Sertraline-induced akathisia and dystonia misinterpreted as a panic attack.

It is a great honor for me to have been awarded the Sumner Yaffe Lifetime Achievement Award in Pediatric Clinical Pharmacology. Dr. Yaffe has been a lifelong mentor and colleague, a true definer of a discipline, creator of the Pediatric Pharmacology Research Units (PPRU) sponsored by the NICHD, and a dear friend. I am tremendously grateful to the PPAG for honoring me with this award in his name.The last years have been important ones for pediatric therapeutics. The scientific basis has been driven by huge advances in pediatric clinical pharmacology, fundamental understanding of the ontogeny of drug disposition and of drug response. United States legislation including the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act have changed the drug development process, leading to new knowledge about the safe, effective use of medicines in children. Research networks including the Pediatric Pharmacology Research Units (PPRUs), the Children's Oncology Group, and now the Clinical and Translational Science Award (CTSA) network have increased pediatric investigative activities throughout the country. The National Institutes of Health (NIH) and the Food and Drug Administration (FDA) have both played critical roles, with the FDA Critical Path initiative in many ways reflecting scientific thinking about translational medicine driving the NIH CTSAs. Pediatric research incentives and requirements now have been implemented in Europe under the European Medicines Evaluation Agency (EMEA), and the International Conference on Harmonization process has led to harmonization of science, education, and much of regulatory activities among the United States, Europe, and Japan. A new focus on children living in the developing world (really the majority of the world's children) has led to a Pediatric Essential Drug List from the World Health Organization, along with a new "Make Medicines Child-Sized" initiative. Organizations such as the Gates and Clinton Foundations have also focused on the health needs of children throughout the world. All of these activities have engendered a sense of hope for the future of the world's children, and also recognition of the enormous challenges ahead to:1) prevent disease and incapacity; 2)address neglected diseases afflicting the majority of the world's children; 3)develop new knowledge to more effectively understand and treat diseases of the developed and developing world; and 4) assure access of all children to advances in medical science and medical treatment, and equally important, to live in a world of social, political, and economic stability.Perhaps the most exciting scientific advances of the last years have been in the realm of genomics, insights gained literally revolutionizing the way in which we think about disease, diagnosis, and treatment. While we really should not be surprised, with advances in knowledge, much of our previous understanding of biology will have to be changed, and things are turning out not to be as straight forward with respect to organization, expression, and function of our genome as we might have imaged. As we explore the human genome, long standing recognition of human heterogeneity and variability becomes all the more apparent. Claude Bernard, the great 19th century physiologist recognized human idiosyncrasy long ago.Today, we develop ever more targeted medicines, their chemistry designed to interact specifically with human recombinantly expressed targets. Given that we know just how much heterogeneity exists throughout the genome, the questions we should be (but often have not been) asking about a target of a new drug include: 1) Does the target have genetic variants in the population? 2) Are variants likely to alter the effectiveness of the drug? 3) What percentage of the population expresses the variants, and how might this impact the percentage of the population likely to benefit? 4) What is the relevance of the target in the metabolic 'economy' of complex pathways we are trying to impact? 5) Are there alternative/rescue/susceptibility/resilience pathways that may lead to 'escape' from impacting the target, and how do these pathways vary in the population?For so many drugs currently on the market, 40%–80% response (sometimes less) in the population are not uncommon; only rarely will a medicine work in nearly all patients. This may be due to imprecision in diagnosis; in other words, the patient's syndrome is not related to the target of the drug. It could result from inadequate clinical diagnosis (description of the patient's phenotype and resultant treatment of patients with heterogeneous diseases we lump together under a diagnostic category). It could result from a genetic variant in the target for the drug leading to lack of efficacy. It could result from pharmacogenetic variants in drug metabolism or transport, altering the kinetics of the drug, and making standard doses ineffective (or toxic). And, not all variation is genetic, but we need to think about developmental, environmental, dietary, drug-drug and drug-disease interactions and adherence as sources of variability. Traditionally, population variability was "accepted" but not addressed, and drugs were introduced in the hope of being "blockbusters" used by a large population of patients, and if some did not benefit (or developed unexpected side effects), this was unpredictable. We are now moving into a transition period where biomarkers of variability, many based on genomic technologies, will increasingly aid in diagnostic precision, and in selecting medicines most likely to benefit and least likely to harm a specific patient. The era of personalized therapeutics is just beginning, but the promise of an integrated diagnostic/therapeutic approach to individualizing therapeutics holds the opportunity for physicians and patients of establishing individualized benefit: risk, improved health outcomes, and ultimately an increased "value proposition" for pharmacotherapy for the individual and for society as a whole.Before looking in depth at one pediatric therapeutic area as an example, it is worth pointing out an increasing dynamic tension between "comparative effectiveness studies" and "personalized medicine". The key question that needs to be addressed to rise above the politics and focus investigative activities that reflect the realities of human biology and therapeutics is this: In a genetically and environmentally heterogeneous human population with genetically and environmentally heterogeneous diseases (often lumped together under diagnostic categories), are standard comparative efficacy/effectiveness studies and population average outcomes an appropriate approach to improving individual and population health- and cost-benefit? Put differently: Should we be thinking about DRUG OF CHOICE FOR WHOM? Standard comparative effectiveness studies might "demonstrate" no added benefit of a new, more expensive medication over an older generic one on a population basis, but fail to detect those who could optimally benefit from one or the other. I believe we can creatively integrate the best of comparative effectiveness science and genomic science to achieve optimized therapeutic outcomes for each patient, and in so doing, optimize overall health- and cost-effectiveness of therapy. This will require a paradigm shift in effectiveness research, but human diversity in disease causation and response to therapy demands incorporation of individual outcomes and use of biomarkers of efficacy and adverse effects into study designs, and hence to guide rational and effective therapeutics in the real world.It is also important, before focusing on advances in pharmacogenomics and how they will contribute to improve therapeutics, to at least mention that personalized medicine also MUST address issues of patient adherence and the therapeutic relationship between patient and health care provider. In a country where a high percentage of prescriptions are not filled, and many of those that are filled are not taken as prescribed, we have a huge challenge regarding optimizing the social and relational interactions that lead to positive pharmacotherapy. For children, this also includes providing optimal formulations of medicines that enhance administration, accurate and flexible dosing, and long-term adherence. For us all (we are all patients at some time), and for those caring for the sick, somehow we need to re-think the issues of "time and talk", the core of establishing therapeutic relationships. While this is a topic for another article, it is a discussion in which we must engage, and urgently, in our training programs, and in the organization of health care delivery. In summary, optimal personalized therapeutics requires: medicines and formulations that optimize accurate, flexible, palatable, adherent use; personalized care and development of a therapeutic relationship for each patient; and biomarkers to help optimize selection of the right drug for the right patient at the right dose.Using the example of antidepressant treatment of depression in children, I will try to examine some of the features of optimized personalized medicine, from clinical diagnosis through genomic diagnostics, as well as pointing out some hurdles and challenges we face as we enter an increasingly genomic era. While precision in establishing a patient's "phenotype" may seem to be more difficult for depression than for some other conditions, in fact, the issue of phenotypic specificity is crucial to all aspects of medicine. No matter how good a biomarker, genomic or other, may be in predicting outcomes of pharmacotherapy, if applied to a mixed, heterogeneous group of patients, clinical trials and clinical care will fail. True personalized therapeutics will require advances in genomic science, but as we will see in the example of depression, improvements in accurate patient description as well. Clinical diagnosis and the relationship between patient and caregiver will remain the heart of individualized care. Furthermore, electronic medical records will not save us, unless the clinical content, precision of clinical description, standardization of terminology is not markedly enhanced, and linkage enabled, with all appropriate patient confidentiality safeguards, to genomic information. To the extent that "diagnosis" is linked more to billing and codes that do not reflect complex biology, we risk garbage in and garbage out. On the other hand, having rich, detailed phenotypic data and genomic information in formats allowing both for optimized research and patient care will clearly help advance medicine.Recently, there was an excellence "point-counterpoint" discussion about the safety and efficacy of antidepressants in children and adolescents with depression.1,2 Major depressive disorder (MDD) is a potentially life-threatening disease, and its management, pharmacologic and otherwise, remains controversial. Recent studies of selective serotonin reuptake inhibitors (SSRIs), many done by industry under the Best Pharmaceuticals for Children Act and written requests from FDA, have sadly added additional confusion to the field.With respect to efficacy, two carefully conducted trials 7 years apart by the National Institute of Mental Health clearly demonstrated the issue of efficacy of fluoxetine in depression in children and adolescents, with placebo responses around 35% and drug responses around 60%.1 In most of the subsequent industry studies (save for one additional study of industry-sponsored study of fluoxetine), the studies "failed to show efficacy". However, the studies failed NOT because of a decrease in drug effect, but rather because of a very high placebo response rate, often in the mid-50% range. Most of the studies were small; approximately 200 total patients, half on placebo, and, to meet the time requirements for patent expiry, had to be done in a very tight time frame. It appears likely that the studies, rather the drugs, failed, perhaps due to entry criteria (mis-diagnosis of MDD and entry of patients with milder mood disturbance), and other study flaws.From the perspective of adverse drug reactions (ADRs), the issue of suicidal ideation associated with antidepressant therapy has been raised. There is a need for much better ways to monitor and assess suicidal ideation, and no patients in any of the studies actually attempted suicide. Labeling changes, congressional hearings, and associated publicity created the overall impression, however, that SSRIs may not be effective in management of young patients with depression, and that risk of suicidal ideation in younger patients makes the benefit:risk of using the medicines questionable. Concurrent with the publicity, there has been a decreased use of antidepressant drugs in the pediatric population, and a comparable increase in completed suicides.3 While causality is uncertain, the epidemiologic trend is sobering, and many of my pediatric and pediatric psychiatry colleagues now find it increasingly difficult to use these medicines in their patients because of the adverse publicity.Given all this, what is needed for the future, both for clinical trials, but more importantly for patients suffering with MDD? Assay sensitivity in depression studies has long been a problem in adult and pediatric trials.45 Repeated studies of the same drug, seemingly similar in design, often yield conflicting results. This may be due to our inability to define, with adequate precision, the condition we are attempting to treat, the "phenotype" or "diagnosis". The current state of the art in clinical diagnosis, emphasizing the need for accurate ascertainment of phenotype, is thoughtfully discussed by Preskorn.6 The diagnostic process requires expertise, collection of detailed information about the patient's condition, and perhaps most critically, time. The shortage of physicians well-trained in psychiatric diagnosis, and time pressures clearly are impeding care for patients in need. Diagnostic specificity may be all the more difficult in pediatric and adolescent patients, and clinical measures of diagnosis and outcome inconsistently applied among clinicians, investigators, and site. The wide range of placebo responses among studies, from 35%–60% highlights our lack of diagnostic precision.High placebo response is common in most depression trials – many patients do not appear to "need" drugs, although they may benefit from the overall "therapeutic setting". Some patients might not really have the condition we think we are treating – i.e., MDD. Some may have other mood disorders likely to spontaneously improve ("transient depression of adolescence"), and teenagers, in particular, may have mood swings as part of maturation that, if we had better phenotypic and genotypic markers for MDD, we could separate out and avoid drug exposure. The clinical perspective also suggests that it is likely that we may be "over treating" patients who are not likely to need or benefit from a specific intervention. On the other hand, few trials of antidepressants achieve more than 60% benefit. Thus, there are patients suffering from depression who are not helped by a specific drug. One might ask whether they would benefit from a different drug class – see below. Since clinicians will be faced with patients who present with varying mood disorders, they need improved tools for differentiating among those who truly need pharmacotherapy, and those who might be resistant to pharmacotherapy with one or another compound or class of drug.Improvement in benefit to risk also needs to address ADRs. For example, there are data suggesting increased risk of mania in bipolar patients treated with SSRI or tricyclic antidepressants.6 If a patient with bipolar disease presents with depression, and the diagnosis of bipolar disease is not made, they may be at increased risk of "activation" side effects if treated with antidepressants. Similarly, some patients may indeed be at increased risk for drug-mediated suicidal ideation; in the small trials in pediatric patients, one or two of 100 patients in drug treated groups resulted in a "finding" of increase suicidal ideation risk. If we had better phenotypic (clinical) markers of bipolar disease, and other biomarkers of bipolar diagnosis and predictors of suicidal ideation risk, we could better target use of SSRIs and other antidepressant to optimize individual benefit to risk.There are hints beginning to emerge of the future approaches to determining the right treatment for the right patient. Metabolism by polymorphic enzymes, such as CYP2D6 and CYP2C9, can modify half-life of many antidepressants, and have the potential to alter efficacy and dose- (exposure-) related side effects.6 Recent studies of polymorphisms in serotonin and norepinephrine targets of antidepressants suggest altered likelihood of successful treatment with one or another drug class based on genotype.7–11 If we can distinguish patients more likely to benefit from an SSRI, a serotonin-norepinephrine reuptake inhibitor, or other drugs, or who will most likely benefit from psychotherapy (also likely to be modified by both genetic, environment, and developmental factors), we may be able to improve the odds of a beneficial outcome. It is likely that multiple genetic markers will modify outcomes, and genome-controlled trials will contribute to our understanding of the utility of such approaches in the selection of the right treatment for the right patient. Our current therapeutic armamentarium is limited with respect to transmitter targets, and to adequately help all patients, we will need new classes of medicines or combinations of medicines, cognitive behavioral and other "talk" therapies to improve the lives of patients whose condition is resistant to current interventions. Similarly, if we have markers enabling us to diagnose bipolar disease first presenting with depression, we can avoid potentially hazardous therapy and treat these patients with the right medications.An interesting example of interaction among therapeutic modalities was recently published by Walkup et al.12 A comparative study of placebo, an SSRI, and cognitive behavioral therapy was conducted in children with major social phobias/anxiety disorders. Targeted end points were achieved in 23.7% in the placebo group, 54.9% of those receiving an SSRI, and 58.7% of those in the cognitive behavioral therapy group. Both the SSRI and behavioral therapy were statistically significant when compared to placebo, and the two interventions did not differ from each other. A superficial comparative view would argue the two modalities are "the same", and from a cost point of view, the "cheapest" should be the treatment of choice. Looking further at the data, however, the SSRI arm achieved benefit more rapidly, and in an arm including both the SSRI and behavioral intervention, over 80% of patients improved. This could be due to synergy between the two treatments, or that some in either arm who did not respond to that treatment would respond to the alternate therapy. Additional studies, if confirmatory, and perhaps with designs allowing for the treatment of those who failed one arm with the alternative therapy will be important in defining with increased precision those patients most likely to benefit from one or another or both treatments.An FDA review of suicidal ideation suggests possible age dependence in risk.13 Development and ontogenic interactions with drugs in the central nervous system certainly is of concern, both with respect to pathogenesis of disease and the response to interventions. However, the precision of our ability to measure "suicidal ideation" in children and adolescents is uncertain, and the apparent age dependence may be related as much to the diagnostic and clinical trial tools we use, and how they are applied by individual investigators, as to actual drug effects. It is vital that we improve diagnostic precision for adverse effects as well as efficacy. Here, too, there is the opportunity to modify individual benefit to risk using predictive markers of risk. Efforts are underway to look for genomic markers associated with suicidal ideation risk.14It cannot be stressed enough that both improved clinical diagnosis as well genomic and other biomarkers will be needed, that single genomic tests are unlikely to answer complex predictive questions, and that extensive validation of new approaches will need to be done. Outcomes of complex conditions and responses to complex therapies require a thoughtful integration of clinical medicine, genomics, genetics, and understanding of growth and development in children. Gene-gene interactions (epistasis) and genetic penetrance, gene-environment interactions, epigenetics, and development all play roles.15,16 Many whole genome association studies (GWAS), to date, have found highly statistically significant associations between genomic markers and clinical conditions. However, many of the markers account for only a small percent of clinical variability (i.e., have very low penetrance) and GWAS currently are only able to detect variants expressed in 5% of the population. We will need to capture more rare genomic variants with higher predictive relevance, and analyze the consequences of epistasis among multiple loci that will shape susceptibility/resilience to disease and modify outcomes of therapy. Genomic technologies are changing constantly, and we need to be prepared both for some "false starts" as well as markedly enhanced insights into genomic organization and expression over the coming years. All this will require a radical new approach to information acquisition and utilization, and interpretation on both the genomic and clinical side. There is urgent need to improve physicians' sophistication and skillful use of genomic data in the context of complex clinical syndromes, both for diagnosis and treatment. While the majority of physicians are convinced of the importance of genomics in transforming our understanding of health and disease, the vast majority feel ill-prepared to understand much less implement genomic and pharmacogenomic thinking into their practices. Equally important will be the creation and implementation of national and international networks of investigators who can advance this field. It will require cross-disciplinary cooperation among clinical pharmacologists, psychiatrists, pediatricians and developmental biologists, geneticists, bioinformaticists. The European "Genome Based Therapeutic Drugs for Depression – GENDEP" initiative is encouraging, while the loss of the NIMH Research Units in Pediatric Psychiatry is clinical care for patients with depression all thoughtful patient and time is needed for care physicians and who care for patients with depression to about advances in personalized therapeutics, and to implement in their practices. is not in our current health care and scientific advances will have impact a in However, the current one of confusion as to the of medicines in treatment a condition, is and is patients in need at risk. we

In drug development the move from tricyclic antidepressants (TCAs) to selective serotonin reuptake inhibitors (SSRIs) involved not only the loss of the direct receptor interactions responsible for the adverse side effects of TCAs, but also the ability to inhibit the reuptake of noradrenaline. Selectivity for the single neurotransmitter, serotonin, may explain why SSRIs tend to be less efficacious than the TCAs, especially in more serious forms of depression. The advent of selective serotonin and noradrenaline reuptake inhibitors (SNRIs) has tended to confirm the idea that an action on both monoamine systems is important for maximal antidepressant efficacy. This paper reviews clinical trials comparing the new SNRI milnacipran with the SSRIs fluoxetine and fluvoxamine. A meta-analysis of the principal trials shows greater response rates (the proportion of patients with a decrease in symptom scores of 50% or more) with milnacipran (50 mg twice a day) than with fluoxetine (20 mg once a day), or fluvoxamine (100 mg twice a day) (milnacipran: 64%; SSRIs: 50%). Remission rates (the proportion of patients with Hamilton Depression Rating Scores of 7 or below) were also higher with milnacipran than with SSRIs (39 versus 28%). In one study, in which 100 mg milnacipran was given once a day in the evening, the higher response rate obtained with fluoxetine appears to be largely attributable to an inappropriate milnacipran dosage regimen. Data from a pharmacovigilance database including all patients participating in clinical trials with milnacipran (n = 5732) showed that, compared with the SSRIs, milnacipran produced fewer gastrointestinal side effects, such as nausea, and less anxiety. Milnacipran was, however, associated with a higher incidence of headache, dry mouth and dysuria. The results of these studies suggest that milnacipran is superior in efficacy to SSRIs and is equally well tolerated. Milnacipran, therefore, appears to offer a therapeutic advantage over the SSRIs.

Significant improvement in overall survival among patients diagnosed with low-risk myelodysplastic syndrome treated with selective serotonin reuptake inhibitors.

BackgroundThe objective of this research was to examine treatment patterns and health-care costs associated with second-step pharmacotherapy in patients with major depressive disorder (MDD) who initiated monotherapy with a selective serotonin reuptake inhibitor (SSRI) in 2010.MethodsThis claims database study analyzed patients diagnosed with MDD who were prescribed a monotherapy SSRI, with the first prescription identified as the index date. Patients were required to be ≥18 years old, to have continuous insurance coverage from 1 year prior (pre-index) through 1 year post (post-index) from the index date, and to have not received an antidepressant in the pre-index period. The analyses are descriptive of the patient characteristics, initial SSRI prescribed, most commonly prescribed second-step therapies, and annualized health-care costs.ResultsThe identified patients (N = 5,012) were predominantly female (65.2%) with a mean age of 41.9 years. The most frequent index SSRIs were citalopram (30.1%) and sertraline (27.5%), and 52.9% of patients were prescribed a second-step pharmacotherapy during the post-index period. Add-on therapy occurred twice more frequently than switching treatments, with either anxiolytics (40.2%) or antidepressants (37.1%) as the most common classes of add-on pharmacological therapies. Patients who added a second medication or switched therapies had higher annualized medical costs compared with patients who continued their index SSRI or discontinued treatment.ConclusionsFor patients who were initially treated with an SSRI therapy, approximately half were prescribed a second-step treatment. In this comprehensive claims analysis, many of these patients experienced the addition of second medication, rather than switching to a new therapy. Given the type of medications used, it is possible that second-step interventions were targeted toward resolution of residual symptoms; however, this work is limited by the use of claims data without information on dosing or clinical symptoms, side effects, or response. Findings from this study set the expectation that physicians and patients will most likely need to partner for additional interventions in order to achieve remission.

Systematic Review and Meta-Analysis: Early Treatment Responses of Selective Serotonin Reuptake Inhibitors in Pediatric Major Depressive Disorder

Previous research based on either individual studies or meta-analyses has been unable to demonstrate a clear doseresponse relationship for selective serotonin reuptake inhibitors (SSRIs), leading to the conclusion that there is a flat dose-response curve for SSRIs.Themajority of the individual studies comparing doses were not specifically designed to assess dose-response differences and included limited sample sizes. Previous meta-analyses often included doseescalation studies or were based on a smaller number of clinical trials, making it difficult to definitively evaluate the dose-response relationship. The article by Jakubovski et al. (1) in this issue of the Journal addresses this important question of whether higher doses of SSRIs can lead to better efficacy. The authors evaluated 40 randomized controlled trials that included a placebo and 49 active treatment arms. While the results are modest, they do show greater efficacy for higher doses of SSRIs in major depressive disorder. This slight benefit is coupled with a reduction in tolerability. This study overcomes a number of shortcomings from previouswork by incorporating three critical elements. First, it uses continuous outcomes to evaluate efficacy. Second, it includes studies not previously added in the meta-analyses. Third, it restricts the analysis to studies designed to evaluate multiple dose levels as opposed to flexible escalating dose trials. Using these methods, the authors demonstrate that there is a modest but clear dose-response effect for SSRIs. The study also provides an analysis of the dose-related sideeffect burden. However, results point to the likelihood of important individual differences that are masked by group effects in traditional efficacy trials. Resultsmay also argue for aneed to assess specificbiomarkers to carefully identify those who are likely to needhigher doses to achieve the best benefit with the least side-effect burden. Whether biomarkers associatedwith specific side effects (e.g.,CNSversusperipheral side effects) could help tailor treatment in clinical practice was not assessed. One clear limitation of the study is themodest effect of the higher dose of SSRIs. In the absence of a clearmetric that can be easily translated by clinicians to practice and the “small” incremental benefit of the higher dose in terms of efficacy, coupled with the added burden of side effects, generalizability of these results is limited. Themagnitude of this effect is further compromised by the slightly higher effect of adverse events. Furthermore, the dose-response relationship within the narrower 100 mg and 250 mg equivalent doses suggests a more robust dose-response curve. Finally, this meta-analysis combines a number of SSRIs despite the fact that there are pharmacological differences among the SSRIs, which may not have identical dose-response relationships and may be masking higher effects for certain specific SSRIs at specific doses.

Depression is characterized by a wide range of diverse symptoms, the severity of which can be quantified by various depression rating scales, such as the Montgomery Asberg Depression Rating Scale. Analyses of the individual items of this scale in patients treated with the selective serotonin reuptake inhibitors (SSRIs) have shown that not all items respond equally or with the same time of onset of improvement (Table 1).1,2 The items which respond less well or more slowly with SSRIs include lassitude, loss of energy, retardation of thoughts or actions, as well as concentration difficulties and loss of alertness. The loss of interest or pleasure that depressed patients experience (anhedonia) also responds poorly to SSRIs, and patients often complain of emotional indifference or blunting. Certain sleep difficulties are sometimes worsened by SSRIs. Appetite loss can be aggravated by certain SSRIs, an effect which can be made worse by nausea at the beginning of treatment. Table 1 Comparison of core symptoms of depression which respond less well or more slowly to SSRIs and depressive symptoms specifically related to a deficiency of noradrenergic neurotransmission Similarly, a cluster of common depressive symptoms of “decreased positive affect”, including loss of interest or pleasure, fatigue, loss of energy, and decreased motivation, which do not respond adequately to serotonergic antidepressants, have been identified. Antidepressants that enhance noradrenergic (and dopaminergic) activity appear to offer a therapeutic advantage over serotonergic antidepressants in the treatment of these symptoms.3 Based mainly on theoretical considerations, the symptoms of depression have been associated with deficiencies of one or more of the monoamine neurotransmitters.4 In this scheme, decreased concentration, retardation, loss of energy, lassitude, tiredness, and reduced self-care are associated with decreased noradrenergic activity (Table 1). Thus, clinical and theoretical considerations combine to define the noradrenergic symptom cluster, ie, decreased concentration, retardation, loss of energy, lassitude, tiredness, and reduced self-care. This supplement, which is based on a symposium held at the International Forum on Mood and Anxiety at Vienna in November 2010, discusses the noradrenergic symptom cluster, the importance of these symptoms in the burden of depression, their clinical and neuropharmacological nature, and how these symptoms can be improved by the serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressant, milnacipran. In the first paper, Lepine presents recent epidemiological data on the prevalence of depression and the associated risk of mortality by suicide, as well as cardiovascular and other deaths. Studies of the familial and financial burden of depression show an increased risk of loss of productivity and absenteeism in depression, which frequently result in decreased income or unemployment. The importance of the burden of depression is underlined by the estimation of the World Health Organization that, by 2030, unipolar major depression will become the leading worldwide cause of disease burden. The second paper by Moret examines the importance of norepinephrine in the etiology of depression. Evidence for the involvement of norepinephrine including recent studies on neuronal pathways and symptoms, highlights the determinant role of norepinephrine in key symptoms, including executive functioning, which regulates cognition, motivation, and intellect, which are of fundamental importance in social relationships, that are impoverished in depression. In the third paper, Blier explains the reciprocal interactions between the serotonin system and norepinephrine and dopamine neurotransmission. Enhanced serotonin transmission, as during SSRI treatment, attenuates noradrenergic and dopaminergic activity. This can contribute to the residual symptoms of fatigue and lack of energy that are often reported by patients responding to SSRI. Milnacipran, by increasing norepinephrine (and dopamine), as well as serotonin neurotransmission is less likely to induce or aggravate such residual symptoms. Milnacipran’s potentiation of norepinephrine and serotonin (and indirectly dopamine) neurotransmission contributes to its antidepressant action, while its attenuation of phasic noradrenergic reactivity reduces the risk of anxiety. In the fourth and final paper, Kasper discusses the importance of social dysfunction in depressed patients which can lead to family disruption, social isolation, absenteeism, and potential unemployment. The symptoms of the noradrenergic symptom cluster are important factors in social dysfunction, and antidepressants with a strong noradrenergic component improve social functioning. Preliminary data suggest that milnacipran improves social functioning to a greater extent than SSRIs.

Dysfunction of the brain serotonergic system is implicated in the pathogenesis of major depressive disorder (MDD). Serotonin is also a vasoactive signaling molecule, the effects of which are modulated by both nitric oxide (NO) and the serotonin transporter [the primary target of selective serotonin reuptake inhibitors (SSRIs)]. Despite its role in the neurobiology of depression, serotoninergic signaling mechanisms in the microvasculature of adults with MDD are unknown. We hypothesized that 1) cutaneous microvascular responsiveness to serotonin would be attenuated in MDD and mediated by reductions in both 2) NO-dependent and 3) serotonin reuptake-dependent mechanisms. In 12 adults with MDD (nonmedicated) and 12 nondepressed adults, red cell flux (laser-Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of 1) serotonin (10-10 to 10-1 mol/L) alone and in combination with a nonselective NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 15 mmol/L) and the SSRI paroxetine (10 μmol/L); and 2) paroxetine (n = 6; 10-9 to 10-2 M) alone and in combination with l-NAME. Serotonin-induced vasodilation was preserved in MDD. The NO-dependent component of serotonin-induced vasodilation was not different between groups. Paroxetine augmented vasodilatory responsiveness to serotonin via NO-dependent mechanisms in both groups; however, the magnitude was blunted in MDD. The NO contribution to direct paroxetine-induced vasodilation was also reduced in adults with MDD. Collectively, these preliminary data suggest that cutaneous microvascular serotoninergic signaling is dysregulated in adults with MDD and mediated by NO-dependent and serotonin reuptake-dependent mechanisms, providing initial mechanistic insight to the purported vasculoprotective effect of chronic SSRI treatment.NEW & NOTEWORTHY Cutaneous microvascular vasodilatory responsiveness to serotonin was preserved in adults with major depressive disorder (MDD). However, the contribution of serotonin reuptake-dependent mechanisms to serotonin-induced dilation was reduced in MDD. Direct perfusion of the selective serotonin reuptake inhibitor (SSRI) paroxetine elicited vasodilation that is partially mediated by nitric oxide (NO)-dependent mechanisms, but these responses were blunted in MDD, reflective of a diminished contribution of NO to the direct effects of a SSRI on the cutaneous microvasculature.

Background Selective serotonin reuptake inhibitors (SSRI) are the gold standard treatment for major depressive disorder (MDD). However, the use of phosphodiesterase (PDE) inhibitors in treatment of MDD remains unclear. The aim of our study was to compare the effect of PDE inhibitor + SSRI combination therapy to SSRI monotherapy for the treatment of MDD. Methods We performed a comprehensive literature search using PubMed, EMBASE, and Web of Science databases from inception to 07/08/2022, for studies that assess the impact of PDE inhibitor therapy on MDD patients. The primary outcome of our study was treatment response rate (defined as ≥50% reduction in the Hamilton Rating Scale for Depression score) at the end of study time. Secondary outcomes included specific side effect rates. Pooled odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated using the random-effects model. A P-value 50% implied the presence of significant heterogeneity). Results A total of four randomized control trials (RCTs), including 270 patients with MDD (mean age: 34.9±8.4 years, 135 patients received PDE inhibitor + SSRI combination therapy and 135 received SSRI monotherapy), were included in the analysis. The follow up period ranged from 6 to 12 weeks. The PDE inhibitor group was associated with a significantly higher treatment response rate (OR:4.77; 95% CI:2.05-11.12; P = 0.0003). Additionally, there was no significant difference in side effect rates between the two treatment modalities. Conclusion Our study supports the use of PDE inhibitor + SSRI combination therapy in patients with MDD, since it is associated with a significantly higher treatment response rate compared to patients receiving SSRI monotherapy (90.4% vs 64.4%, respectively). Further large-scale RCTs with long-term follow-up are necessary to validate our findings. Ultimately, use of PDE inhibitors in MDD patients should be considered on a case-by-case basis to maximize patient benefits.

“Ms. A” was a 35-year-old married Caucasian health care professional with a history of recurrent major depressive disorder that responded well to treatment with a selective serotonin reuptake inhibitor (SSRI). She discontinued her antidepressant prior to conception for a planned pregnancy because she did not want to expose her baby to medication. She soon relapsed, and by the first trimester of her pregnancy, she was in a major depressive episode. Her symptoms included anhedonia, tearfulness, irritability, insomnia, and diminished appetite. She presented for participation in an open-label pilot trial of omega-3 fatty acids for antenatal major depressive disorder (1). At intake, after hearing the risks and benefits of available treatment options, Ms. A declined antidepressant medication and a referral for psychotherapy and consented to participate in the study of omega-3 fatty acids, which she started at 16 weeks’ gestation. She was assessed every 2 weeks throughout pregnancy. At 8 weeks she had not responded to omega-3 fatty acids and was again presented with other treatment options, including medication and psychotherapy. She again declined these treatments and continued to do so throughout the remainder of her pregnancy. She was concerned about the safety of medications in pregnancy and believed that taking medication would make her a bad mother. She also declined referral for psychotherapy, stating that she was “too busy.”

The selective serotonin reuptake inhibitors (SSRIs) (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) are the most widely prescribed class of antidepressants in the United States and a number of other countries. All the SSRIs except fluvoxamine have an indication for major depressive disorder (MDD) in the United States. The SSRIs were the first rationally developed class of psychiatric medications and thus share many similarities: equivalent acute and maintenance antidepressant efficacy, flat dose-response curve for antidepressant efficacy, ascending dose-response curve for adverse effects, adverse effect profile consistent with excessive serotonin agonism, 60%–80% inhibition of serotonin uptake at their lowest, usually effective antidepressant dose, and efficacy for both depressive and anxiety disorders. The SSRIs have good tolerability and do not cause severe side effects seen with certain other antidepressants (e.g., intracardiac conduction delays, seizures, postural hypotension). Because of their wide therapeutic index, the SSRIs have demonstrated good safety in overdose and there is no evidence of long-term safety problems. However, the different SSRIs do differ considerably in pharmacokinetics and effects on cytochrome P450 enzymes. Three of the SSRIs—fluoxetine, fluvoxamine, and paroxetine—inhibit one or more CYP enzymes to a substantial degree and have the potential to cause clinically meaningful drug-drug interactions. There is some debate about the efficacy of SSRIs in patients with more severe depression. If a patient has not been able to tolerate one SSRI, many clinicians will try a second SSRI; however, most psychiatrists prefer to switch to a drug with a different mechanism of action if a patient has had an inadequate response to an adequate trial of one SSRI, since there is no compelling evidence showing that nonresponders to one SSRI will respond to a trial of a different SSRI. All the SSRIs have a flat dose-response curve, so that there is usually no advantage in using doses above the usually effective minimum dose.

BackgroundHealth‐related quality of life (HRQL) is an important goal for patients with major depressive disorder (MDD), but whether antidepressants improve HRQL in these patients is unclear. Here, we describe the real‐world effects of trazodone once‐a‐day (TzOAD) and selective serotonin reuptake inhibitor (SSRI) treatments on HRQL and functioning in adults with MDD.MethodsThis 8‐week prospective, observational, open‐label, multicenter study was conducted in adults with moderate or severe MDD for whom TzOAD or SSRI were prescribed as monotherapy. The primary outcome was life enjoyment and satisfaction assessed via the patient‐reported Quality‐of‐Life Enjoyment and Satisfaction Questionnaire Short Form (Q‐LES‐Q‐SF) from baseline to week 8. Secondary outcomes included change in Q‐LES‐Q‐SF from baseline to weeks 1 and 2; severity of depressive symptoms using the Montgomery Åsberg Depression Rating Scale (MADRS) and sleep disturbance via the PROMIS SF‐SD 8b questionnaire at weeks 1, 2, and 8; and overall functioning via the Sheehan Disability Scale (SDS), hedonic capacity using the Snaith–Hamilton Pleasure Scale (SHAPS), and cognitive dysfunction using the Perceived Deficits Questionnaire (PDQ‐5) at baseline and week 8.ResultsThe study included 208 adults with MDD (mean [SD] age = 50.2 [14.3] years; 68.6% female; 98.4% White). Life enjoyment and satisfaction improved from baseline to week 8 for both treatment groups: Q‐LES‐Q‐SF mean (SD) scores were 27.5 (20.4) for the SSRI group and 39.0 (22.1) for the TzOAD group. Depressive symptoms and sleep disturbances also reduced from baseline to week 8: MADRS (SSRI, −15.7 [8.3]; TzOAD, −21.0 [9.8]); PROMIS SF‐SD 8b (SSRI, −9.9 [12.6]; TzOAD, −22.0 [12.6]). Mean change scores in Q‐LES‐Q‐SF, MADRS, and PROMIS SF‐SD 8b improved as early as week 1 in both groups. Mean scores also improved from baseline to week 8 on SDS (SSRI, −9.2 [7.4]; TzOAD, −14.3 [7.5]), SHAPS (SSRI, −6.6 [4.3]; TzOAD, −8.3 [4.4]), and PDQ‐5 (SSRI, −5.8 [4.5]; TzOAD, −7.7 [5.0]).ConclusionsIn adults with MDD who received TzOAD or SSRIs, overall and individual HQRL domains improved rapidly and in parallel with improvements in depressive symptoms, with a slightly greater improvement observed in the TzOAD group.

Objective To investigate whether the corticotropin-releasing hormone binding protein (CRHBP) gene polymorphisms is associated with the therapeutic response to selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder. Methods Routine dosage of SSRIs was given by six weeks to 207 patients who was diagnosed as major depressive disorder (MDD) according to Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-Ⅳ) criteria.The Hamilton Depression Rating Scale 17 (HAMD17) was used to assess the illness severity before and after the treatment.The patients were grouped into responder (reduction rate of HAMD17score≥50%) and non-responder (reduction rate of HAMD17score<50%).Taq Man MGB was used to analyze the differences of the 5 SNPs polymorphisms between the responder group and non-responder group. Results (1) At weeks 4,there was no statistically significant difference in the 5 CRHBP polymorphism genotypes,allele frequency and haplotype analysis between the two MDD groups with different responsiveness to SSRIs (P>0.05). (2) At weeks 6,allele frequency analysis of rs1715751 and rs32897 was statistically significant between the responder group and non-responder group (χ2=4.185,P=0.041,χ2=5.191,P=0.023).The frequency of CT+ CC genotype carriers of rs1715751 were higher in responder group than that in non-responder group (75/151,49.7% and 7/ 31,22.6% respectively,χ2=9.324,P=0.004; after Bonferroni Correction,P=0.020).The frequency of CT+ CC genotype of rs32897 in responder group was higher than that in non-responder group (63/151,41.7% and 7/31,22.6% respectively,χ2=4.905,P=0.029; after Bonferroni Correction,P=0.145). (3) At weeks 6,three haplotypes were associated with SSRIs therapeutic response in haplotype analyses including C-C (rs1715751-rs3792738,P=0.024;adjusted P=0.120; rs3792738-rs32897,P=0.013;adjusted P=0.065),C-C-C (rs1715751-rs3792738-rs32897,P=0.022; adjusted P=0.110). Conclusions The results support that CRHBP gene be involved in SSRIs therapeutic response in MDD. Key words: Polymorphism,single nucleotide; Serotonin uptake inhibitors; Treatment outcome; Corticotropin-releasing hormone binding protein gene

O-04 - Switching after treatment failure with an SSRI among older depressed inpatients: venlafaxine or a second SSRI?

Major depressive disorder (MDD) is the most common and widespread mental disorder. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for MDD. The relation between the inhibition of serotonin reuptake in the central nervous system and remission from MDD remains controversial, as reuptake inhibition occurs rapidly, but remission from MDD takes weeks to months. Myelination-related deficits and white matter abnormalities were shown to be involved in psychiatric disorders such as MDD. This may explain the delay in remission following SSRI administration. The raphe nuclei (RN), located in the brain stem, consist of clusters of serotonergic (5-HT) neurons that project to almost all regions of the brain. Thus, the RN are an intriguing area for research of the potential effect of SSRI on myelination, and their involvement in MDD. MicroRNAs (miRNAs) regulate many biological features that might be altered by antidepressants. Two cohorts of chronic unpredictable stress (CUS) mouse model for depression underwent behavioral tests for evaluating stress, anxiety, and depression levels. Following application of the CUS protocol and treatment with the SSRI, citalopram, 48 mice of the second cohort were tested via magnetic resonance imaging and diffusion tensor imaging for differences in brain white matter tracts. RN and superior colliculus were excised from both cohorts and measured for changes in miRNAs, mRNA, and protein levels of candidate genes. Using MRI-DTI scans we found lower fractional anisotropy and axial diffusivity in brains of stressed mice. Moreover, both miR-30b-5p and miR-101a-3p were found to be downregulated in the RN following CUS, and upregulated following CUS and citalopram treatment. The direct binding of these miRNAs to Qki, and the subsequent effects on mRNA and protein levels of myelin basic protein (Mbp), indicated involvement of these miRNAs in myelination ultrastructure processes in the RN, in response to CUS followed by SSRI treatment. We suggest that SSRIs are implicated in repairing myelin deficits resulting from chronic stress that leads to depression.