Results:
In the quetiapine-XR group, patients with a recent ALC/CAN (n = 22) had significant decreases in QIDS-SR-16 (-9.6 ± 1.6 vs. -3.7 ± 1.7) and CGI-BP-S (-1.6 ± 0.4 vs. -0.8 ± 0.03) than those without a recent ALC/CAN (n = 24). In the placebo group, both patients with a recent ALC/CAN (n = 23) and those without (n = 21) had similar reductions in these measures. The reduction of QIDS-SR-16 scores in patients with a recent ALC/CAN was also significantly different from that of their counterparts in the placebo group. Patients who received quetiapine-XR had larger decreases in the number of drinking days/week (p = 0.17) and number of cannabis joints/week (p = 0.09) compared to those who received placebo.
Conclusion:
Quetiapine-XR was superior to placebo in reducing QIDS-SR-16 total score in patients with a recent ALC/CAN. Patients taking quetiapine-XR used less alcohol and cannabis than patients on placebo, suggesting that quetiapine-XR may be of use in patients with bipolar disorder accompanied by GAD and other comorbidities.
... When used in patients with a history of mania or hypomania and cocaine dependence, it decreased cocaine use and was effective in memory enhancement but did not change mood symptoms. 15 When citicoline was used in patients with methamphetamine use and unipolar or bipolar depression, it reduced depressive symptoms but did not change the methamphetamine use rate. 16 In summary, citicoline has been found to affect brain neurotransmitters in animal studies and has shown therapeutic potential in human trials as an antidepressant and for mood management. ...
... 13 We found no citicoline adverse effects on patients, which is consistent with previous studies demonstrating that the drug was well tolerated. 15,26 We found a significant improvement in HDRS scores in the citicoline group compared with the placebo group. This enhanced reduction of depressive symptoms was present as early as 2 weeks after the start of the intervention, was maintained at 4 and 6 weeks of therapy, and resulted in a significantly greater rate of remission. ...
Objective:
Residual symptoms of major depressive disorder are a source of long-term morbidity. New therapeutic strategies are required to alleviate this morbidity and enhance patient quality of life. Citicoline has been used for vascular accidents and has been effective in cognitive rehabilitation. It has been used successfully to reduce craving in patients with substance abuse disorder and for mood management of bipolar disorder. Here, we test citicoline effectiveness as an adjuvant therapy in major depression.
Method:
A double-blind randomized trial was designed on 50 patients with major depressive disorder who were under treatment with citalopram. Patients were allocated to 2 groups and received citicoline (100 mg twice a day) or placebo as an adjuvant treatment for 6 weeks. Depressive symptoms were assessed by the Hamilton Depression Rating Scale (HDRS) at baseline and at weeks 2, 4, and 6.
Results:
Significantly greater improvement was observed in the HDRS scores of the citicoline group compared with the placebo group from baseline to weeks 2, 4, and 6 (Ps = 0.030, 0.032, and 0.021, respectively). Repeated-measures general linear model demonstrated a significant effect for time × treatment interaction on the HDRS score (F2.10,101.22 = 3.12, P = 0.04). Remission rate was significantly higher in the citicoline group compared with the placebo group (P = 0.045).
Conclusions:
Citicoline was an effective adjuvant to citalopram in the therapy of major depressive disorder.
... Para aliviar síntomas psiquiátricos y el craving, la quetiapina como fármaco único o principal 32,36,38 y la risperidona 36 o la olanzapina 37 también han ofrecido buenos resultados. Sin embargo, la citicolina ha demostrado abordar estos síntomas además de favorecer una mayor adhesión al tratamiento 26 , aunque estos resultados no se confirman por otros grupos de trabajo 33 . En estudios con pacientes con TB de ciclación rápida donde la lamotrigina no ha resultado efectiva 27 , el tratamiento clásico con litio sí ha demostrado serlo en lo que respecta a la sintomatología psiquiátrica 33 . ...
... Sin embargo, la citicolina ha demostrado abordar estos síntomas además de favorecer una mayor adhesión al tratamiento 26 , aunque estos resultados no se confirman por otros grupos de trabajo 33 . En estudios con pacientes con TB de ciclación rápida donde la lamotrigina no ha resultado efectiva 27 , el tratamiento clásico con litio sí ha demostrado serlo en lo que respecta a la sintomatología psiquiátrica 33 . Estas investigaciones fundamentan sus conclusiones en la utilización de grupo control y el empleo de pruebas o instrumentos similares para medir las variables dependientes, a pesar de adolecer de muestras en ocasiones escasas y de grandes tasas de abandono. ...
The aim of this study was to provide a descriptive overview of different psychological and pharmacological interventions used in the treatment of patients with bipolar disorder and substance abuse, in order to determine their efficacy. A review of the current literature was performed using the databases Medline and PsycINFO (2005-2015). A total of 30 experimental studies were grouped according to the type of therapeutic modality described (pharmacological 19; psychological 11). Quetiapine and valproate have demonstrated superiority on psychiatric symptoms and a reduction in alcohol consumption, respectively. Group psychological therapies with education, relapse prevention and family inclusion have also been shown to reduce the symptomatology and prevent alcohol consumption and dropouts. Although there seems to be some recommended interventions, the multicomponent base, the lack of information related to participants during treatment, experimental control or the number of dropouts of these studies suggest that it would be irresponsible to assume that there are well established treatments.
Copyright © 2015. Published by Elsevier España.
... But Licata et al [759] reported that citicoline is not an effective treatment reducing craving for heavy cocaine users. Also have been reported positive effects in patients with mood disorders related with the use of cocaine [760,761], antidepressant properties in methamphetamine dependence [762], and a role facilitating the treatment of marijuana use disorders by improving the cognitive skills necessary to fully engage in comprehensive treatment programs [763]. There is a clear implication of the cerebral metabolism in the drug addiction pathophysiology [764,765]. ...
This review is based on the previous one published in 2016 (Secades JJ. Citicoline: pharmacological and clinical
review, 2016 update. Rev Neurol 2016; 63 (Supl 3): S1-S73), incorporating 176 new references, having all the information
available in the same document to facilitate the access to the information in one document. This review is focused on the
main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain
injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
... But Licata et al [759] reported that citicoline is not an effective treatment reducing craving for heavy cocaine users. Also have been reported positive effects in patients with mood disorders related with the use of cocaine [760,761], antidepressant properties in methamphetamine dependence [762], and a role facilitating the treatment of marijuana use disorders by improving the cognitive skills necessary to fully engage in comprehensive treatment programs [763]. There is a clear implication of the cerebral metabolism in the drug addiction pathophysiology [764,765]. ...
This review is based on the previous one published in 2016 (Secades JJ. Citicoline: pharmacological and clinical review, 2016 update. Rev Neurol 2016; 63 (Supl 3): S1-S73), incorporating 176 new references, having all the information available in the same document to facilitate the access to the information in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
... In addition to many other therapeutic applications, citicoline has been investigated as a treatment for substance use disorder (Wignall and Brown, 2014;Shen, 2018b). In various randomized, double-blind, placebo-controlled clinical studies of patients with bipolar disorder and comorbid cocaine addiction, citicoline was shown to significantly reduce cocaine consumption, although in one study a habituation effect with continual effect reduction was shown (Brown et al., 2007(Brown et al., , 2015. Citicoline has also been tested in other substance use disorders, such as methamphetamine dependence with comorbid bipolar or unipolar depression, although the drug did Frontiers in Pharmacology frontiersin.org ...
Compounds known to be successful in the treatment of alcohol use disorder include the aversive agent, Disulfiram, the glutamatergic NMDA receptor antagonist, Acamprosate, and the opioid receptor antagonists, Naltrexone and Nalmefene. Although all four are effective in maintaining abstinence or reduction of alcohol consumption, only a small percentage of patients receive pharmacological treatment. In addition, many other medications have been investigated for their therapeutic potential in the treatment of alcohol use disorder. In this review we summarize and compare Baclofen, Gabapentin, Topiramate, Ondansetron, Varenicline, Aripiprazole, Quetiapine, Clozapine, Antidepressants, Lithium, Neuropeptide Y, Neuropeptide S, Corticotropin-releasing factor antagonists, Oxytocin, PF-05190457, Memantine, Ifenprodil, Samidorphan, Ondelopran, ABT-436, SSR149415, Mifepristone, Ibudilast, Citicoline, Rimonabant, Surinabant, AM4113 and Gamma-hydroxybutyrate While some have shown promising results in the treatment of alcohol use disorder, others have disappointed and should be excluded from further investigation. Here we discuss the most promising results and highlight medications that deserve further preclinical or clinical study. Effective, patient-tailored treatment will require greater understanding provided by many more preclinical and clinical studies.
... Among anti-craving medications, Naltrexone was effective in decreasing drinking days and alcohol cravings in AUD-BD patients [134], while only limited benefits over placebo were provided by Acamprosate [135]. As for other substances, promising results are available for Citicoline in BD patients with cocaine dependence, in terms of negative urine tests and cognitive outcomes, though differences from placebo declined over time [136,137]. Finally, a recent 1week, double-blind, placebo-controlled, crossover, magnetic resonance imaging pilot study found that Gabapentin was well tolerated in 22 adults with comorbid CUD-BD and may be considered, based on the observed modulation of brain GABA/glutamate levels, as a candidate adjuvant medication for cannabis use warranting further investigation [138]. ...
Background
Bipolar Disorder (BD) is a highly comorbid condition, and rates of co-occurring disorders are even higher in youth. Comorbid disorders strongly affect clinical presentation, natural course, prognosis, and treatment.
Method
This review focuses on the clinical and treatment implications of the comorbidity between BD and Attention-Deficit/Hyperactivity Disorder (ADHD), disruptive behavior disorders (Oppositional Defiant Disorder and/or Conduct Disorder), alcohol and substance use disorders, Autism Spectrum Disorder, anxiety disorders, Obsessive-Compulsive Disorder, and eating disorders.
Results
These associations define specific conditions which are not simply a sum of different clinical pictures, but occur as distinct and complex combinations with specific developmental pathways over time and selective therapeutic requirements. Pharmacological treatments can improve these clinical pictures by addressing the comorbid conditions, though the same treatments may also worsen BD by inducing manic or depressive switches.
Conclusion
The timely identification of BD comorbidities may have relevant clinical implications in terms of symptomatology, course, treatment and outcome. Specific studies addressing the pharmacological management of BD and comorbidities are still scarce, and information is particularly lacking in children and adolescents; for this reason, the present review also included studies conducted on adult samples. Developmentally-sensitive controlled clinical trials are thus warranted to improve the prognosis of these highly complex patients, requiring timely and finely personalized therapies.
... Badanie ukończyło 2 razy więcej chorych z grupy stosującej cytykolinę niż placebo. odsetek pacjentów, u których stwierdzono kokainę w moczu, był mniejszy w grupie leczonej cytokoliną niż placebo [55]. Chociaż grupy badane były niewielkie, wyniki sugerują dobrą tolerancję leczenia oraz zmniejszenie głodu narkotykowego [52]. ...
Cytykolina jest substancją endogenną odgrywającą rolę w metabolizmie komórkowym. Może być pomocna w leczeniu udaru mózgu, chorób Parkinsona i Alzheimera, jaskry, po urazach głowy itd. Bezpieczeństwo stosowania cytykoliny zostało potwierdzone w wielu badaniach.
Citicoline is an endogenous compound and play important role in cellular metabolism. It may be helpful in treatment of stroke, Parkinson and Alzheimer disease, glaucoma, after head injury etc. The safety of citicoline was confirmed in many studies.
... Since the publication of the systematic reviews by Sarris et al. 5 and Sylvia et al., 6 9 studies have been added to the field. These were studies of acetyl-L-carnitine and a-lipoic acid in combination, 15 coenzyme Q10, 16 creatine monohydrate, 17 S-adenosyl-L-methione (SAMe), 18 folic acid, 19 vitamin D, 20 2 studies of NAC, 21,22 and 1 three-arm study of NAC and a combination of nutraceuticals including NAC. 23 Since the publication of Fusar-Poli, 7 1 new study has been published which explored probiotics for the treatment of BD. 24 The current systematic review also reviewed 3 agents that were not addressed in the previous reviews (SAMe, 18 citicoline, 25 and a probiotic combination 24 ). ...
jats:sec> Background: Certain nutrient supplements (nutraceuticals) may target neurobiological pathways perturbed in bipolar disorder (BD) such as inflammation, oxidative stress, and mitochondrial dysfunction. Nutraceuticals thus may have a potential role as adjunctive treatments for BD. Methods: A search of Embase via embase.com, PubMed via PubMed, Cumulated index to nursing and allied health literature (CINAHL) Complete via EBSCO, and Cochrane Central Register of Controlled Clinical Trials via cochranelibrary.com was conducted to identify published randomized controlled trials assessing the efficacy of nutraceuticals on mood symptomatology in adults with BD. Search terms for BD, nutraceuticals, and clinical trials (total search terms = 75) were used to search from inception to February 20, 2020. The Cochrane Collaboration’s tool for assessing the risk of bias in randomized trials was used to assess the risk of bias. Results: A total of 1,712 studies were identified through the search. After rigorous screening, 22 studies were included in the review. There was large variability across the studies with 15 different nutraceutical agents assessed and as such insufficient homogeneity for a meta-analysis to be conducted ( I 2 > 50%). Studies revealed promising, albeit conflicting, evidence for omega-3 fatty acids and N-acetylcysteine. Isolated positive results were reported for coenzyme Q10. Conclusion: Given nutraceuticals are tolerable and accessible, they may be useful as potential adjunctive treatments for BD. Nutraceuticals targeting neuroinflammation or mitochondrial activity may have the most potential for the depressive phase. However, further studies are required to determine efficacy. </jats:sec
... Since the publication of the systematic reviews by Sarris et al. 5 and Sylvia et al., 6 9 studies have been added to the field. These were studies of acetyl-L-carnitine and a-lipoic acid in combination, 15 coenzyme Q10, 16 creatine monohydrate, 17 S-adenosyl-L-methione (SAMe), 18 folic acid, 19 vitamin D, 20 2 studies of NAC, 21,22 and 1 three-arm study of NAC and a combination of nutraceuticals including NAC. 23 Since the publication of Fusar-Poli, 7 1 new study has been published which explored probiotics for the treatment of BD. 24 The current systematic review also reviewed 3 agents that were not addressed in the previous reviews (SAMe, 18 citicoline, 25 and a probiotic combination 24 ). ...
Background:
Certain nutrient supplements (nutraceuticals) may target neurobiological pathways perturbed in bipolar disorder (BD) such as inflammation, oxidative stress, and mitochondrial dysfunction. Nutraceuticals thus may have a potential role as adjunctive treatments for BD.
Methods:
A search of Embase via embase.com, PubMed via PubMed, Cumulated index to nursing and allied health literature (CINAHL) Complete via EBSCO, and Cochrane Central Register of Controlled Clinical Trials via cochranelibrary.com was conducted to identify published randomized controlled trials assessing the efficacy of nutraceuticals on mood symptomatology in adults with BD. Search terms for BD, nutraceuticals, and clinical trials (total search terms = 75) were used to search from inception to February 20, 2020. The Cochrane Collaboration's tool for assessing the risk of bias in randomized trials was used to assess the risk of bias.
Results:
A total of 1,712 studies were identified through the search. After rigorous screening, 22 studies were included in the review. There was large variability across the studies with 15 different nutraceutical agents assessed and as such insufficient homogeneity for a meta-analysis to be conducted (I2 > 50%). Studies revealed promising, albeit conflicting, evidence for omega-3 fatty acids and N-acetylcysteine. Isolated positive results were reported for coenzyme Q10.
Conclusion:
Given nutraceuticals are tolerable and accessible, they may be useful as potential adjunctive treatments for BD. Nutraceuticals targeting neuroinflammation or mitochondrial activity may have the most potential for the depressive phase. However, further studies are required to determine efficacy.
... But Licata et al. [641] reported that citicoline is not an effective treatment reducing craving for heavy cocaine users. Also have been reported positive effects in patients with mood disorders related with the use of cocaine [642,643], antidepressant properties in methamphetamine dependence [644], and a role facilitating the treatment of marijuana use disorders by improving the cognitive skills necessary to fully engage in comprehensive treatment programs [645]. There is a clear implication of the cerebral metabolism in the drug addiction pathophysiology [646,647]. ...
Summary. This review is based on the previous one published in 2006 –Secades JJ, Lorenzo JL. Citicoline: pharmacological
and clinical review, 2006 update. Methods Find Exp Clin Pharmacol 2006; 28 (Suppl B): S1-56–, incorporating the new
references until now, having all the information available to facilitate the access to the información in one document. This
review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment,
and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both
indications.
Key words. Alcoholism. Alzheimer disease. Amblyopia. Apoptosis. CDP-choline. Cerebral edema. Cerebral ischemia. Citicoline.
Cognitive disorder. Drug addiction. Glaucoma. Head injury. Memory. Neuronal membrane. Neuroplasticity. Neuroprotection.
Neurorepair. Neurotransmission. Parkinson disease. Phosphatidylcholine. Phospholipase. Senile dementia. Stroke. Structural
phospholipids. Traumatic brain injury.
... Sin embargo, Licata et al [641] han comunicado que la citicolina no es eficaz para reducir el consumo en consumidores empedernidos. También se han comunicado efectos positivos en pacientes con problemas bipolares asociados al uso de cocaína [642,643], efectos antidepresivos en adictos a metanfetamina [644] y efectos procognitivos en adictos a marihuana [645]. Cada vez parece más evidente la implicación del metabolismo cerebral en los procesos de drogadicción [646,647], por lo que resulta de especial interés el uso de técnicas de neuroimagen para el estudio de estos trastornos (648). ...
This review is based on the previous one published in 2010 -Secades JJ. Citicoline: pharmacological and clinical review, 2010 update. Rev Neurol 2011; 52 (Suppl 2): S1-62-, incorporating 183 new references, having all the information available to facilitate the access to the information in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
... ). The effect of quetiapine on specific cannabis use-related outcomes was not reported.Stimulants: cocaine, amphetamine, and methamphetamine use disorders Citicoline adjunctive therapy had a positive outcome in two RCTs in patients with BD with comorbid cocaine use disorder, although the benefits of citicoline decreased over time in the more recent study (level 2).705,706 Lithium or divalproex, either alone or in combination, were proven useful in small studies addressing cocaine use disorder682,[685][686][687]707,708 (level 4). ...
The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third- line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment-emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second- line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence-based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first-line treatments for acute mania. First-line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first-line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.
... But Licata et al. [641] reported that citicoline is not an effective treatment reducing craving for heavy cocaine users. Also have been reported positive effects in patients with mood disorders related with the use of cocaine [642,643], antidepressant properties in methamphetamine dependence [644], and a role facilitating the treatment of marijuana use disorders by improving the cognitive skills necessary to fully engage in comprehensive treatment programs [645]. There is a clear implication of the cerebral metabolism in the drug addiction pathophysiology [646,647]. ...
This review is based on the previous one published in 2010 -Secades JJ. Citicoline: pharmacological and clinical review, 2010 update. Rev Neurol 2011; 52 (Suppl 2): S1-62-, incorporating 183 new references, having all the information available to facilitate the access to the information in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
... The precursor for the synthesis of phosphatidylcholine (a key component of cell membranes) citicoline reduces cellmembrane breakdown during ischemic or hypoxia conditions and glutamate-mediated injury, and improves cognition in animal models. An RCT therefore examined the effects of 12 weeks citicoline (N= 23; 500-2000 mg/day) versus placebo (N = 21) on verbal memory and mood symptoms in symptomatic BD or schizoaffective (SZA) patients with cocaine dependence (Brown et al., 2007). Citicoline improved one measure of verbal memory, which would have survived Bonferroni correction for the three employed memory measures. ...
Cognitive dysfunction is an emerging treatment target in bipolar disorder (BD). Several trials have assessed the efficacy of novel pharmacological and psychological treatments on cognition in BD but the findings are contradictory and unclear. A systematic search following the PRISMA guidelines was conducted on PubMed and PsychInfo. Eligible articles reported randomized, controlled or open-label trials investigating pharmacological or psychological treatments targeting cognitive dysfunction in BD. The quality of the identified randomized controlled trials (RCTs) was evaluated with the Cochrane Collaboration’s Risk of Bias tool. We identified 19 eligible studies of which 13 were RCTs and six were open-label or non-randomized studies. The findings regarding efficacy on cognition were overall disappointing or preliminary, possibly due to several methodological challenges. For the RCTs, the risk of bias was high in nine cases, unclear in one case and low in three cases. Key reasons for the high risk of bias were lack of details on the randomization process, suboptimal handling of missing data and lack of a priori priority between cognition outcomes. Other challenges were the lack of consensus on whether and how to screen for cognitive impairment and on how to assess efficacy on cognition. In conclusion, methodological problems are likely to impede the success rates of cognition trials in BD. We recommend adherence to the CONSORT guidelines for RCTs, screening for cognitive impairment before inclusion of trial participants and selection of one primary cognition outcome. Future implementation of a ‘neurocircuitry-based’ biomarker model to evaluate neural target engagement is warranted.
... The participants pretreated with citicoline had no potentiated cardiovascular, physiologic or subjective effects after cocaine, suggesting that citicoline is safe to use in this population. Brown and colleagues (2007) [30] conducted a 12-week randomized placebo controlled trial of citicoline in patients with both bipolar disorder and cocaine dependence and examined a number of clinical, cognitive and substance use variables. Results indicated a significant effect for the citicoline treated group on the alternative word list of the Rey Auditory Learning Test (RAVLT), a measure of verbal learning. ...
Objective:
Citicoline is an endogenous nucleotide that has historically been used to treat stroke, traumatic brain injury, and cognitive dysfunction. Research has also shown that citicoline treatment is associated with improved cognitive performance in substance-abusing populations. We hypothesized that marijuana (MJ) smokers who received citicoline would demonstrate improvement in cognitive performance as well as increased neural efficiency during tasks of cognitive control relative to those who received placebo.
Method:
The current study tested this hypothesis by examining the effects of citicoline in treatment-seeking chronic MJ smokers. In an 8-week double-blind, placebo-controlled study, 19 MJ smokers were randomly assigned via a double-blind procedure to the citicoline (8 Males, 2 Females) or placebo group (9 Males, 0 Females). All participants completed fMRI scanning at baseline and after 8 weeks of treatment during two cognitive measures of inhibitory processing, the Multi Source Interference Test (MSIT) and Stroop Color Word Test, and also completed the Barratt Impulsiveness Scale (BIS-11), a self-report measure of impulsivity.
Results:
Following the 8 week trial, MJ smokers treated with citicoline demonstrated significantly lower levels of behavioral impulsivity, improved task accuracy on both the MSIT and Stroop tasks, and exhibited significantly different patterns of brain activation relative to baseline levels and relative to those who received placebo.
Conclusions:
Findings suggest that citicoline may facilitate the treatment of MJ use disorders by improving the cognitive skills necessary to fully engage in comprehensive treatment programs.
... In a 20-week RCT involving 80 patients with BD and comorbid SUD (cocaine or methamphetamine dependence), both quetiapine and risperidone improved manic and depressive symptoms, as well as drug cravings and use, with no significant differences between treatments (325); however, this study lacked a placebo group. In another placebocontrolled, 12-week RCT, involving 44 patients with BD I or BD II and cocaine dependence, citicoline significantly improved some aspects of declarative memory and cocaine use, but not mood (326). ...
Background:
Individuals with bipolar disorder (BD) often have co-occurring substance use disorders (SUDs), which substantially impoverish the course of illness. Despite the importance of this dual diagnosis, the evidence of the efficacy and safety of adjuvant treatments is mostly unknown.
Objective:
To perform a meta-analysis to evaluate the efficacy and safety of adjuvant drugs in patients with co-occurring BD and SUD.
Methods:
We searched PubMed, Scopus, and Web of Knowledge until 30th April 2022 for randomized clinical trials (RCT) evaluating the efficacy and safety of adjuvant drugs compared to placebo in patients with a dual diagnosis of BD and SUD. We meta-analyzed the effect of adjuvant drugs on general outcomes (illness severity, mania, depression, anxiety, abstinence, substance craving, substance use, gamma-GT, adherence, and adverse events) and used the results to objectively assess the quality of the evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. For completeness, we also report the specific effects of specific adjuvant drugs in patients with specific substance disorders.
Results:
We included 15 RCT studies (9 alcohol, 3 cocaine, 2 nicotine, and 1 cannabis) comprising 628 patients allocated to treatment and 622 to placebo. There was low-quality evidence that adjuvant drugs may reduce illness severity (g=-0.25, 95% CI: -0.44, -0.06), and very-low quality evidence that they may decrease substance use (g=-0.23, 95% CI: -0.44, -0.02) and increase substance abstinence (g=0.21, 95% CI: 0.04, 0.38).
Discussion:
There is low-quality evidence that adjuvant drugs may help reduce illness severity, probably via facilitating abstinence and lower substance use. However, the evidence is weak; thus, these results should be considered cautiously until better evidence exists.
Despite the lack of guidance available for practitioners, extensive polypharmacy has become the primary method of treating patients with severe and chronic mood, anxiety, psychotic or behavioral disorders. This ground-breaking new book provides an overview of psychopharmacology knowledge and decision-making strategies, integrating findings from evidence-based trials with real-world clinical presentations. It adopts the approach and mind-set of a clinical investigator and reveals how prescribers can practice 'bespoke psychopharmacology', tailoring care to the individualized needs of patients. Practitioners at all levels of expertise will enhance their ability to devise rationale-based treatments, targeting manifestations of dysfunctional neural circuitry and dimensions of psychopathology that cut across conventional psychiatric diagnoses. Presented in a user-friendly, practical, full-colour layout and incorporating summary tables, bullet points, and illustrative case vignettes, it is an invaluable guide for all healthcare professionals prescribing psychotropic medications, including psychiatry specialists, primary care physicians, and advanced practice registered nurses.
Das Versorgungssystem für Menschen mit alkoholbezogenen Störungen in Deutschland umfasst eine Vielzahl von differenzierten Angeboten, ist jedoch aufgrund historisch gewachsener Strukturen und den spezifischen Zuständigkeiten der Leistungsträger stark fragmentiert. Zu unterscheiden sind die speziell für Menschen mit Störungen durch Alkoholkonsum (SdA) ausgerichteten Systeme der Suchtberatung, der suchtmedizinischen, suchtpsychiatrischen, suchttherapeutischen, und suchtrehabilitativen Behandlung einerseits, von Hilfesystemen mit anderen Schwerpunkten in der Aufgabenstellung, Kompetenz und Verantwortung, wie z. B. medizinische Versorgung (durch niedergelassene ÄrztInnen und Allgemeinkrankenhäuser), die ambulante psychotherapeutische Versorgung, die Altenhilfe, die Jugendhilfe, die Wohnungslosenhilfe, das System der Arbeitslosenhilfen (z. B. Jobcenter, Agenturen für Arbeit) usw. andererseits (DHS, 2019).
Medikamentenbezogene Störungen, beziehungsweise ein schädlicher Gebrauch oder eine Abhängigkeit von Arzneimitteln im Sinne dieser Leitlinie sind Störungen, die im Rahmen einer medizinisch indizierten Therapie mit Arzneimitteln entstehen. Es gibt Wirkstoffe, welche einen schädlichen Gebrauch oder eine Abhängigkeit begünstigen beziehungsweise hervorrufen können. Die Identifikation dieser medikamentenbezogenen Störungen im Versorgungsalltag ist allerdings nicht einfach, was eine verstärkte Aufmerksamkeit aller an der Versorgung Beteiligten auf diese möglichen Probleme erfordert.
Purpose of review:
There is a large evidence base of clinical trials that have investigated the efficacy of a range of nutraceuticals on mood disorders. The aim of the current review is to provide an update regarding the efficacy and safety of nutraceutical agents in mood disorders and to highlight considerations for future research.
Recent findings:
Nutraceuticals such as omega-3, probiotics, zinc, saffron and curcumin have been recommended as adjunctive interventions to standard treatments for people with depression, while St John's wort has been recommended as a monotherapy. In contrast, less research has been devoted to investigating the effect of nutraceuticals in bipolar disorder, with omega-3 being weakly recommended as an adjunctive to standard treatments. Although the safety profile of most nutraceuticals appears acceptable, more insight into the long-term effects within a range of cohorts is recommended.
Summary:
There are a number of nutraceuticals that have clinical trial support for their use as either adjunctive interventions for depression; however, there is mostly limited support for their use in bipolar disorder. Further randomized controlled trials that take into consideration a number of emerging mechanisms, potential nutraceutical combinations and factors that may predict treatment response are required to inform clinical use.
Substance use disorders (SUD) are highly prevalent in bipolar disorder (BD) and significantly affect clinical outcomes. Incidence and management of illicit drug use differ from alcohol use disorders, nicotine use of behavioral addictions. It is not yet clear why people with bipolar disorder are at higher risk of addictive disorders, but recent data suggest common neurobiological and genetic underpinnings and epigenetic alterations. In the absence of specific diagnostic instruments, the clinical interview is conducive for the diagnosis. Treating SUD in bipolar disorder requires a comprehensive and multidisciplinary approach. Most treatment trials focus on single drugs, such as cannabis alone or in combination with alcohol, cocaine, or amphetamines. Synopsis of data provides limited evidence that lithium and valproate are effective for the treatment of mood symptoms in cannabis users and may reduce substance use. Furthermore, the neuroprotective agent citicoline may reduce cocaine consumption in BD subjects. However, many of the available studies had an open-label design and were of modest to small sample size. The very few available psychotherapeutic trials indicate no significant differences in outcomes between BD with or without SUD. Although SUD is one of the most important comorbidities in BD with a significant influence on clinical outcome, there is still a lack both of basic research and clinical trials, allowing for evidence-based and specific best practices.
Background
Cytidine-5′-diphosphate choline (CDP-choline) has been suggested to exert neuroprotective and neuroreparative effects and may be beneficial for patients with stimulant dependence. This randomized, double-blind, placebo-controlled study in methamphetamine (MA) dependence investigated effects of CDP-choline on the brain structures and their associations with craving and MA use.
Methods
MA users (n = 44) were randomized to receive 2 g/day of CDP-choline (n = 22) or placebo (n = 22) for 8 weeks. Patients underwent brain magnetic resonance imaging (MRI) at baseline and 8-week follow-up. Healthy individuals (n = 27) were also examined using brain MRI at the same interval. Voxel-based morphometry analysis was conducted to examine changes in gray matter (GM) volumes and their associations with craving and MA use.
Results
Craving for MA was significantly reduced after the 8 week-treatment with CDP-choline (p = 0.01), but not with the placebo treatment (p = 0.10). There was no significant difference in the total number of MA-negative urine samples between the two groups (p = 0.19). With CDP-choline treatment, GM volumes in the left middle frontal gyrus (p = 0.001), right hippocampus (p = 0.009), and left precuneus (p = 0.001) were significantly increased compared to the placebo and control groups. Increased GM volumes in the left middle frontal gyrus with CDP-choline treatment were associated with reduced craving for MA (Spearman's ρ = −0.56, p = 0.03). In addition, the right hippocampal volume increases were positively associated with the total number of MA-negative urine results in the CDP-choline group (Spearman's ρ = 0.67, p = 0.006).
Conclusion
Our findings suggest that CDP-choline may increase GM volumes of MA-dependent patients, which may be related to decreases in MA use and craving.
Background
: Bipolar disorder (BD) frequently co-occurs with substance use disorders (SUDs), and both are associated with cognitive impairment. This study compares cognition between individuals with BD with and without current alcohol use disorder (AUD), cocaine use disorder (CUD), or both, as these disorders may be linked with additive cognitive impairment.
Methods
: Baseline data were analyzed from five clinical studies of individuals with the aforementioned disorders (N = 373). Participants were grouped as follows: BD-only, BD+AUD, BD+CUD, or BD+AUD+CUD. Cognition was assessed with the Rey Auditory Verbal Learning Test (RAVLT) (verbal learning and memory) and Stroop Color Word Test (executive function). Multiple linear regression models determined if SUD diagnosis, among other demographic and clinical variables, predicted each cognitive test's T-score. Regression equations were used to compute each group's mean T-scores.
Results
: All groups demonstrated below-average mean T-scores on all tests, with no significant between-group score differences. RAVLT total T-scores were lower than Stroop color-word T-scores within all groups (non-overlapping 95% confidence intervals). Higher daily cocaine use predicted higher Stroop T-scores (p < 0.01) and RAVLT delayed recall T-scores (p < 0.05). No other non-demographic variable, including AUD/CUD group status, predicted cognitive performance.
Limitations
: A full cognitive battery and some relevant variables (e.g. BD lifetime illness course) were not available. Many participants (42.1%) had additional SUDs.
Conclusions
: BD with and without AUD/CUD was found to be associated with greater deficits in verbal learning and memory than in executive function. Addressing these impaired domains in dually-diagnosed patients may improve treatment and functional outcomes.
In the present study, the effects of intraperitoneal (i.p.) injections of citalopram and citicoline on morphine-induced anxiolytic effects were investigated in non-sensitized and morphine-sensitized mice using elevated plus-maze (EPM). Subcutaneous (s.c.) administration morphine (5 mg/kg) increased the percentage of open arm time (%OAT, in morphine-sensitized mice), and open arm entries (%OAE, in non-sensitized mice), but not a locomotor activity, indicating an anxiolytic response to morphine. On the other hand, i.p. administration of naloxone decreased %OAT (morphine-sensitized mice), and %OAE (non-sensitized and morphine-sensitized mice), but not a locomotor activity, showing an anxiogenic effect to naloxone. Moreover, i.p.co-administration of citalopram (5 and 10 mg/kg) and citicoline (75 mg/kg) induced the anxiolytic effect. Interestingly, i.p. co-administration of low doses of citalopram (0.5, 1 and 2.5 mg/kg) and citicoline (25 mg/kg) significantly increased %OAT and %OAE in non-sensitized as well as %OAT in morphine-sensitized mice, indicating an anxiolytic effect. An isobolographic analysis of data was performed, presenting a synergistic interaction between citalopram and citicoline upon the production of anxiolytic effect in non-sensitized and morphine-sensitized mice. In conclusion, it seems that (1) morphine sensitization affects the anxiety behavior in the EPM, (2) μ-opioid receptors play an important role in morphine anxiolytic effect, (3) citalopram and citicoline induced anti-anxiety effect, (4) a synergistic effect of citalopram and citicoline upon induction of anti-anxiety behavior in non-sensitized and morphine-sensitized mice.
Background:
The Psychopharmacology Algorithm Project at the Harvard South Shore Program (PAPHSS) published algorithms for bipolar depression in 1999 and 2010. Developments over the past 9 years suggest that another update is needed.
Methods:
The 2010 algorithm and associated references were reevaluated. A literature search was conducted on PubMed for recent studies and review articles to see what changes in the recommendations were justified. Exceptions to the main algorithm for special patient populations, including those with attention-deficit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), substance use disorders, anxiety disorders, and women of childbearing potential, and those with common medical comorbidities were considered.
Results:
Electroconvulsive therapy (ECT) is still the first-line option for patients in need of urgent treatment. Five medications are recommended for early usage in acute bipolar depression, singly or in combinations when monotherapy fails, the order to be determined by considerations such as side effect vulnerability and patient preference. The five are lamotrigine, lurasidone, lithium, quetiapine, and cariprazine. After trials of these, possible options include antidepressants (bupropion and selective serotonin reuptake inhibitors are preferred) or valproate (very small evidence-base). In bipolar II depression, the support for antidepressants is a little stronger but depression with mixed features and rapid cycling would usually lead to further postponement of antidepressants. Olanzapine+fluoxetine, though Food and Drug Administration (FDA) approved for bipolar depression, is not considered until beyond this point, due to metabolic side effects. The algorithm concludes with a table of other possible treatments that have some evidence.
Conclusions:
This revision incorporates the latest FDA-approved treatments (lurasidone and cariprazine) and important new studies and organizes the evidence systematically.
Objectives
Substance use disorders (SUDs), including those for alcohol, stimulants, tobacco, opioids and cannabis, in patients with bipolar disorder are a major clinical and public health problem, and are present in the majority of these patients. Nonetheless, the development of effective pharmacological treatments for co‐occurring SUDs in bipolar illness have not been well‐developed and may be an important practical reason for the reduced effectiveness of these medications in community practice.
Methods
We conducted a systematic review of the literature (PubMed, Medline, Google Scholar), and identified N=29 clinical studies, which evaluated both mental health and SUD outcomes in patients with co‐occurring bipolar disorders and SUDs.
Results
Our findings suggest the potential of valproate sodium and lamotrigine as preferred pharmacological agents for the treatment of co‐occurring psychiatric and substance use outcomes in these patients. However, many of the reviewed studies are of open‐label designs and of modest sample sizes.
Conclusions
Thus, given the gaps in our knowledge, recommendations for treatment of this common and important co‐morbidity are preliminary. Accordingly, the conduct of larger, randomized controlled trials for this co‐morbidity is clearly needed.
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Considering the complex nature of alcohol use disorder (AUD) and the limitations of the three US Food and Drug Administration (FDA) approved medications, clinical trials for diverse treatment options are required. During the last decade, several interesting clinical trials with over‐the‐counter (OTC) supplements have been conducted for AUD by taking advantage of less vulnerable nature in regard to toxicity and side effects. In this commentary, we discuss the article describing “A randomized, double‐blind, placebo‐controlled trial of citicoline in patients with alcohol use disorder” (Brown et al., 2018).
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Background
Alcohol use disorder is a major societal and individual burden that exacerbates health outcomes, decreases quality of life, and negatively affects U.S. healthcare spending. Although pharmacological treatments are available for alcohol use disorder, many of them are limited by small effect sizes and used infrequently. Citicoline is a widely available over‐the‐counter supplement with a favorable side effect profile. It acts through cholinergic pathways and phospholipid metabolism. The current report examines the effect of oral citicoline on alcohol use, craving, depressive symptoms and cognitive outcomes in individuals with alcohol use disorder.
Methods
A 12‐week, randomized, double‐blind, parallel‐group, placebo‐controlled, pilot study of citicoline (titrated to 2000 mg/day) in 62 adults (age 18‐75) with alcohol use disorder was conducted. Alcohol use, such as number of drinking days, amount used, and number of heavy drinking days, was assessed using the Timeline Followback method and liver enzymes, while alcohol craving was measured using the Penn Alcohol Craving Scale. A neurocognitive battery (e.g., Rey Auditory Verbal Learning Test – RAVLT) and depressive symptoms scales (e.g., Inventory of Depressive Symptomatology Self‐Report – IDS‐SR) scores were also collected. Data were analyzed using a random regression analysis.
Results
The primary outcome analysis was conducted in the intent‐to‐treat sample and consisted of n=55 participants (78.2% men and 21.8% women, mean age of 46.47 ± 9.15 years) with a mean of 77% of days accounted for were drinking days. Significant between‐group differences were not observed on alcohol use, craving, cognitive or depressive symptom measures. Citicoline was well tolerated.
Conclusions
This proof‐of‐concept study observed that citicoline was well tolerated, but was not associated with a reduction in alcohol use or other outcomes, as compared to placebo. The favorable effects reported with citicoline for cocaine use, cognitive disorders, and other conditions do not appear to extend to alcohol use disorder.
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Les troubles bipolaires et les troubles de l’utilisation fréquente de substances se produisent de façon concomitante, compliquant le diagnostic et le traitement, ce qui entraîne souvent des résultats plus graves pour les deux troubles. Un cas clinique est utilisé pour illustrer des moyens pour différencier le trouble bipolaire des symptômes induits par des substances, puis examiner les options de traitement fondées sur des données probantes pour les troubles bipolaires simultanés et les troubles liés à la consommation de substances.
ABSTRACT
Bipolar disorders and substance use disorders frequently co-occur complicating diagnosis and treatment, often resulting in worse outcomes for both disorders. A clinical case is used to illustrate means to differentiate bipolar disorder from substance-induced symptoms, then review evidence-based treatment options for comorbid bipolar and substance use disorders.
Background:
The comorbidity of substance use disorders (SUDs) in bipolar disorder is among the highest in psychiatric disorders. Evidence-based controlled psychosocial or pharmacological interventions trials, which may guide treatment decisions, have not been systematically reviewed.
Objective:
To present a narrative review of the public health and clinical significance of this condition, including diagnostic and treatment implications, and to evaluate controlled trials conducted to date.
Methods:
Controlled trials reports in the English language were identified from multiple electronic databases and hand-searching bibliographies. We searched for treatment studies of bipolar disorder and comorbid SUDs (alcohol, cocaine, stimulants, opioid, tobacco, cannabis). Search period included all reports through September of 2016. We selected only randomized psychosocial studies or double-blind, placebo-controlled pharmacotherapy trials. We also reviewed reports of the public health and clinical significance and principle of managements of this condition.
Results:
We identified 16 treatment studies: 3 psychotherapy, and 13 pharmacotherapy trials. The following medications were evaluated: lithium carbonate, valproate, lamotrigine, topiramate, naltrexone, acamprosate, disulfiram, quetiapine, and citicoline. SUDs have substantial impact on the recognition and management of bipolar disorder. Integrated psychosocial interventions are helpful in decreasing substance abuse. Valproate and naltrexone may decrease alcohol use and citicoline may decrease cocaine use and enhance cognition.
Conclusions:
There is a very limited number of pharmacotherapy and an even smaller number of psychosocial interventions. Our review highlights the need for more research in this area and for larger, multisite studies with generalizable samples to provide more definite guidance for clinical practice.
The devastating impact of substance use disorders (SUDs) among older adults has only recently attracted the attention of researchers, clinicians, and the general public. Despite the evidence that alcohol and other SUDs affect nearly 1 in 5 older adults, there has been limited examination of these areas in the substance abuse or gerontology literature. Bearing in mind the paucity of research on the screening, assessment, and treatment protocols for older adults with bipolar disorder and coexisting SUD, in this chapter, we outline the state of current knowledge and where possible, make clinical recommendations on the assessment and management of SUDs among older adults with bipolar disorder. Adults with bipolar disorder (compared to other psychiatric disorders) have the highest rate of alcohol use disorder [3]. With the predicted dramatic growth of the aging population, as well as more geriatric patients in outpatient opioid maintenance programs both due to the aging of patients first enrolled in the 1990s and due to patients with prescription opioid misuse in later life, the need and demand for effective, comprehensive mental health services for older adults with psychiatric illness and substance use disorders will continue to grow. Other disorders, such as benzodiazepines, cannabis, and psychostimulants are also described, with future directions for research outlined.
Several studies have provided evidence that patients with bipolar disorder (BD) show high prevalence of a comorbid substance use disorder (47–60 %) (SUD). The cause of the high comorbidity rate between BD and SUD has not been clearly established; the relationship is probably bidirectional. This combination of entities is characterized by frequent relapses, suicide attempts, elevated impulsivity, and greater frequency of rapid cycles, more severe picture, complicated diagnosis, poor adherence, and poor response to treatment. Patients who suffer this dual diagnosis have worse clinical course. The substances that were most frequently associated to SUD were alcohol, nicotine, and cocaine. Patients with BD should be warned about the risk of developing an SUD and about the importance of its early detection. Different pharmacotherapies have been studied in open and non-blind studies and in small groups and in same well-controlled trials in which patients whose mood disorder had been stabilized were treated with a double-blind medication. In these studies, adding a medication to reduce substance use to a pharmacotherapy for treating bipolar disorder did not consistently reduce substance use in this patient group. Antiseizure agents are profiled as the most promising treatments. In addition, there is an increase in the use of atypical antipsychotics, although there are few double-blind, controlled studies and the role of the adjuvant therapy for SUD must still be evaluated.
Una revisione della letteratura e delle linee guida internazionali sulla diagnosi e trattamento del Disturbo Bipolare I
Introduction Bipolar disorder (BD) is commonly associated with different kinds of co-morbidities. Addictions, mainly substance abuse or dependence, are one of the most common. Substance-use disorder (SUD) is defined by DSM-IV-TR (APA, 2000) as a maladaptive pattern of a substance use in a recurrent way and with significant adverse consequences associated with the use of these substances. Co-morbidity with SUD is complex, as each disorder has an impact on the outcome of the other, and multiple co-morbidities are frequent. In clinical practice, when BD complicates with SUD, the outcome is seriously compromised in all senses: clinical, functional and therapeutic. These patients require intensive treatment, ideally in the same setting, where the whole patient can be treated by the same therapeutic team. Pharmacologically, it is difficult to make sound recommendations given the scarcity of randomised, controlled trials. To date, only valproate and lithium have one positive trial of these characteristics. More studies are needed to assess the efficacy and safety of current drugs. Even in the absence of these data, current practice should be improved as SUDs are pharmacologically undertreated and benzodiazepines are overprescribed in this population. Specific psychotherapies that integrate psychological treatment of both disorders have shown positive results and are likely to be the most efficient treatment for co-morbidity. Despite the clinical severity of these patients, a subgroup in which SUD precedes onset of BD shows a milder form of illness with a better prognosis.
IntroductionFaces of comorbidity in bipolar disorderManagement issuesDiagnostic considerationsThe role of systematic screeningGeneral treatment considerationsTreatment phasesPharmacotherapyIssues related to specific medicationsConclusion
References
Recognition and management of mood symptoms in individuals using alcohol and/or other drugs represent a daily challenge for clinicians in both inpatient and outpatient treatment settings. Diagnosis of underlying mood disorders in the context of ongoing substance abuse requires careful collection of psychiatric history, and is often critical for optimal treatment planning and outcomes. Failure to recognize major depression or bipolar disorders in these patients can result in increased relapse rates, recurrence of mood episodes, and elevated risk of completed suicide. Over the past decade, epidemiologic research has clarified the prevalence of comorbid mood disorders in substance-dependent individuals, overturning previous assumptions that depression in these patients is simply an artifact of intoxication and/or withdrawal, therefore requiring no treatment. However, our understanding of the bidirectional relationships between mood and substance use disorders in terms of their course(s) of illness and prognoses remains limited. Like-wise, strikingly little treatment research exists to guide clinical decision making in co-occurring mood and substance use disorders, given their high prevalence and public health burden. Here we overview what is known and the salient gaps of knowledge where data might enhance diagnosis and treatment of these complicated patients.
Alcohol use disorders such as dependence, abuse, or hazardous use are frequently seen as comorbid conditions in bipolar affective disorders. These comorbid disorders significantly mutually influence each other’s severity and prognosis, result in a more severe course of both diseases and lead to more complications such as rapid cycling or mixed episodes prospectively. Individuals with a primary alcohol use disorder onset may have a better prognosis for the affective symptoms but for not drinking and drug use consequences.
Treatment options have been extended by a number of studies during the last half decade. In comorbid patients, cognitive behavioral therapy can be employed, when the patient is stabilized affectively using a mood stabilizer such as lithium. A significant reduction of alcohol use was reported from a study adding valproate to lithium, while other studies with antipsychotics or naltrexone and acamprosate did not yield any efficacy on affective symptoms or drinking patterns.
In summary, comorbid individuals with bipolar and alcohol and substance use disorders are severely and chronically affected by both diseases. Treatment options are increasing, including psychotherapy and treatment with mood stabilizers.
Bien que la cooccurrence d’un trouble de l’humeur et d’un trouble addictif soit fréquente, à ce jour, peu de travaux scientifiques recommandent une ou plusieurs stratégies de prise en charge pharmacologique de ces troubles comorbides. Dans cette revue non systématique de la littérature, nous avons recherché les essais cliniques randomisés contrôlés en double aveugle ayant évalué une ou plusieurs stratégies pharmacologiques utilisées pour prendre en charge un trouble de l’humeur cooccurrent à un trouble dû à l’usage de substances. Les troubles de l’humeur inclus ont été le trouble bipolaire et le trouble dépressif. Les approches psychosociales n’ont pas été évaluées. La prévalence vie entière des troubles du spectre bipolaire et du trouble dépressif sont respectivement de 4,4 % et de 14,9 %. La prévalence vie entière d’un trouble du à l’usage de substance est de 43 % et de 17,2 %, respectivement chez les patients souffrant d’un trouble bipolaire (60,3 % pour le trouble bipolaire I) et chez les patients souffrant d’un trouble dépressif. Un seul essai clinique randomisé contrôlé en double aveugle a montré une association positive entre la prise d’un traitement supplémentaire au traitement normothymique, la citicoline, et la diminution de la consommation d’une substance autre que l’alcool, la cocaïne, par des patients souffrant d’un trouble bipolaire. Le corpus d’études scientifiques actuellement disponible ne nous permet pas de déterminer précisément si un traitement antidépresseur est efficace pour prendre en charge les patients déprimés avec un trouble addictif cooccurrent, mais seulement de supposer un effet bénéfique modeste sur cette population de patients. Dans les essais cliniques ayant évalué l’efficacité d’un traitement dans le trouble bipolaire ou le trouble dépressif, les patients avec un trouble addictif cooccurrent ont été le plus souvent exclus. La réalisation d’autres études est indispensable à l’élaboration des premières stratégies de prise en charge pharmacologique de patients souffrant d’un trouble dû à l’usage de substance et d’un trouble de l’humeur comorbide. En pratique clinique courante, la prise en charge du trouble dû à l’usage de substances doit être intégrée à la prise en charge du trouble de l’humeur. La prévention et la prise en charge d’un trouble dû à l’usage de substance est particulièrement recommandée pour les patients dont l’âge de début du trouble bipolaire est précoce.
The prevalence of comorbid alcohol, other drug, and mental disorders in the US total community and institutional population was determined from 20,291 persons interviewed in the National Institute of Mental Health Epidemiologic Catchment Area Program. Estimated US population lifetime prevalence rates were 22.5% for any non-substance abuse mental disorder, 13.5% for alcohol dependence-abuse, and 6.1% for other drug dependence-abuse. Among those with a mental disorder, the odds ratio of having some addictive disorder was 2.7, with a lifetime prevalence of about 29% (including an overlapping 22% with an alcohol and 15% with another drug disorder). For those with either an alcohol or other drug disorder, the odds of having the other addictive disorder were seven times greater than in the rest of the population. Among those with an alcohol disorder, 37% had a comorbid mental disorder. The highest mental-addictive disorder comorbidity rate was found for those with drug (other than alcohol) disorders, among whom more than half (53%) were found to have a mental disorder with an odds ratio of 4.5. Individuals treated in specialty mental health and addictive disorder clinical settings have significantly higher odds of having comorbid disorders. Among the institutional settings, comorbidity of addictive and severe mental disorders was highest in the prison population, most notably with antisocial personality, schizophrenia, and bipolar disorders.
Brain phosphatidylcholine (PC) levels are regulated by a balance between synthesis and hydrolysis. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1alpha/beta) activate phospholipase A(2) (PLA(2)) and PC-phospholipase C (PC-PLC) to hydrolyze PC. PC hydrolysis by PLA(2) releases free fatty acids including arachidonic acid, and lyso-PC, an inhibitor of CTP-phosphocholine cytidylyltransferase (CCT). Arachidonic acid metabolism by cyclooxygenases/lipoxygenases is a significant source of reactive oxygen species. CDP-choline might increase the PC levels by attenuating PLA(2) stimulation and loss of CCT activity. TNF-alpha also stimulates proteolysis of CCT. TNF-alpha and IL-1beta are induced in brain ischemia and may disrupt PC homeostasis by increasing its hydrolysis (increase PLA(2) and PC-PLC activities) and inhibiting its synthesis (decrease CCT activity). The beneficial effects of CDP-choline may result by counteracting TNF-alpha and/or IL-1 mediated events, integrating cytokine biology and lipid metabolism. Re-evaluation of CDP-choline phase III stroke clinical trial data is encouraging and future trails are warranted. CDP-choline is non-xenobiotic, safe, well tolerated, and can be considered as one of the agents in multi-drug treatment of stroke.
Background:
CDP-choline has a widespread, but not exclusive use in the treatment of disorders of a cerebrovascular nature. The many years of its use have caused an evolution in dosage, method of administration, and selection of patients to which the treatment was given. Design of the clinical studies, including length of observation, severity of disease, and methodology of evaluation of the results have also varied. In spite of uncertainties about its efficacy, CDP-choline is frequently prescribed for cognitive impairment in several continental European countries, especially when the clinical picture is predominantly one of cerebrovascular disease.
Objectives:
The objective is to assess the efficacy of CDP-choline (cytidinediphosphocholine) in the treatment of cognitive, emotional, and behavioural deficits associated with chronic cerebral disorders of older people.
Search strategy:
The CDCIG register of trials and other databases were searched in July 2000 for all relevant, non-animal randomized controlled trials using the terms CDP-choline/CDP, Citicoline, Cytidine Diphosphate choline and Diphosphocholine. The Psychlit (1974-1996), Psychiatry (1980-1996) and MEDLINE electronic databases have been searched independently by the reviewers. The reviewers have also contacted manufacturers of CDP-choline.
Selection criteria:
All relevant, non-animal, unconfounded, double-blind, placebo-controlled, randomized trials of CDP-choline for patients with cognitive impairment due to chronic cerebral disorders are considered for inclusion in the review.
Data collection and analysis:
Two reviewers independently reviewed the included studies, extracted the data, and pooled when appropriate and possible. The pooled odd ratios (95% CI) or the average differences (95% CI) were estimated. No intention-to-treat data were available from the studies included.
Main results:
Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, 3 studies used cycles extending over 2 and 3 months and one study observed continuous administration over 3 months. The studies differed in dose, inclusion criteria for subjects, and outcome measures. Results are reported for the domains of attention, memory testing, behavioural rating scales, global clinical impression and tolerability. There is no significant evidence of a beneficial effect of CDP-choline on attention. There are modest, but statistically significant, beneficial effects of CDP-choline on memory function and behaviour. For the outcome of clinical global impression, the odds ratio for improvement in the subjects treated with CDP-choline as opposed to the subjects treated with placebo is 8.89 [5.19 to 15.22]. The drug is well tolerated.
Reviewer's conclusions:
There is some evidence that CDP-choline has a positive effect on memory and behaviour in at least the short term. The evidence of benefit from global impression is stronger, but is still limited by the duration of the studies. There is evidence that the effect of treatment is more homogeneous for patients with cognitive impairment secondary to cerebrovascular disorder. Further studies with a more appropriate length of treatment are recommended owing to the chronic and irreversible nature of the disorders for which this treatment is indicated.
Background:
Despite the high prevalence of dysthymia and its associated morbidity, few controlled trials have evaluated the efficacy of antidepressant medication for this disorder. A 12-week, double-blind, placebo-controlled, randomized, multicenter trial was performed to evaluate the safety and efficacy of sertraline hydrochloride and imipramine hydrochloride in treating dysthymia.
Methods:
A total of 416 outpatients (271 women and 145 men) aged 25 to 65 years with DSM-III-R-difined, early-onset, primary dysthymia without concurrent major depression were randomized to 12 weeks of treatment with sertraline, imipramine, or placebo.
Results:
Both active treatments resulted in significantly reduced scores on the 17-item Hamilton Rating Scale for Depression (P=.04 and P=.01 for sertraline and imipramine vs placebo, respectively), the Montgomery Asberg Depression Rating Scale (P=.01 and P=.003 vs pIacebo, respectively), Hopkins Symptom Checklist (P<.05), and the self-rated version of the Inventory of Depressive Symptoms (P<.05). With the use of a Clinical Global Impressions improvement score of 1 or 2 (very much or much improved) to define response, response rates were 59% for sertraline, 64% for imipramine, and 44% for pIacebo (P=.02 for sertraline vs placebo and P<.001 for imipramine vs placebo). A significantly greater proportion of patients receiving imipramine than those receiving sertraline or placebo discontinued treatment because of adverse events (P=.001 and P<.001, respectively).
Conclusions:
Pharmacotherapy provides considerable relief from the symptoms of dysthymia in patients suffering from this chronic affective disorder, with both sertraline and imipramine being more effective than pIacebo. The greater tolerability of sertraline is an important consideration because of the chronicity of dysthymia, which may require prolonged treatment with antidepressant medication.
An eleven item clinician-administered Mania Rating Scale (MRS) is introduced, and its reliability, validity and sensitivity are examined. There was a high correlation between the scores of two independent clinicians on both the total score (0.93) and the individual item scores (0.66 to 0.92). The MRS score correlated highly with an independent global rating, and with scores of two other mania rating scales administered concurrently. The score also correlated with the number of days of subsequent stay in hospital. It was able to differentiate statistically patients before and after two weeks of treatment and to distinguish levels of severity based on the global rating.
The therapeutic effect of CDP choline was investigated in 8 patients with depressive disease. The effect of acute i.v. CDP choline administration on plasma growth hormone (GH) levels was also evaluated. The finding of a reduced GH response confirms that an impairment in dopamine metabolism can be a decisive feature in the genesis of depressive disease. Moreover, the good improvement in the mental state obtained in all the patients suggests the possibility of a new causal therapy.
1. The effects of Adafenoxate (Adf), meclofenoxate (Mf) and citicholine (CCh) administered at a daily dose of 100 mg/kg for 7 days on the levels of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the frontal cerebral cortex, striatum, hippocampus and hypothalamus of rats were studied. 2. Adafenoxate increased the NA level in the striatum and decreased it in the hypothalamus; it increased the DA level in the cerebral cortex and hypothalamus and decreased it in the striatum; it increased the 5-HT level in the cerebral cortex and decreased it in the hippocampus. 3. Meclofenoxate decreased the NA level in the cerebral cortex and hypothalamus; it increased the DA level in the hippocampus and hypothalamus and the 5-HT level in the cerebral cortex, striatum, hippocampus and hypothalamus. 4. Citicholine increased the NA level in the cerebral cortex and hypothalamus; it increased the DA level in the striatum and the 5-HT level in the cerebral cortex, striatum and hippocampus. 5. An attempt is made to explain some similarities and differences in the behavioral effects of the drugs tested (and those observed in other studies) by the changes they induce in brain biogenic monoamines.
Abuse of multiple substances can coexist in many patients who present with symptoms indistinguishable from any Bipolar Disorder. Failure to recognize and treat this coexistent substance abuse may preclude the proper management of the bipolar disorder.
To test the verbal memory of older volunteers given citicoline.
A randomized, double-blind, placebo-controlled, parallel group design was employed in the initial study. After data analysis, a subgroup was identified whose members had relatively inefficient memories. These subjects were recruited for a second study that used a crossover design. The subjects took either placebo or citicoline, 1000 mg/d, for 3 months in the initial study. In the crossover study, subjects took both placebo and citicoline, 2000 mg/d, each for 2 months.
The subjects were 47 female and 48 male volunteers 50 to 85 years old. They were screened for dementia, memory disorders, and other neurological problems. Of the subjects with relatively inefficient memories, 32 participated in the crossover study.
Verbal memory was tested at each study visit using a logical memory passage. Plasma choline concentrations were measured at baseline; at days 30, 60, and 90 in the initial study; and at day 60 of each treatment condition in the crossover study. Plasma choline concentrations and memory scores were analyzed using repeated-measures analysis of variance and covariance, followed by planned comparisons when appropriate.
In the initial study, citicoline therapy improved delayed recall on logical memory only for the subjects with relatively inefficient memories. In the crossover study, the higher dosage of citicoline was clearly associated with improved immediate and delayed logical memory.
Citicoline therapy improved verbal memory functioning in older individuals with relatively inefficient memories. Citicoline may prove effective in treating age-related cognitive decline that may be the precursor of dementia.
Synopsis
The psychometric properties of the 28- and 30-item versions of the Inventory of Depressive Symptomatology, Clinician-Rated (IDS-C) and Self-Report (IDS-SR) are reported in a total of 434 (28-item) and 337 (30-item) adult out-patients with current major depressive disorder and 118 adult euthymic subjects (15 remitted depressed and 103 normal controls). Cronbach's α ranged from 0·92 to 0·94 for the total sample and from 0·76 to 0·82 for those with current depression.
Item total correlations, as well as several tests of concurrent and discriminant validity are reported. Factor analysis revealed three dimensions (cognitive/mood, anxiety/arousal and vegetative) for each scale. Analysis of sensitivity to change in symptom severity in an open-label trial of fluoxetine ( N = 58) showed that the IDS-C and IDS-SR were highly related to the 17-item Hamilton Rating Scale for Depression. Given the more complete item coverage, satisfactory psychometric properties, and high correlations with the above standard ratings, the 30-item IDS-C and IDS-SR can be used to evaluate depressive symptom severity. The availability of similar item content for clinician-rated and self-reported versions allows more direct evaluations of these two perspectives.
Despite the high prevalence of dysthymia and its associated morbidity, few controlled trials have evaluated the efficacy of antidepressant medication for this disorder. A 12-week, double-blind, placebo-controlled, randomized, multicenter trial was performed to evaluate the safety and efficacy of sertraline hydrochloride and imipramine hydrochloride in treating dysthymia.
A total of 416 outpatients (271 women and 145 men) aged 25 to 65 years with DSM-III-R-defined, early-onset, primary dysthymia without concurrent major depression were randomized to 12 weeks of treatment with sertraline, imipramine, or placebo.
Both active treatments resulted in significantly reduced scores on the 17-item Hamilton Rating Scale for Depression (P = .04 and P = .01 for sertraline and imipramine vs placebo, respectively), the Montgomery-Asberg Depression Rating Scale (P = .01 and P = .003 vs placebo, respectively), Hopkins Symptom Checklist (P < .05), and the self-rated version of the Inventory of Depressive Symptoms (P < .05). With the use of a Clinical Global impressions improvement score of 1 or 2 (very much or much improved) to define response, response rates were 59% for sertraline, 64% for imipramine, and 44% for placebo (P = .02 for sertraline vs placebo and P < .001 for imipramine vs placebo). A significantly greater proportion of patients receiving imipramine than those receiving sertraline or placebo discontinued treatment because of adverse events (P = .001 and P < .001, respectively).
Pharmacotherapy provides considerable relief from the symptoms of dysthymia in patients suffering from this chronic affective disorder, with both sertraline and imipramine being more effective than placebo. The greater tolerability of sertraline is an important consideration because of the chronicity of dysthymia, which may require prolonged treatment with antidepressant medication.
This study examined choline augmentation of lithium for rapid-cycling bipolar disorder. Choline bitartrate was given openly to 6 consecutive lithium-treated outpatients with rapid-cycling bipolar disorder. Five patients also underwent brain proton magnetic resonance spectroscopy. Five of 6 rapid-cycling patients had a substantial reduction in manic symptoms, and 4 patients had a marked reduction in all mood symptoms during choline therapy. The patients who responded to choline all exhibited a substantial rise in the basal ganglia concentration of choline-containing compounds. Choline was well tolerated in all cases. Choline, in the presence of lithium, was a safe and effective treatment for 4 of 6 rapid-cycling patients in our series. A hypothesis is suggested to explain both lithium refractoriness in patients with bipolar disorder and the action of choline in mania, which involves the interaction between phosphatidylinositol and phosphatidylcholine second-messenger systems.
The exogenous administration of cytidine-5'-diphosphate (CDP)-choline has been used extensively as a brain activator in different neurological disorders that are associated with memory deficits. A total of 50 rats were utilized to (a) determine whether exogenously administered CDP-choline could attenuate posttraumatic motor and spatial memory performance deficits and (b) determine whether intraperitoneal (i.p.) administration of CDP-choline increases acetylcholine (ACh) release in the dorsal hippocampus and neocortex. In the behavioral study, traumatic brain injury (TBI) was produced by lateral controlled cortical impact (2-mm deformation/6 m/sec) and administered CDP-choline (100 mg/kg) or saline daily for 18 days beginning 1 day postinjury. At 1 day postinjury, rats treated with CDP-choline 15 min prior to assessment performed significantly better than saline-treated rats. Between 14-18 days postinjury, CDP-choline-treated rats had significantly less cognitive (Morris water maze performance) deficits that injured saline-treated rats. CDP-choline treatment also attenuated the TBI-induced increased sensitivity to the memory-disrupting effects of scopolamine, a muscarinic antagonist. The microdialysis studies demonstrated for the first time that a single i.p. administration of CDP-choline can significantly increase extracellular levels of ACh in dorsal hippocampus and neocortex in normal, awake, freely moving rats. This article provides additional evidence that spatial memory performance deficits are, at least partially, associated with deficits in central cholinergic neurotransmission and that treatments that enhance ACh release in the chronic phase after TBI may attenuate cholinergic-dependent neurobehavioral deficits.
The Mini-International Neuropsychiatric Interview (M.I.N.I.) is a short structured diagnostic interview, developed jointly by psychiatrists and clinicians in the United States and Europe, for DSM-IV and ICD-10 psychiatric disorders. With an administration time of approximately 15 minutes, it was designed to meet the need for a short but accurate structured psychiatric interview for multicenter clinical trials and epidemiology studies and to be used as a first step in outcome tracking in nonresearch clinical settings. The authors describe the development of the M.I.N.I. and its family of interviews: the M.I.N.I.-Screen, the M.I.N.I.-Plus, and the M.I.N.I.-Kid. They report on validation of the M.I.N.I. in relation to the Structured Clinical Interview for DSM-III-R, Patient Version, the Composite International Diagnostic Interview, and expert professional opinion, and they comment on potential applications for this interview.
The administration of cytidine-5'-diphosphate choline (CDP-choline, citicoline) to animals increases the rate of membrane phospholipid synthesis and elevates brain dopamine levels. Because cocaine dependence has been associated with increases in brain phospholipid precursors, as well as depletion of dopamine within the central nervous system, the present outpatient study was conducted to assess the safety of citicoline (500 mg bid) and to determine if short-term treatment alters mood states and cocaine craving in subjects with a history of cocaine dependence. In addition, measures of drug craving and mood states after presentation of cocaine-related cues were collected on two occasions: before and after 14 days of double-blind treatment with either citicoline or placebo. Subjects did not experience any side effects and citicoline treatment was associated with decreases in self-reported mood states associated with cocaine craving. These preliminary data are encouraging and suggest that citicoline warrants further study as a promising potential treatment for cocaine abuse and dependence that is devoid of side effects.
Memory function is an important but under researched area for neuropsychological investigation in persons with bipolar disorder. Previous studies have reported cognitive deficits on tasks of declarative memory in bipolar patients in the euthymic state.
This study extended these findings by investigating declarative as well as procedural learning and memory in bipolar patients (with and without alcohol abuse) who were examined in the euthymic state. The California Verbal Learning Test, Star Mirror Tracing Task, Pursuit Rotor Task, American National Adult Reading Test, and the Vocabulary Subtest of the WAIS-R, were administered to bipolar patients and control subjects by researchers who were blind to the subject's group.
Bipolar patients performed worse than control subjects on a measure of declarative memory (California Verbal Learning Test) but did not differ from the performance of control subjects on either of the two procedural learning tasks (Pursuit Rotor Task and Star Mirror Task).
These results suggest disturbed function of temporal lobe, but not basal ganglia, structures in persons with bipolar disorder.
Citicoline (cytidine-5'-diphosphocholine; CDP-choline) may reduce central nervous system ischemic injury by stabilizing cell membranes and reducing free radical generation. A previous dose-comparison trial in patients with acute stroke found that 500 mg of citicoline appeared to improve neurological outcome with minimal side effects.
The current trial was a 33-center, randomized, double-blind, efficacy trial in 394 patients comparing placebo (n=127) with citicoline (n=267) (500 mg po daily) for 6 weeks, with a 6-week posttreatment follow-up period. Patients with acute (24 hours) ischemic strokes clinically assessed to be in the middle cerebral artery territory with National Institutes of Health Stroke Scale (NIHSS) > or = 5 were enrolled.
Mean time to treatment was 12 hours, and mean age was 71 for placebo and 70 for citicoline. Although mean baseline NIHSS were similar for both groups, there was a higher percentage of placebo patients with NIHSS <8 (34% vs 22%; P<0.01). The incidence and type of side effects were similar between the groups. The planned primary analysis (logistic regression: 5 categories Barthel) failed the proportional odds assumption and was rendered unreliable. There were no between-group differences seen on the planned secondary assessment analyses at 90 days, including the Barthel Index > or = 95 at 12 weeks (last observation carried forward: placebo 40%; citicoline 40%) or mortality rate (placebo 18%; citicoline 17%). However, post hoc analyses in a subgroup of patients with baseline NIHSS > or = 8 found that citicoline-treated patients were more likely to have a full recovery (Barthel > or = 95): placebo 21%; citicoline 33%; P=0.05; whereas no difference was seen in patients with baseline NIHSS<8 (placebo 77%; citicoline 69%; P>0.1.
The results of this study indicate that citicoline was safe but ineffective in improving the outcome of patients with acute ischemic stroke who were enrolled in this trial. Post hoc analyses indicate that there may be a subgroup of patients with moderate to severe strokes who would benefit.
Bipolar disorder is a common, severe and cyclic psychiatric illness. A strong association between alcohol dependence and bipolar disorder has been reported in numerous studies. The abuse of other drugs including cocaine, amphetamines, opiates, cannabis, and prescription medications in bipolar patients is also an important public health concern and has been less extensively investigated. This review examines the abuse of drugs other than alcohol or nicotine in people with bipolar disorder. The high rates of milder affective symptoms but not mania observed in patients in drug abuse treatment settings suggests the symptoms may in many cases be associated with the drug use. However, such patients presenting in psychiatric settings might be suffering from cyclothymic and related attenuated bipolar disorders (type II). Substance abuse may be associated with medication non-compliance, more mixed or dysphoric mania and possibly an earlier onset of affective symptoms and more hospitalizations. The pharmacotherapy of patients with bipolar disorder and drug abuse is examined, including evidence on the use of mood stabilizers, neuroleptics and the newer atypical antipsychotics in this population.
The majority of pharmacotherapies proposed for cocaine dependence have been marginally effective and frequently have undesirable side effects. We recently demonstrated that short-term treatment with citicoline decreased self-reported desire to use cocaine in crack cocaine users.
The present study was conducted to assess the safety of citicoline in combination with cocaine by investigating whether cocaine-induced cardiovascular and behavioral effects and cocaine plasma levels are altered by citicoline pretreatment.
Eight healthy male and female volunteers who used cocaine on an occasional basis participated in this randomized, placebo-controlled, three-visit study. During all three visits, subjects received an acute intranasal dose of cocaine (0.9 mg/kg) and were continuously monitored for the ensuing 3.5 h. The first visit involved no pretreatment, and visits 2 and 3 were preceded by a 4-day pretreatment period of either citicoline (1 g/day) or placebo.
Citicoline pretreatment did not alter the cardiovascular, physiologic, or subjective effects of acute cocaine.
Although citicoline did not block the acute subjective effects of cocaine in a laboratory environment, the combined use of citicoline and a moderate dose of intranasal cocaine presented no added risk of cardiovascular effects. Further study is necessary to determine whether this medication (which is currently used to treat strokes) will be a useful adjunct to treat cocaine dependence.
Altered brain phospholipid metabolism may be involved in the pathophysiology of cocaine dependence and mood disorders. Evidence suggests that citicoline, a rate-limiting metabolite for phospholipid synthesis, reduces cocaine craving in human addicts. Because antidepressants can reduce cocaine craving, we explored in rats the possibility that citicoline has antidepressant effects. We also tested the primary metabolites of citicoline, cytidine and choline.
We examined if citicoline or metabolites alter immobility in the forced swim test. We used two scoring methods: latency to become immobile, a simple method that identifies antidepressants, and behavioral sampling, a complex method that differentiates antidepressants according to pharmacological mechanisms.
Over a range of doses, citicoline did not affect behavior in the forced swim test. At molar equivalent doses, cytidine dramatically decreased immobility, whereas choline tended to increase immobility. The effects of cytidine resemble those of desipramine, a standard tricyclic antidepressant. None of the treatments affected locomotor activity, and cytidine did not establish conditioned place preferences.
Citicoline does not have effects in the forced swim test, but its primary metabolites have opposing effects: cytidine has antidepressant-like actions, whereas choline has prodepressant-like actions. At antidepressant doses, cytidine lacks stimulant and rewarding properties. This is the first report of potential antidepressant effects of cytidine.
This article discusses the evaluation of cognition in bipolar disorder. The relationships between neuroimaging and neurocognitive abnormalities in bipolar disorder are worthy of additional investigation. Clearly, efforts directed toward phenotyping neuropsychiatric disorders using such measures, in addition to other clinical, neuroimaging, neurophysiologic, and genotypic information, may yield important insights into the development, nature, and course of illness. It is hoped that this understanding will lead to better identification of individuals who may be prone to greater cognitive impairment or decline and those who might be more responsive to specific treatments.
The epidemiology of co-occurring addictive and mental disorders: implications for prevention and service utilization.
- Kessler
Cytidine 5-diphosphocholine (CDP-choline) in stroke and other CNS disorders.
- Adibhatla