The role of pharmacogenetics in treating central nervous system disorders

Symptoms of central nervous system (CNS) disorders include abnormalities in both physical and psychological domains. Many drugs indicated for the treatment of CNS disorders are fraught with side effects and/or poor efficacy which impact patients' quality of life and drives non-compliance. Moreover, for many CNS drugs such as antidepressants and antipsychotics, it takes time to determine whether a particular drug is efficacious in an individual patient. To optimize drug treatment for each patient, prescribing physicians often need to raise or lower doses, switch drug classes, or prescribe additional drugs to mitigate side effects, often in a "trial and error" fashion. Pharmacogenetic (PGx) testing, particularly in the realm of CNS therapy, can reduce the unpredictability of this process. By determining a patient's genetic profile, individual therapy parameters may be predicted pre-treatment for drug efficacy, optimal drug dose, and the risk of adverse drug reactions (ADRs). The intent of this review is to highlight the power of PGx testing to predict the likelihood of ADRs and efficacy during the treatment of the following CNS disorders: epilepsy, bipolar disorder, schizophrenia and depression.     

St John's wort for depression--an overview and meta-analysis of randomised clinical trials.

OBJECTIVE--To investigate if extracts of Hypericum perforatum (St John''s wort) are more effective than placebo in the treatment of depression, are as effective as standard antidepressive treatment, and have fewer side effects than standard antidepressant drugs. DESIGN--Systematic review and meta-analysis of trials revealed by searches. TRIALS--23 randomised trials including a total of 1757 outpatients with mainly mild or moderately severe depressive disorders: 15 (14 testing single preparations and one a combination with other plant extracts) were placebo controlled, and eight (six testing single preparations and two combinations) compared hypericum with another drug treatment. MAIN OUTCOME MEASURES--A pooled estimate of the responder rate ratio (responder rate in treatment group/responder rate in control group), and numbers of patients reporting and dropping out for side effects. RESULTS--Hypericum extracts were significantly superior to placebo (ratio = 2.67; 95% confidence interval 1.78 to 4.01) and similarly effective as standard antidepressants (single preparations 1.10; 0.93 to 1.31, combinations 1.52; 0.78 to 2.94). There were two (0.8%) drop outs for side effects with hypericum and seven (3.0%) with standard antidepressant drugs. Side effects occurred in 50 (19.8%) patients on hypericum and 84 (52.8%) patients on standard antidepressants. CONCLUSION--There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe depressive disorders. Further studies comparing extracts with standard antidepressants in well defined groups of patients and comparing different extracts and doses are needed.     

Antidepressant drugs in the elderly: Are the indications as long term as the treatment?

In a community study of 761 people aged 70 years and over 45 (5·9%) were found to be taking long term tricyclic antidepressants. Forty four were compared with matched controls. There was no evidence that tricyclic antidepressants were being used to compensate for poor physical health or function. Twenty subjects had a clear history of depression; three of these required additional treatment and five might have coped without continued drug treatment. Twelve of the remainder had started treatment with tricyclic antidepressants as hypnotics and 11 as a trial because of suspected depression. They had continued taking the drugs over a long period.Regular review of both the adequacy of and the necessity for continued treatment with tricyclic antidepressants in the elderly is recommended.     

Lay people's attitudes to treatment of depression: results of opinion poll for Defeat Depression Campaign just before its launch.

OBJECTIVE: To investigate the attitudes of the general public towards depression before the Defeat Depression Campaign of the Royal Colleges of Psychiatrists and General Practitioners; these results form the baseline to assess the change in attitudes brought about by the campaign. DESIGN: Group discussions generated data for initial qualitative research. The quantitative survey comprised a doorstep survey of 2003 people in 143 places around the United Kingdom. RESULTS: The lay public in general seemed to be sympathetic to those with depression but reluctant to consult. Most (1704 (85%)) believed counselling to be effective but were against antidepressants. Many subjects (1563 (78%)) regarded antidepressants as addictive. CONCLUSIONS: Although people are sympathetic towards those with depression, they may project their prejudices about depression on to the medical profession. Doctors have an important role in educating the public about depression and the rationale for antidepressant treatment. In particular, patients should know that dependence is not a problem with antidepressants.     

A systematic review of comparative efficacy of treatments and controls for depression

Background

Although previous meta-analyses have examined effects of antidepressants, psychotherapy, and alternative therapies for depression, the efficacy of these treatments alone and in combination has not been systematically compared. We hypothesized that the differences between approved depression treatments and controls would be small.

Methods and Findings

The authors first reviewed data from Food and Drug Administration Summary Basis of Approval reports of 62 pivotal antidepressant trials consisting of data from 13,802 depressed patients. This was followed by a systematic review of data from 115 published trials evaluating efficacy of psychotherapies and alternative therapies for depression. The published depression trials consisted of 10,310 depressed patients. We assessed the percentage symptom reduction experienced by the patients based on treatment assignment. Overall, antidepressants led to greater symptom reduction compared to placebo among both unpublished FDA data and published trials (F = 38.5, df = 239, p<0.001). In the published trials we noted that the magnitude of symptom reduction with active depression treatments compared to controls was significantly larger when raters evaluating treatment effects were un-blinded compared to the trials with blinded raters (F = 2.17, df = 313, p<0.05). In the blinded trials, the combination of antidepressants and psychotherapy provided a slight advantage over antidepressants (p = 0.027) and psychotherapy (p = 0.022) alone. The magnitude of symptom reduction was greater with psychotherapies compared to placebo (p = 0.019), treatment-as-usual (p = 0.012) and waiting-list (p<0.001). Differences were not seen with psychotherapy compared to antidepressants, alternative therapies or active intervention controls.

Conclusions

In conclusion, the combination of psychotherapy and antidepressants for depression may provide a slight advantage whereas antidepressants alone and psychotherapy alone are not significantly different from alternative therapies or active intervention controls. These data suggest that type of treatment offered is less important than getting depressed patients involved in an active therapeutic program. Future research should consider whether certain patient profiles might justify a specific treatment modality.     

Theory of active antidepressants: a nonsynaptic approach to the treatment of depression

Although depression is one of the major neuropsychiatric disorders, the success rate of medication for any drug is about 60%, which means that approximately 40% of the patients does not respond to the initial treatment. The major aim of this review is to provide a possible explanation for the relative inefficacy of currently used antidepressants and to propose a novel mechanism of action, which might improve the success rate of clinical treatment. According to the monoamine theory the most important neurochemical process in depression is the impairment of monoaminergic neurotransmission and the concomitant decrease of extracellular concentration of noradrenaline and/or serotonin. Since the vast majority of monoaminergic varicosities makes no synaptic contact but is able to release transmitters directly into the extrasynaptic space, the monoaminergic neurotransmission is predominantly nonsynaptic in nature. Depression can be regarded, therefore, as a disease, which is developed (at least in part) on the basis of the impairment of nonsynaptic interactions and the effective treatment has to improve this non-conventional communication in the nervous system. The currently used antidepressants (reuptake inhibitors, negative feedback inhibitors, monoamino oxidase inhibitors) can increase the monoamine levels in the extracellular space only if the monoaminergic cells are electrically active and without an action potential-induced vesicular exocytosis these compounds are ineffective. It is proposed that a selective and moderate induction of the carrier-mediated release of NA and 5-HT might be a better therapeutic approach to the treatment of depression, since this new class of antidepressants, the so-called 'active antidepressants' have a mechanism of action, which is independent from the electrical activity of monoaminergic cells, therefore the extrasynaptic concentration of monoamines and thereby the nonsynaptic communication can be enhanced more efficiently.     

Antidepressants are a rational complementary therapy for the treatment of Alzheimer's disease

There is a high prevalence rate (30-50%) of Alzheimer's disease (AD) and depression comorbidity. Depression can be a risk factor for the development of AD or it can be developed secondary to the neurodegenerative process. There are numerous documented diagnosis and treatment challenges for the patients who suffer comorbidity between these two diseases. Meta analysis studies have provided evidence for the safety and efficacy of antidepressants in treatment of depression in AD patients. Preclinical and clinical studies show the positive role of chronic administration of selective serotonin reuptake inhibitor (SSRI) antidepressants in hindering the progression of the AD and improving patient performance. A number of clinical studies suggest a beneficial role of combinatorial therapies that pair antidepressants with FDA approved AD drugs. Preclinical studies also demonstrate a favorable effect of natural antidepressants for AD patients. Based on the preclinical studies there are a number of plausible antidepressants effects that may modulate the progression of AD. These effects include an increase in neurogenesis, improvement in learning and memory, elevation in the levels of neurotrophic factors and pCREB and a reduction of amyloid peptide burden. Based on this preclinical and clinical evidence, antidepressants represent a rational complimentary strategy for the treatment of AD patients with depression comorbidity.     

Efficacy of New Generation Antidepressants: Differences Seem Illusory

Background

Recently, Cipriani and colleagues examined the relative efficacy of 12 new-generation antidepressants on major depression using network meta-analytic methods. They found that some of these medications outperformed others in patient response to treatment. However, several methodological criticisms have been raised about network meta-analysis and Cipriani''s analysis in particular which creates the concern that the stated superiority of some antidepressants relative to others may be unwarranted.

Materials and Methods

A Monte Carlo simulation was conducted which involved replicating Cipriani''s network meta-analysis under the null hypothesis (i.e., no true differences between antidepressants). The following simulation strategy was implemented: (1) 1000 simulations were generated under the null hypothesis (i.e., under the assumption that there were no differences among the 12 antidepressants), (2) each of the 1000 simulations were network meta-analyzed, and (3) the total number of false positive results from the network meta-analyses were calculated.

Findings

Greater than 7 times out of 10, the network meta-analysis resulted in one or more comparisons that indicated the superiority of at least one antidepressant when no such true differences among them existed.

Interpretation

Based on our simulation study, the results indicated that under identical conditions to those of the 117 RCTs with 236 treatment arms contained in Cipriani et al.''s meta-analysis, one or more false claims about the relative efficacy of antidepressants will be made over 70% of the time. As others have shown as well, there is little evidence in these trials that any antidepressant is more effective than another. The tendency of network meta-analyses to generate false positive results should be considered when conducting multiple comparison analyses.     

普拉克索治疗帕金森病合并抑郁的系统评价

目的:评价普拉克索治疗帕金森病合并抑郁的疗效和安全性。方法:通过电子检索和手工检索,运用Cochrance协作网系统评价的方法对纳入所有应用普拉克索治疗帕金森病合并抑郁的随机对照试验(RCT)进行系统评价。结果:共检出5个RCT,其中3个(454例)符合纳入标准,三项研究随访时间为3-57个月。Meta分析结果显示:1)抑郁改善情况:3项研究随访结束后,应用量表进行评分,普拉克索治疗组抑郁症状改善率明显对照组,两组差异有统计学意义[RR=0.63,95%CI(0.48,0.83),P<0.001];2)UPDRS评分变化:2项研究在治疗末应用UPDRS进行评分,UPDRSⅢ和Ⅱ相对于基线评分,普拉克索组均较对照组明显下降,两组之间差别有统计学意义;3)不良反应:与普拉克索组相比,对照组中因药物不良反应而终止试验研究的病例增多,两组相比有统计学差异[RR=0.48,95%CI(0.34,0.69),p<0.0001]。结论:现有的临床研究证据表明,与对照组相比,普拉克索能够改善帕金森病伴发抑郁病人的抑郁症状,并减轻帕金森病的运动症状,提高病人日常生活活动能力,且安全性较高。但因研究样本局限性,尚需进行大样本长期...     

Fluoxetine subsensitizes a nicotinic mechanism involved in the regulation of core temperature

Fluoxetine HCl, 10 mg/kg ip, twice daily produced subsensitivity to the hypothermic effects of nicotine (base), 1 mg/kg ip, after 1 (p less than 0.02) and 2 (p less than 0.002) weeks of treatment. Phenelzine sulfate, desipramine HCl and bright artificial light produced the same effect. The capacity of three chemically distinct classes of antidepressants and bright artificial light (a treatment for seasonal depression) to produce this result suggests that effects on nicotinic mechanisms may be involved in the mechanism of action of these treatments.     

Repetitive transcranial magnetic stimulation (rTMS) in major depressive episode during pregnancy

Sir: For women diagnosed with Recurrent depressive disorder, pregnancy poses a major treatment challenge. Apart from antidepressants, the most commonly used biological therapeutical method is ECT (electroconvulsive therapy). We believe that similar efficacy can be achieved using rTMS as a safer option with substantially less side effects. So far, only a few case-reports reporting the use of rTMS for treatment of pregnant patients with depression were published.     

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

Antidepressants are commonly used in the treatment of anxiety and depression, medical conditions that affect approximately 17-20% of the population. The clinical effects of antidepressants take several weeks to manifest, suggesting that these drugs induce adaptive changes in brain structures affected by anxiety and depression. In order to develop shorter-acting and more effective drugs for the treatment of anxiety and depression, it is important to understand how antidepressants bring about their beneficial effects. Recent reports suggest that antidepressants can induce neurogenesis in the adult brain, although the mechanisms involved are not clearly understood. In this review, we describe the different neurotransmitter systems that are affected by anxiety and depression and how they are modulated by antidepressant treatment with a focus on signaling molecules and pathways that are activated during neurotransmitter receptor induced neurogenesis.     

Influence of body mass index on the choice of therapy for depression and follow‐up care

Objective: Overweight and obese patients commonly suffer from depression and choice of depression therapy may alter weight. We conducted a cohort study to investigate whether obesity is associated with treatment choices for depression; and whether obesity is associated with appropriate duration of depression treatment and receipt of follow‐up visits. Design and Methods: Adults with a diagnosis of depression between January 1, 2006 and March 31, 2010 who had 1+ new episodes of an antidepressant medication and/or psychotherapy were eligible. Medication use, encounters, diagnoses, height, and weight were collected from health plan databases. We modeled receipt of the different therapies (medication and psychotherapy) by BMI and BMI trajectory during the 9‐months prior to initiation of therapy using logistic regression models that accommodated correlation within provider and adjusted for covariates. We modeled BMI via a restricted cubic spline. Fluoxetine was the reference treatment option in the medication models. Results: Lower BMI was associated with greater use of mirtazapine, and a declining BMI prior to treatment was associated with greater odds of initiating mirtazapine and paroxetine. Higher BMI was associated with greater odds of initiating bupropion even after adjustment for smoking status. Obese patients were less likely to receive psychotherapy and less likely to receive appropriate duration (180‐days) of depression treatment compared to normal weight subjects. Conclusions: Our study provides evidence that BMI is considered when choosing therapy but associations were weak. Our results should prompt discussion about recommending and choosing depression treatment plans that optimize depression care and weight management concurrently. Differences in care and follow‐up by BMI warrant additional research.     

Childhood and adolescent depression: why do children and adults respond differently to antidepressant drugs?

Childhood and adolescent depression is an increasingly problematic diagnosis for young people due to a lack of effective treatments for this age group. The symptoms of adult depression can be treated effectively with multiple classes of antidepressant drugs which have been developed over the years using animal and human studies. But many of the antidepressants used to treat adult depression cannot be used for pediatric depression because of a lack of efficacy and/or side effects. The reason that children and adolescents respond differently to antidepressant treatment than adults is poorly understood. In order to better understand the etiology of pediatric depression and treatments that are effective for this age group, the differences between adults, children and adolescents needed to be elucidated. Much of the understanding of adult depression has come from studies using adult animals, therefore studies using juvenile animals would likely help us to better understand childhood and adolescent depression. Recent studies have shown both neurochemical and behavioral differences between adult and juvenile animals after antidepressant treatment. Juvenile animals have differences compared to adult animals in the maturation of the serotonergic and noradrenergic systems, and in dose of antidepressant drug needed to achieve similar brain levels. Differences after administration of antidepressant drug have also been reported for adrenergic receptor regulation, a physiologic hypothermic response, as well as behavioral differences in two animal models of depression. The differences between adults and juveniles not only in the human response to antidepressants but also with animals studies warrant a specific distinction between the study of pediatric and adult depression and the manner in which new treatments are pursued.     

The Norwegian naturalistic treatment study of depression in general practice (NORDEP)-I: randomised double blind study

ObjectiveTo evaluate the efficacy of emotional support and counselling combined with placebo or antidepressants with single or dual mechanism of action in the treatment of depression in primary care.DesignRandomised double blind study.SettingSeveral locations in Norway.Subjects372 patients with depression.Results Intention to treat analyses showed 47% remission in patients randomised to placebo compared with 61% remission in patients randomised to sertraline (odds ratio 0.56, 95% confidence interval 0.33 to 0.96) and 54% in patients randomised to mianserin (0.75, 0.44 to 1.27). Women responded better than men (1.86, 1.17 to 2.96). Subgroup analyses showed that subjects with recurrent depression (n=273) responded more frequently to sertraline than to placebo (0.43, 0.23 to 0.82) than those having their first episode of depression (1.18, 0.39 to 3.61). Statistically significant interactions between type of drug treatment and history of depression were not shown by logistic regression.Conclusion The combination of active drug and simple psychological treatment (counselling, emotional support, and close follow up over a 24 week period) was more effective than simple psychological treatment alone, in particular for those with recurrent depression. Overall, women may benefit more than men. If confirmed in future studies, the findings should lead to more differentiated treatment guidelines for depression in primary care.

Key messages

• The effectiveness of simple psychological treatment and active drug provided by general practitioners is comparable to treatment results reported by psychiatrists and clinical psychologists
• Treatment benefits women more than men
• There may be differences in response to treatment depending on the nature of depression
• A 6 month treatment period is necessary to evaluate effectiveness of treatments for depression in general practice
• The development of more differentiated treatment guidelines for depression in primary care is needed

     

Goldenhar syndrome associated with prenatal maternal Fluoxetine ingestion: Cause or coincidence?

Goldenhar syndrome, also known as oculo‐auriculo‐vertebral spectrum, is a complex, heterogeneous condition characterized by abnormal prenatal development of facial structures. We present the occurrence of Goldenhar syndrome in an infant born to a woman with a history of prenatal Fluoxetine ingestion throughout her pregnancy. Because this is the first reported case associating maternal Fluoxetine intake with fetal craniofacial malformations, a potential mechanism of injury is discussed. The propositus, a male born from nonconsanguinous parents, had facial asymmetry with right microtia and mandibular hypoplasia; he also had bilateral hypoplastic macula, scoliotic deformity of the thoracic spine, and ventricular septal defect. The mother was under treatment with Fluoxetine 20 mg/day prior to conception and maintained the same dosage throughout her pregnancy. The drug is a selective serotonin re‐uptake inhibitor, the most widely prescribed for the treatment of depression. The occurrence of developmental aberrations may be caused by a profound serotonin receptor suppressive state in utero leading to aberrant clinical manifestations of the first and second branchial arches. Despite the very many limitations of case reporting of teratogenic events, it remains an important source of information on which more advanced research is based. Birth Defects Research (Part A) 2010. © 2010 Wiley‐Liss, Inc.     

Protocol of a randomized controlled trial of the effectiveness of physician education and activation versus two rehabilitation programs for the treatment of Whiplash-associated Disorders: The University Health Network Whiplash Intervention Trial

Background

Depression frequently occurs in the elderly. Its cause is largely unknown, but several studies point to disturbances of biological rhythmicity. In both normal aging, and depression, the functioning of the suprachiasmatic nucleus (SCN) is impaired, as evidenced by an increased prevalence of day-night rhythm perturbations, such as sleeping disorders. Moreover, the inhibitory SCN neurons on the hypothalamus-pituitary adrenocortical axis (HPA-axis) have decreased activity and HPA-activity is enhanced, when compared to non-depressed elderly. Using bright light therapy (BLT) the SCN can be stimulated. In addition, the beneficial effects of BLT on seasonal depression are well accepted. BLT is a potentially safe, nonexpensive and well accepted treatment option. But the current literature on BLT for depression is inconclusive.

Methods/Design

This study aims to show whether BLT can reduce non-seasonal major depression in elderly patients. Randomized double blind placebo controlled trial in 126 subjects of 60 years and older with a diagnosis of major depressive disorder (MDD, DSM-IV/SCID-I). Subjects are recruited through referrals of psychiatric outpatient clinics and from case finding from databases of general practitioners and old-people homes in the Amsterdam region. After inclusion subjects are randomly allocated to the active (bright blue light) vs. placebo (dim red light) condition using two Philips Bright Light Energy boxes type HF 3304 per subject, from which the light bulbs have been covered with bright blue- or dim red light- permitting filters. Patients will be stratified by use of antidepressants. Prior to treatment a one-week period without light treatment will be used. At three time points several endocrinological, psychophysiological, psychometrically, neuropsychological measures are performed: just before the start of light therapy, after completion of three weeks therapy period, and three weeks thereafter.

Discussion

If BLT reduces nonseasonal depression in elderly patients, then additional lightning may easily be implemented in the homes of patients to serve as add-on treatment to antidepressants or as a stand-alone treatment in elderly depressed patients. In addition, if our data support the role of a dysfunctional biological clock in depressed elderly subjects, such a finding may guide further development of novel chronobiological oriented treatment strategies.

Trial registration

ClinicalTrials.gov identifier: NCT00332670     

Value of adjuvant treatment with imipramine for lumbosacral pain syndrome]

The antidepressants have been reported to be effective in the treatment of many pain syndromes, for example headache and neuralgia. The pain of the study was to evaluate the effectiveness on small (75 mg per die) dose of imipramine administered additionally to the routine. Conservative treatment of patients with acute low back pain. The analysis of six different indices of improvement revealed, that the outcome of therapy in the group of 50 patients treated with imipramine was significantly better, than in comparable group treated routinely. The effect of imipramine have not been related to the occurrence of depression or to the other factors from anamnesis and physical examination influencing pain.