New-generation Antidepressants Research Articles

New-Generation, Non-SSRI Antidepressants: Therapeutic Drug Monitoring and Pharmacological Interactions. Part 1: SNRIs, SMSs, SARIs

New-generation antidepressants (NGAs) are the latest additions to the clinician's arsenal in the fight against depression. After the introduction of selective serotonin reuptake inhibitors (SSRIs), a plethora of other groups followed, identified by their main mechanisms of activity: serotonin and norepinephrine reuptake inhibitors (SNRI); serotonin modulators and stimulators (SMS); serotonin antagonists and reuptake inhibitors (SARI); noradrenergic and selective serotonergic antidepressants (NaSSA); norepinephrine reuptake inhibitors (NeRI); serotonin, norepinephrine and dopamine reuptake inhibitors (SNDRI) or triple reuptake inhibitors (TRI); and melatonin and serotonin agonists (MaSA). Although SSRIs are still the most widely used and well known NGAs, the other groups are increasingly being used in the current therapeutic settings obtaining comparable clinical results, and with tolerability and safety profiles that can often provide significant advantages over those of SSRIs. Scopus and PubMed databases were searched for the most significant papers centered on the medicinal chemistry, pharmacodynamics, pharmacokinetics and analysis in human biological fluids of the following antidepressants: venlafaxine, duloxetine, milnacipran, trazodone, vortioxetine, vilazodone. The main characteristics of commercially available non-SSRI NGAs (belonging to the SNRI, SARI and SMS classes) are described, focusing on the role of analytical methods that can be applied to perform therapeutic drug monitoring (TDM), but also including drug pharmacokinetics, metabolism and interactions.

Comparative efficacy and tolerability of new-generation antidepressants for major depressive disorder in children and adolescents: protocol of an individual patient data meta-analysis

IntroductionAlthough previous conventional meta-analyses and network meta-analyses have provided some important findings about pharmacological treatments for children and adolescents with depressive disorders in the past decades, several questions still remain...

A retrospective historical study evaluating the safe use of current antidepressants in cardiology practice

To confirm the data available in the literature on the cardiac safety of antidepressants. The archival data of 146 case histories were retrospectively analyzed. A study sample consisted of 96 cardiac inpatients regularly taking an antidepressant for more than 3 days during treatment for the underlying cardiovascular disease. The safe use of antidepressants was evaluated in terms of initial electrocardiogram (ECG) QTc interval changes, systolic and diastolic blood pressures (BP) (SBP and DBP), heart rate (HR), and hemorrhagic complications. The data obtained over periods of 3- and 6-8 days were analyzed. The sample showed no clinically significant ECG QTc interval changes when taking regularly antidepressants within 8 days. Analysis of the dynamics of BP and HR in patients receiving antidepressants revealed no statistically significant differences in these indicators before and 3 and 6-8 days after drug administration. No case of hemorrhagic complications was seen in the study group taking antidepressants. The investigation generally confirms the high cardiac safety of new-generation antidepressants within at least the first week of therapy. Noteworthy are the low daily drug dosages (relatively specified in the instructions) that are sufficient for most cardiac patients with depressive disorders and an additional factor for minimizing adverse reactions.

Antidepressants and risk of dementia in migraine patients: A population-based case-control study

To ascertain the relationship between receipt of antidepressant agents and the risk of subsequent dementia in migraine patients. A population-based case-control analysis, using the Taiwan National Health Insurance Research Database. We identified 1774 patients with dementia and 1774 matched nondementia controls from migraine patients enrolled in the Taiwan National Health Insurance program between 2005 and 2011. The proportional distributions of exposure to three classes of antidepressant were compared between dementia and nondementia groups. Univariable and multivariable logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of dementia based on antidepressant exposure. The proportions of subjects taking tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and new-generation antidepressants (NGAs) in dementia versus nondementia groups are 52.3 vs 51.2%, 25.5 vs 30.7%, and 18.8 vs 6.26%, respectively. The adjusted ORs of dementia were 1.02 (95% CI=0.89, 1.17; P=0.56) for TCAs, 0.58 (95% CI=0.50, 0.69; P<0.001) for SSRIs, and 4.23 (95% CI=3.34, 5.37; P<0.001) for NGAs. Treatment with SSRIs was associated with a decreased risk of dementia in migraine patients. TCAs showed no association with dementia risk, and NGAs showed increased risk. Given the possibility of confounding by indication, additional prospective trials and basic research are needed before drawing conclusions about the population-level risks for dementia onset conferred by antidepressant medications.

Quantifying indirect evidence in network meta-analysis.

Network meta-analysis enables comprehensive synthesis of evidence concerning multiple treatments and their simultaneous comparisons based on both direct and indirect evidence. A fundamental pre-requisite of network meta-analysis is the consistency of evidence that is obtained from different sources, particularly whether direct and indirect evidence are in accordance with each other or not, and how they may influence the overall estimates. We have developed an efficient method to quantify indirect evidence, as well as a testing procedure to evaluate their inconsistency using Lindsay's composite likelihood method. We also show that this estimator has complete information for the indirect evidence. Using this method, we can assess the degree of consistency between direct and indirect evidence and their contribution rates to the overall estimate. Sensitivity analyses can be also conducted with this method to assess the influences of potentially inconsistent treatment contrasts on the overall results. These methods can provide useful information for overall comparative results that might be biased from specific inconsistent treatment contrasts. We also provide some fundamental requirements for valid inference on these methods concerning consistency restrictions on multi-arm trials. In addition, the efficiency of the developed method is demonstrated based on simulation studies. Applications to a network meta-analysis of 12 new-generation antidepressants are presented. Copyright © 2016 John Wiley & Sons, Ltd.

Associations of Adverse Clinical Course and Ingested Substances among Patients with Deliberate Drug Poisoning: A Cohort Study from an Intensive Care Unit in Japan.

ObjectivesSome patients with deliberate drug poisoning subsequently have an adverse clinical course. The present study aimed to examine whether the type of drugs ingested and psychiatric diagnoses were related to an adverse clinical course.MethodsWe conducted a cohort study of patients with deliberate drug poisoning admitted to the intensive care unit of a university hospital located in Tokyo, Japan, between September 2006 and June 2013. Intensive care unit (ICU) stay of ≥4 days was used as a primary outcome measure, while the incidence of aspiration pneumonitis was used as a secondary outcome measure. Ingested substances and psychiatric diagnoses were used as explanatory variables.ResultsOf the 676 patients with deliberate drug poisoning, 88% had a history of psychiatric treatment and 82% had ingested psychotropic drugs. Chlorpromazine-promethazine-phenobarbital combination drug (Vegetamin®) ranked fifth among the most frequently ingested substances in cases of deliberate drug poisoning and had the highest incidence of prolonged ICU stay (20%) and aspiration pneumonitis (29%). The top three major classes consisted of benzodiazepines (79%), new-generation antidepressants (25%), and barbiturates/non-barbiturates (23%). Barbiturate overdose was independently associated with increased odds of both prolonged ICU stay (8% vs. 17%; odds ratio [OR], 2.97; 95% confidence interval [CI], 1.60–5.55) and aspiration pneumonitis (8% vs. 24%; OR, 3.83; 95% CI, 2.18–6.79) relative to those associated with overdose of only other sedative-hypnotics (i.e., benzodiazepines).ConclusionThese results suggest that judicious prescribing of barbiturates by psychiatrists could reduce the risk of an adverse clinical course when a patient attempts an overdose.

Protocol registration and selective outcome reporting in recent psychiatry trials: new antidepressants and cognitive behavioural therapies.

The selective reporting of favorable outcomes has a serious influence on our evidence base. However, this problem has not yet been systematically investigated in the field of psychiatry. Our study aimed to evaluate registration and outcome reporting in randomized controlled trials (RCTs) of standard treatments for depression: cognitive behavioural therapy (CBT) or new-generation antidepressants (ADs). We searched for reports of RCTs examining the efficacy of CBT or AD for depression that were published between 2011 and 2013. We then compared their primary outcomes in the trial registries and those in publications. We identified 170 trials. Among them, 92 trials (54.1%) were registered, 43 trials (25.3%) were properly registered, and only 32 (18.8%) trials were both properly registered and reported (the primary outcomes as recorded in the registries were reported in publications). There was no statistically significant difference in the proportions of properly registered and reported trials for CBT or AD (relative risk: 0.51, 95% CI: 0.25-1.03). High impact factor journals, commercial funding, publication of protocol, and relatively large sample size were significant predictors of proper registration and reporting. The prevalence of proper registration and reporting is still very low in depression trials.

Prozac Politics: How a Drug Helps Us to Understand Transparency in the Health Sector

While Prozac initially came to be termed the ‘wonder-drug’ for adults suffering from depression, the trend inevitably spread to the treatment of the pediatric population – that is, to children and adolescents aged 8 to 17 years. In 2003, however, America’s main drug regulator – the Food and Drug Authority (FDA) – was the first to approve Prozac for this age group. But reports of the scientific community followed soon, claiming that patients under the age of 18 should not be given antidepressants. There had been disturbing evidence that Prozac’s risks outweighed its benefits and that it led to severe adverse effects, most notably aggressive and suicidal behavior. Unfortunately, their voice was only partly heard: later that same year, the British Medicine and Healthcare Products Regulatory Agency (MHRA) issued a ban on new-generation antidepressants for the treatment of the pediatric population. But while it excluded Prozac from the ban, the European Medicine Agency (EMA) thought differently: it did not only decide to join the bandwagon of prohibiting the prescription of antidepressants for children two years later, but to extend the ban to Prozac as well. Eventually, the decisions by different European drug regulators – and their clashes with the American FDA – unleashed a heated debate about secretive proceedings in the health sector that affected the industry, its regulators, the scientific community, and the patient population. Only three years later, in 2006, the EMA suddenly approved Prozac for the treatment of children and adolescents under the condition that further clinical research was done – notwithstanding previous skepticism. And the debate continues until today. As such, it illustrates the thin line between economic benefit, consumer protection, and scientific progress, together with its mediating factor: disclosure of information or transparency. Furthermore, the case-study mentioned above serves well to highlight the shallow proceedings in the pharmaceutical industry, which, to date, remain corrupt and secretive.

Pharmacological interventions for somatoform disorders in adults.

Pharmacological interventions for somatoform disorders in adults.

What are the effects of newer generation antidepressants in children and adolescents with depressive disorders?

What are the effects of newer generation antidepressants in children and adolescents with depressive disorders?

Амперометрические моноаминоксидазные биосенсоры на основе графитовых электродов и оксида графена как модификатора поверхности для определения некоторых антидепрессантов

Амперометрические моноаминоксидазные биосенсоры на основе графитовых электродов и оксида графена как модификатора поверхности для определения некоторых антидепрессантов

Efficacy of New Generation Antidepressants: Differences Seem Illusory

BackgroundRecently, 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 MethodsA 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.FindingsGreater 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.InterpretationBased 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.

Histamine H1 receptor occupancy by the new-generation antidepressants fluvoxamine and mirtazapine: a positron emission tomography study in healthy volunteers

Histamine H₁ antagonists have hypnotic, appetite-promoting, and sedative effects. The affinities of various antidepressants for histamine receptors have only been partially determined in vitro and animal study. Positron emission tomography (PET) can clarify the in vivo dynamics of antidepressants at histamine receptors. We performed human PET imaging with [¹¹C]doxepin, a selective PET ligand of the histamine H₁ receptor (H₁R), to study the in vivo affinities of fluvoxamine and mirtazapine for the H₁R. The subjects were five male healthy Japanese volunteers. We performed cross-randomized PET imaging after single oral administration of fluvoxamine (25mg), mirtazapine (15 mg), or placebo. PET data were analyzed by region-of-interest and voxel-by-voxel analysis. We concurrently measured plasma drug concentrations, using liquid chromatography/tandem mass spectrometry and subjective sleepiness. The binding potential ratio of mirtazapine in brain cortex was significantly lower than that of fluvoxamine or placebo. Fluvoxamine did not occupy the H₁R, whereas H₁R occupancy (H₁RO) of mirtazapine reached 80-90 % in the cerebral neocortex. In the voxel-by-voxel analysis, the binding potential of mirtazapine was significantly lower than placebo in the dorsolateral prefrontal cortex, lateral temporal cortex, anterior cingulate gyrus, and posterior cingulate gyrus. The H₁RO of mirtazapine depended on the plasma drug concentration (AUC(0-180 min)) and was related to subjective sleepiness. Our results demonstrate a low affinity of fluvoxamine and a very high affinity of mirtazapine for the human brain H₁R in vivo. This study provides a basis for investigating the efficacy of new-generation antidepressants in central histamine systems.

Mirtazapine improves visual hallucinations in Parkinson's disease: a case report

Psychotic symptoms often occur as a complication in Parkinson's disease patients, and a set of criteria for Parkinson's disease with psychosis (PDPsy) has been established. Among these criteria, hallucinations are one of the specific symptoms, with visual hallucinations being the most common. While atypical antipsychotic agents are often used for the treatment of PDPsy, adverse effects, including extrapyramidal symptoms, often hinder its continuation or tolerance. There have been some reports and reviews indicating that antidepressants may be effective for PDPsy and other forms of dementia with psychosis. In this report, we present a patient with PDPsy who was treated with one of the new-generation antidepressants, mirtazapine. Mirtazapine improved the patient's refractory psychotic symptoms, especially her visual hallucinations, without worsening her motor symptoms.

Duloxetine and Pregabalin for Pain Management in Multiple Rheumatic Diseases Associated with Fibromyalgia

The fibromyalgia syndrome (FMS) is characterized by chronic and widespread musculoskeletal pain and soreness accompanied by sleep disorders, chronic fatigue and affective disorders. FMS is often associated with other forms of immuno-rheumatic diseases. Although FMS pathophysiology is still not fully understood, a number of neuroendocrine, neurotransmission and neurosensitive disorders might generate a mechanism for the elicitation of pain by "central sensitization," which is common to many other painful conditions. The present case describes the success of a therapeutic scheme, which associates two different pharmacological classes, anticonvulsants and new-generation antidepressants, when FMS complicates a rare pathology called Cogan's syndrome. The association of two drugs might noticeably affect the molecular mechanisms of difficult pain, thus solving painful conditions of multifactorial origin.

Is the Efficacy of Antidepressants Truly a Myth?

Is the Efficacy of Antidepressants Truly a Myth?

Simultaneous determination of new-generation antidepressants in plasma by gas chromatography–mass spectrometry

We have developed a gas chromatography–mass spectrometry (GC–MS) method for plasma for the determination of new-generation antidepressants, including olanzapine (antipsychotic used in bipolar disorder), and antidepressant selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine and its metabolite norfluoxetine, paroxetine, sertraline, venlafaxine, and mirtazapine. Sample preparation was performed by liquid–liquid extraction with tert-butyl methyl ether. Fluoxetine, norfluoxetine, sertraline, and paroxetine required subsequent derivatization with 1-(heptafluorobutyryl) imidazole (HFBI). The GC separation lasts a total of 23.76 min. Qualitative and quantitative analysis were performed using an electron-impact ionization gas chromatograph interfaced to a mass-selective detector in selected-ion monitoring mode to increase the sensitivity of the method. Method validation was performed taking into account linearity, sensitivity, selectivity, accuracy, precision, and recovery, achieving good results for all the parameters studied. Calibration curves were prepared in the range of 0.005–2 μg/ml (according to the therapeutic and toxic concentrations of each individual compound), with all correlation coefficients R2 > 0.99. The limit of quantification was between 0.005 and 0.1 μg/ml, depending on the compound, whereas the limit of detection ranged from 0.0025 to 0.05 μg/ml. The method is fast and simple, allowing the identification and quantification of some of the most widely used antidepressants at therapeutic or toxic concentrations, and may be useful in routine clinical and forensic toxicology analysis.

A Possible Paradigm Shift

This month, guest editors Laura N. Antar, MD, PhD, and Eric Hollander, MD, and colleagues examine hypotheses about the relationship between inflammation and psychiatric illness. Their articles focus on a possible mechanism of psychiatric disorders that could constitute a major paradigm shift. As a psychiatry resident in the 1960s, I was taught that depression was caused by “anger turned inward,” rather than the humoral theories based on early Greek and Chinese medicine. About the same time, the effectiveness of antipsychotics was becoming realized with the use of chlorpromazine. This, taken together with the antidepressant effects of imipramine and iproniazid, led to the psychopharmacologic revolution and a marked increase in neurobiologic research. Following my residency, I was a fellow at the National Institute of Mental Health (NIMH), also in the mid-1960s, where I was focused on the norepinephrine depletion theory of depression. Also at that time, the NIMH was investigating the role of serotonin. We discovered changes in MHPG (a metabolite of norepinephrine) in patients with depression and our excitement grew. Had we established a biochemical basis for depression? My excitement was immense. The development of fluoxetine in the midto late-1980s shifted the attention to selective serotonin reuptake inhibitors (SSRIs). It was a new twist on the neurotransmitter theme, ultimately becoming the dominant truth. For a while, norepinephrine was nearly forgotten, as was dopamine, despite the fact that it is key in hedonic functions (one of the primary dysfunctions in depression). Maybe the avoidance of developing more potent dopaminergic medications was due to the fear of developing addictive substances. As the therapeutic limitations of the new-generation antidepressants that were more specific in their effect became evident, the field started to realize that the “dirtier” the drug (meaning it affected more neurotransmitters), the more effective it might be for treatment-resistant patients. (Tricyclic antidepressants and monoamine oxidase inhibitors are in this category.)

Presynaptic Selectivity of a Ligand for Serotonin 1A Receptors Revealed by In Vivo PET Assays of Rat Brain

A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT1A) receptor, called Wf-516 (structural formula: (2S)-1-[4-(3,4-dichlorophenyl)piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride), has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET) and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT1A receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT1A receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT1A receptors. In addition, [35S]guanosine 5′-O-[γ-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT1A receptors. This finding has lent support to reports that diverse partial agonists for 5-HT1A receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants.

Major depressive disorder: treatment and future perspective

SUMMARY Major depressive disorder is a mood disorder characterized by both severe affective and neurovegetative symptoms together. It is a common disorder seen in a quarter of consecutively admitted depressed patients and is often associated with severe symptomatology, increased suicide risk, poor acute response to antidepressants and poor acute and long-term treatment outcome. The question of the optimal duration of pharmacotherapy in order to prevent relapse and improve the long-term (i.e., 5-year) outcome is a focus of current investigation. This article will review currently recommended treatment strategies for the acute, continuation and maintenance phases of therapy. In particular, it will address the role of newer-generation antidepressants, the use of mood stabilizers and indications for electroconvulsive therapy. Other possible treatment strategies such as transcranial magnetic stimulation, vagus nerve stimulation, deep brain stimulation and glucocorticoid receptor antagonists will be discussed.