Long-term Antidepressant Use Research Articles

Antidepressant Prescribing and Rapid Cycling

Back to table of contents Previous article Next article Letters to the EditorFull AccessAntidepressant Prescribing and Rapid CyclingJOSEPH GOLDBERG M.D.,JOSEPH GOLDBERG M.D.Search for more papers by this author,Published Online:1 Aug 2008https://doi.org/10.1176/appi.ajp.2008.08030346AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: The editorial (1) commenting on the recent study of rapid cycling by Dr. Schneck et al. emphasized the causal effects of antidepressant use, although the article itself cautioned against making causal inferences. In the article, no discernible relationship between antidepressant use and the number of prospectively observed episodes was reported in Table 3. However, among subjects who were not prescribed antidepressants, most of these subjects had no subsequent depressive episodes, while fewer had one episode, two to three episodes, or four episodes. The significant overall association was driven by the rarity of episodes among patients who were not taking antidepressants or the rarity of antidepressants among patients who had few depressive episodes. More telling clues might have come from examining the incidence of prospective episodes, stratified by antidepressant use, solely among the 356 subjects who experienced rapid cycling during the preceding year. Dr. Ghaemi’s editorial contrasts the higher prevalence rate of the subjects’ retrospectively identified rapid cycling during the year before they entered the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) with a low prospective incidence, attributing the reduction to either “appropriate treatment in STEP-BD or…natural history” ( 1 , p. 300). Another plausible explanation is that retrospective and prospective assessments of rapid cycling are not comparable methodologically. As a co-author of the original retrospective STEP-BD rapid cycling study, I will reiterate the caveat that interepisode recovery was not verifiable (in the original study) between alleged recurrences, making it hard to differentiate incomplete remissions with a waxing and waning course from multiple truly new episodes. Retrospective rates also may have been inflated by impressionistic recall or lay confusion between true rapid cycling versus mood lability without associated syndromic criteria. Moreover, the prospective study conducted by Schneck et al. did not discriminate cycling patterns for subjects who were taking antidepressants during the pre-enrollment year and discontinued these medications, continued to take these medications, or began taking these medications anew after the enrollment year. STEP-BD physicians may have avoided antidepressants or simply did not see the need to use them when episodes were infrequent, making antidepressant use a result rather than cause of multiple episodes. Dr. Ghaemi, with co-authors Soldani, Tondo, Akiskal, and Goodwin (2) , rightly levied this same critique (“confounding by indication”) against an earlier nonrandomized study that sought to interpret long-term antidepressant use as the cause (rather than result) of few relapses. It is likely that antidepressants are neither all good nor all bad. STEP-BD has taught us that broad generalizations regarding the use of antidepressants are relatively uninformative. Much as antibiotics or antineoplastics exert different effects in different subgroups, so too are antidepressants likely to be safe and effective in a definable bipolar subtype—most likely bipolar II depressed patients with no mixed features, no recent mania, no prior antidepressant-associated mania, and no comorbid substance abuse (3) . Far from being the nail in any coffin, the heterogeneity of antidepressant outcomes demands further controlled trials to discern more sophisticated profiles for guiding treatment decisions. New York, N.Y.Dr. Goldberg has served on the scientific advisory boards of Eli Lilly and GlaxoSmithKline and has served on the speakers bureaus of AstraZeneca, Eli Lilly, GlaxoSmithKline, Pfizer, and Abbott Laboratories.This letter (doi: 10.1176/appi.ajp.2008.08030346) was accepted for publication in April 2008.

Osteoporosis after combined use of a neuroleptic and antidepressants

Bone mineral density may be negatively influenced by hyperprolactinemia, which can be caused by atypic neuroleptics and antidepressants. The present paper reports about a spontaneous rib fracture in a female patient (age 52) taking neuroleptics (mainly risperidone), antidepressants (mainly sertraline), and anxiolytics (mainly lorazepam). At the time of the fracture a severe osteoporosis and a strongly enhanced plasma prolactin level (117 ng/ml; normal values: 3-24 ng/ml) were detected. The latter one normalized 2 months after abandoning sertraline and risperidone. After this normalization, the patient did not report further accidents up to now. Enhancement of plasma prolactin levels is linked to the mechanism of action of risperidone. Mammoplasia and increased plasma prolactin can occur during SSRI (Selective Serotonin Reuptake Inhibitors) or trazodone administration. The role of anxiolytics is less clear. The causal relationship between osteoporosis and long-term use of neuroleptics and antidepressants was assessed using probability scores, more particularly the Naranjo probability scale and the Bradford-Hill criteria of causality. A score of 6/13 (probable) was obtained with the Naranjo scale, whereas all 9 Bradford-Hill criteria were fulfilled. Although this case could not be fully explored, attention should be paid to bone mineral density loss in depressed patients taking a combined therapy of atypic antipsychotics and antidepressants.

Restraint Urged in Adding Antidepressant to Mood Stabilizer

Restraint Urged in Adding Antidepressant to Mood Stabilizer

양극성 장애 환자의 기분 전환 현상 연구를 위한 다단계 모형의 적용

양극성 장애 (bipolar disorder)는 조증 삽화 (manic episode)와 우울증 삽화 (depression episode)를 반복적으로 경험하는 기분장애이다. 양극성 장애환자에게 우울증은 조증보다 심각한 결과를 가져오며, 치료의 효과를 측정하기도 어렵다고 알려져 있다. 본 연구의 목적은 우울증(depression) 상태에 있는 환자들을 대상으로 항우울제를 사용하여 정상 (normal) 상태로 전환했을 때, 약물의 장기 사용으로 일어날 수 있는 조증 (mania)과 같은 부작용을 통제하고자 한다. 이를 위해 정상 상태에서 조증으로 전환하는데 소요되는 시간의 분포를 추정한다. 본 연구에서는 세 가지 방법, 모수적, 비모수적 그리고 준모수적 방법을 차례대로 적용하였다. 특히 기분 전환의 흐름을 파악하기 위해 3단계 모형을 사용하였다. 예를 들어, Illness-Death 모형하에서 기분 전환의 발생시점에 대한 분포를 추정하기 위해 계수 과정에 의해 기분 전환에 대한 과정을 모형화하였다. Bipolar disorder, also known as manic-depressive illness, is a brain disorder that causes unusual shifts in person's mood, energy, and ability to function. Compared with manic episode, the depression episode causes more serious results such as restless, loss of interest or pleasure, or thoughts of death or suicide and the cure rate of depression episode is lower than that of manic episode. Furthermore, a long term use of antidepressants in bipolar patients may result in manic episode. Our interest is to investigate the effect of antidepressant on switch of moods of bipolar patients and to estimate the transition probabilities of switch between moods, depression and (hypo) manic. In this study, three approaches are applied in terms of multi state model. Parametric model is applied using left censoring data and nonparametric model is implemented under illness-death model with counting process. In order to estimate the effect of covariates, a multiplicative model is used. These all methods have similar results.

Authors' Response to Hockey and Reidak

Because the increased prescriptions of antidepressants are correlated to increased medical visits, it is tempting to conclude, as Hockey did [1], that decreased suicides are a function of greater recognition of depression. It should be noted that the biggest cause of suicide is clinical major depression and increased visits do not treat that; antidepressants do. In a comprehensive review of the literature on the role of long-term antidepressant use to prevent relapse of major depression, Geddes et al. [2] reported that “data were pooled from 31 randomised trials (4410 participants). Continuing treatment with antidepressants reduced the odds of relapse by 70% (95% CI 62–78; 2p<0.00001) compared with treatment discontinuation. The average rate of relapse on placebo was 41% compared with 18% on active treatment”. We therefore conclude that just seeing a doctor is in the long term not protective against major depression and its consequences, such as suicide. The weight of existing data supports a positive effect of antidepressants. It is plausible that effective long-term treatment of depression by other methods might also be beneficial. In response to the query from Reidak regarding Eli Lilly, I must say that I completely disclose all my activities, and that is why Aasa Reidak was able to write her letter [3]. I had published before on this topic in Nature Reviews Drug Discovery and had data (which were widely known to all in the field, including Eli Lilly) that since fluoxetine was introduced, prescriptions had gone up and suicide rates had gone down. There is nothing really conceptually new there. That was what was presented at one of Eli Lilly’s regular weekly scientific sessions, which exist at most research institutions, including Lilly Research Laboratories. The paper published here is on the modelling of suicide rates using pre-1988 data to estimate what suicide rates would be now and therefore to predict a potential putative effect of fluoxetine and other selective serotonin reuptake inhibitors [4] . These mathematical modelling data are new to this paper, and that entire analysis and manuscript content took place without the knowledge, support, or input of Eli Lilly. The work reported in the article was done in the absence of any conflict of interest or pharmaceutical industry support. After the paper was submitted for publication in PLoS Medicine, I agreed to provide consultations for Eli Lilly, the manufacturer of fluoxetine. This has been a minor, occasional role, with very limited compensation. Such a relationship did not exist and was not planned when the work was done or the article written and submitted, and it is being disclosed here in the interests of transparency.

Characterization of cytotoxic actions of tricyclic antidepressants on human HT29 colon carcinoma cells

Preclinical studies have suggested that the long-term use of antidepressants may result in the initiation and/or promotion of tumor in the gastrointestinal tract. However, a possible relationship between the use of antidepressants and the production of colon cancer has not yet been confirmed, and hence requires to be further investigated. To address this issue, the effects of antidepressants on the proliferation of colorectal tumor cells were examined using human HT29 colon carcinoma cells, and tricyclic antidepressant, such as imipramine, desipramine and amitriptyline, were shown to reduce the cell viability in a manner dependent on the time exposing to these drugs. In addition to these drugs, a selective serotonin reuptake inhibitor fluoxetine, but not a monoamine oxidase inhibitor tranylcypromine, caused the reduction of cell viability, similar in extent to that caused by imipramine. Further studies showed that desipramine caused the apoptotic cell death, which could be prevented by neither catalase, reduced-form glutathione (GSH), nor N-acetylcysteine (NAC), without accompanying the disruption of mitochondrial membrane potential within the cells and the release of cytochrome c into the cell cytoplasm. Moreover, desipramine caused the arrest of cell-cycle progression at either G0/G1-phase or G2/M-phase, which might be depending upon the drug concentration. Thus, these results suggest that tricyclic antidepressants may be cytotoxic, and induce the non-oxidative apoptotic death of human HT29 colon carcinoma cells probably through a non-mitochondrial pathway associated with the cell-cycle progression.

Cognitive performance in depressed patients after chronic use of antidepressants

Depressive disorders are conditions that often require continuous treatment, and it is therefore important to evaluate the consequences of prolonged administration. There are few studies assessing cognitive functions of depressed patients after long-term use of antidepressants. This study evaluated the cognitive performance of depressed patients treated with antidepressants for at least 6 months. Patients with major depression (DSM-IV) using imipramine for 2.4+/-0.6 years (mean+/-SE), clomipramine for 2.8+/-1.2 years, fluoxetine for 1.8+/-0.3 years and sertraline for 1.5+/-0.3 years were compared to matched controls (sex, age and educational level) without any psychiatric diagnosis. Memory evaluation consisted of episodic, implicit and working memory tests as well as metamemory assessment. (a) Psychomotor performance of patients taking imipramine was worse than that of controls in inserting pins and a visual reaction time task; on the performance of tapping the difference from controls varied according to dose/weight for patients taking clomipramine and fluoxetine. (b) For memory tests, differences between patients taking sertraline and controls were observed in the number of digits and words recalled; the difference between patients and controls varied according to dose/weight on the number of familiar words correctly completed for patients taking clomipramine and on digit span backward for those taking sertraline. (c) Metamemory was worse in all patient groups irrespective of patients' clinical state. The impairment in psychomotor and memory performances associated with these antidepressants seems to be of low intensity and of questionable clinical relevance.

Dr. Gijsman and Colleagues Reply

Dr. Gijsman and Colleagues Reply

Antidepressants for Bipolar Depression

Back to table of contents Previous article Next article Letter to the EditorFull AccessAntidepressants for Bipolar DepressionS. NASSIR GHAEMI, M.D., M.P.H., , and FREDERICK K. GOODWIN, M.D., S. NASSIR GHAEMISearch for more papers by this author, M.D., M.P.H., Atlanta, Ga., and FREDERICK K. GOODWINSearch for more papers by this author, M.D., Washington, D.C.Published Online:1 Aug 2005https://doi.org/10.1176/appi.ajp.162.8.1545-aAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Meta-analysis represents an “observational study of studies.” The benefits of random assignment and the removal of confounding bias within a sample are lost with meta-analysis, resulting in the problem of “heterogeneity” between study samples. Just as randomized clinical trials are more valid than observational studies, a meta-analysis of one to five randomized clinical trials is not necessarily more valid than one well-designed randomized clinical trial. This issue may be less relevant if studies agree, as it appears they did in the meta-analysis by Harm J. Gijsman, Ph.D., M.R.C.Psych., et al. (1). However, this apparent agreement hides important unexplored heterogeneity, which does not invalidate the meta-analysis but can lead to its misinterpretation.For instance, the only placebo-controlled study that found no evidence of acute antidepressant response is the only study, to our knowledge (2), in which all patients received baseline lithium. Among other studies, one (3) nonrandomly assigned 37% of the patients in the antidepressant arm to lithium versus 21% in the placebo arm—a relative 77% increased lithium use in the antidepressant arm—hardly a fair assessment of fluoxetine versus placebo. Two compared antidepressant alone to placebo alone, and one large study (58.5% of all meta-analysis patients) (4) compared olanzapine plus fluoxetine to olanzapine alone (“placebo” improperly referred to olanzapine plus placebo). These studies may suggest acute antidepressant efficacy compared to no treatment or olanzapine alone but not compared to the most proven mood stabilizer, lithium, which is also the most relevant clinical issue.Regarding antidepressant-induced mania, two studies comparing antidepressants without mood stabilizer to no treatment (placebo only) reported no mania in any patients: an oddity, if true, since it would suggest that even spontaneous mania did not occur while those patients were studied or that perhaps manic symptoms were not adequately assessed. As described, another study preferentially prescribed lithium more in the antidepressant group (3), providing possibly unequal protection against mania. Although the olanzapine-fluoxetine data suggest no evidence of switching while using antipsychotics, in our reanalysis of the lithium-plus-paroxetine (or imipramine) study, there was a threefold higher manic switching rate with imipramine versus placebo (risk ratio=3.14), with asymmetrically positively skewed confidence intervals (0.34–29.0). Combined with other studies reviewed that showed higher tricyclic antidepressant switching rates than other antidepressants, attention to this heterogeneity suggests that one cannot rule out antidepressant switching.Finally, these short-term (up to 10 weeks) studies are only relevant, if at all, to the acute depressive episode. Contrary to the highly selective review in the discussion, they do not provide any evidence to support long-term maintenance use of antidepressants in bipolar disorder, which was previously shown ineffective in multiple randomized clinical trials in a systematic review (5).In summary, our critique touches partly on the validity of this meta-analysis, but more importantly, on its generalizability due to unexplored heterogeneity. Apparent agreement among studies hides major conflicting results between the only adequately designed study using the most proven mood stabilizer, lithium, and the rest. It would appear that the rosy conclusions of the meta-analysis are premature when the clinical options involve use of proven mood stabilizers, such as lithium, with or without antidepressants.

Antidepressant-associated chronic irritable dysphoria (acid) in bipolar disorder: a case series

Background Antidepressants administered to bipolar subjects may induce manias, mixed states, or rapid cycling. More recently, we have noted that long-term use of antidepressants may induce a chronic dysphoric, irritable state. Method A case series is presented in which six type I bipolar subjects receiving antidepressants continuously for several years developed chronic irritable dysphoria. Results A triad of dysphoric mood, irritability, and middle insomnia that is frequently associated with occupational and social dysfunction can occur in some bipolar patients receiving antidepressants for at least 3 years. Typically, initial treatments with antidepressants for the index episode were effective. Over time, depressive symptoms returned and would transiently improve with dose increase or change of agents. Ultimately, the dysphoria and associated symptoms became chronic and resulted in dysfunction. Concomitant mood stabilizer did not appear to alter this pattern. Discontinuation of antidepressants was associated with a slow and gradual improvement in these symptoms over the ensuing year. Conclusion Additional studies are required to investigate safety of long-term use of antidepressants in bipolar illness.

`Switching' Risks Minimal In Bipolar Treatment

Back to table of contents Previous article Next article Clinical & Research NewsFull Access`Switching' Risks Minimal In Bipolar TreatmentJim RosackJim RosackSearch for more papers by this authorPublished Online:1 Oct 2004https://doi.org/10.1176/pn.39.19.0390022Antidepressants are effective in the treatment of bipolar depression and are safe when used for short-term treatment. That is the conclusion of new research whose findings do not support a risk of “switching” patients to mania.A wide-ranging review of data from randomized controlled trials of antidepressants in bipolar patients also found that selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) are more prudent choices for first-line therapy than tricyclics.The data were reported in the September American Journal of Psychiatry. The analysis, which was not supported by any pharmaceutical industry funding, was done with the help of the Cochrane Collaboration Depression, Anxiety, and Neurosis Group in the United Kingdom.“The gap between practice and theory should make us all uncomfortable,” wrote the authors, led by Guy Goodwin, M.D., Ph.D., a professor of psychiatry at Warneford Hospital in Oxford, U.K. The question at hand, they noted, is how best to treat a patient in a depressive phase of bipolar disorder. In most countries, the authors stressed, “patients are offered antidepressants with little deliberation. By contrast, in all treatment guidelines, experts appear to agonize over whether antidepressants should be offered at all, at least as monotherapy.”Goodwin and his coauthors systematically assessed data from randomized controlled trials of antidepressants in the short-term treatment of bipolar depression. Using rigorous methods developed by the Cochrane Collaboration, they sought to “produce the best available quantitative estimates of the risks and benefits of antidepressant treatment in bipolar disorder.”The group reviewed 12 randomized, controlled trials, with a total of 1,088 patients enrolled. Five of these trials were direct comparisons of a medication and placebo; three-quarters of those patients were on a concurrent mood stabilizer or an atypical antipsychotic.The authors noted that one limitation of the study was the fact that“ the numbers of bipolar depressed patients entered into clinical trials is around 1 percent of the figures for unipolar depression.” However,“ the data nevertheless strongly support an average positive efficacy for antidepressants versus placebo in trials up to 10 weeks.”They added, “There is no coherent basis for doubting that conventional antidepressants have efficacy in bipolar depression on the basis of the existing evidence.”Because the trials reviewed were relatively short (between 4 and 12 weeks), the rates of switching from depression to mania were low, and overall antidepressants “did not induce more switching to mania.” Switching in patients on antidepressants in the trials occurred at a rate of 3.8 percent, compared with 4.7 percent for those taking a placebo.Six other trials compared two antidepressants. In these trials, the rate of switching was noted to be 10 percent for tricyclics, compared with only 3.2 percent for all other antidepressants combined.Goodwin and his colleagues compared their conclusions with the APA Practice Guideline for the Treatment of Patients With Bipolar Disorder, and determined that contrary to what the practice guideline notes—recommending lithium or lamotrigine as first-line treatment for bipolar depression—“there is no strong reason to avoid antidepressants” for these patients. In fact, Goodwin and his colleagues concluded, “we advise adding an antidepressant as a first-line treatment” for those patients already taking a mood stabilizer.Also in contrast to the practice guideline, which specifically recommends paroxetine and bupropion as antidepressants, Goodwin and colleagues saw“ only very limited evidence for bupropion and only limited evidence for a special place for paroxetine among the SSRIs. To prefer either is to move beyond the evidence.”APA practice guidelines undergo regular revision, about every five years, according to Robert Kunkle, M.A., APA's senior program manager for practice guidelines. The bipolar guideline is scheduled for review in 2005. If evidence suggests that recommendations are dated, APA will develop and publish a guideline watch, a guideline revision, or both. Watches briefly summarize major developments since guideline publication that could lead clinicians to treat patients in a manner different from what the guideline recommends.Finally, the authors concluded, future research is needed to answer several questions: Are patients with bipolar II disorder similar to patients with bipolar I in their response to antidepressants? Does use of antidepressants lead to mood instability or increased cycling? And “is there actually any disadvantage to the long-term use of non-tricyclic antidepressants for the prevention of depressive relapse?”The report, “Antidepressants for Bipolar Depression: A Systematic Review of Randomized Controlled Trials,” is posted online at<http://ajp.psychiatryonline.org/cgi/content/abstract/161/9/1537>.▪ Am J Psychiatry 2004 161 1537 ISSUES NewArchived

Incidence and determinants of long-term use of antidepressants.

The use of antidepressants has increased over the years, which may be due to more new antidepressant users, but also may be due to a longer duration of use. We aimed to assess the prevalence, incidence and average duration of selective serotonin reuptake inhibitor (SSRI) and tricyclic antidepressant (TCA) use in the Netherlands during 1992-2001. In addition, we assessed the incidence of long-term use of SSRIs and identified possible determinants of long-term use. We assessed prevalence (number of current users of an antidepressant per 1000 persons assessed on a single day) and incidence (number of new users per 1000 persons per year) of antidepressant use for each year in the PHARMO record linkage system. Long-term use was defined as the consecutive use of any antidepressant for at least 12 months. Relative risks and hazard ratios were calculated and adjusted for possible determinants using Poisson and Cox regression analyses. Both prevalent and incident use of SSRIs increased during 1992-2001, while TCA use remained stable. A total of 9857 patients using SSRIs were included in a follow-up study. During the follow-up period, more patients became long-term users, either directly after the start of the initial SSRI or anytime during follow-up (29.5%). The average number of days before start of long-term use decreased from 595 days in 1991 to 19 days in 1997. Female patients, older age, previous use of benzodiazepines and being treated by a psychiatrist increased the probability of becoming a long-term user. Both prevalent and incident use of SSRIs increased during the 1990s, implicating an increased number of patients starting SSRIs, but also a longer duration of use of antidepressant therapy. Over the entire follow-up period, almost 30% of the patients became long-term users at anytime during the follow-up period.

Researchers Probe Depression in Children

FOR MORE THAN TWO DECADES, childhood depression has presented researchers and clinicians with some of the most fascinating and anxiety-provoking questions in the fields of psychiatric and psychological research. Some, like whether prepubertal youth are even capable of being depressed and successfully treated, have been answered with a resounding “yes.” Others, like the impact of long-term antidepressant use on the developing brain, remain for the future frontiers of research. According to epidemiological studies, about 2.5% of prepubertal children and up to 8.3% of adolescents in the United States have depression (J Am Acad Child Adolesc Psychiatry. 1996; 35:1427-1439). But surprisingly, it wasn’t until the late 1970s, through pioneering studies of researchers such as the late Joachim Puig-Antich, MD, of the Western Psychiatric Institute and Clinic in Pittsburgh, Pa, that groundbreaking findings demonstrated that children do, indeed, possess a strong enough concept of “self” to experience such feelings as guilt, which is a central component of depression. Puig-Antich developed a medical model for assessing depression in children that involved direct interviews with the children themselves rather than observing how they play. “Children were asked about symptoms, whether they feel sad, if they cry, and if they feel guilty—it was revolutionary when the kids were interviewed directly,” explains Barbara Geller, MD, professor of psychiatry at Washington University in St Louis, Mo. “With that came the recognition that children, even the very young, can have serious, major depression the same as adults.” Since then, researchers have attempted to determine whether depression in children really is the same disorder as in adolescents and adults, or if there are important differences. What they are finding is a mixed picture. Although the basic underpinnings—the fact that both environmental and biological factors play a role—are the same, some notable differences (including dif-

Development and use of a computer program to detect potentially inappropriate prescribing in older adults residing in Canadian long-term care facilities.

BackgroundInappropriate prescribing has been estimated to be as high as 40% in long-term care. The purpose of this study was to develop a computer program that identifies potentially inappropriate drug prescriptions and to test its reliability.MethodsPotentially inappropriate prescriptions were identified based on modified McLeod guidelines. A database from one pharmacy servicing long-term care facilities in Ontario was utilized for this cross-sectional study. Prescription information was available for the 356 long-term care residents and included: the date the prescription was filled, the quantity of drug prescribed and the eight-digit drug identification number. The pharmacy database was linked to the computer-based program for targeting potential inappropriate prescriptions. The computer program's reliability was assessed by comparing its results to a manual search conducted by two independent research assistants.ResultsThere was complete agreement between the computer and manual abstraction for the total number of potentially inappropriate prescriptions detected. In total, 83 potentially inappropriate prescriptions were identified. Fifty-three residents (14.9%) received at least one potentially inappropriate prescription. Of those, twenty (37.7%) received two potential inappropriate prescriptions and eight (15.1%) received 3 or more potential inappropriate prescriptions. The most common potential inappropriate prescriptions were identified as long-term use of non-steroidal anti-inflammatory agents and tricyclic antidepressants with active metabolites.ConclusionA computer program can accurately and automatically detect inappropriate prescribing in residents of long-term care facilities. This tool may be used to identify potentially inappropriate drug combinations and educate health care professionals.

Antidepressants for Bipolar Depression

Back to table of contents Previous article Next article LettersFull AccessAntidepressants for Bipolar DepressionRif S. El-Mallakh, M.D., and Anoop Karippot, M.D.Rif S. El-MallakhSearch for more papers by this author, M.D., and Anoop KarippotSearch for more papers by this author, M.D.Published Online:8 Oct 2014https://doi.org/10.1176/appi.ps.53.10.1331-aAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail In Reply: We appreciate Dr. Robbins' input. We agree with all his comments. Our statement that clinicians may not distinguish between bipolar and unipolar depression was not intended to reflect badly on clinicians' diagnostic skills. Rather, it derives from our observation that in a great many published reports, outcome data from the two groups are often combined.Our comments about minimizing the use of antidepressants for patients with bipolar illness or a family history of bipolar illness are important. Clinical research is conducted in populations taking a particular medication in order to determine how patients will respond to it. Because it is impossible to predict the response of an individual patient on the basis of such research, one is forced to make generalizations that serve to guide treatment decisions. This is the essence of data-based management. There are always individual exceptions that must be addressed individually. But generalizations are important because they apply to most members of a population.Antidepressants are useful agents in the management of bipolar depression, as we stated in our review. However, their use may be problematic. Because there is no evidence that antidepressants can prevent patients' relapse to bipolar depression and there is abundant evidence that long-term use of antidepressants may be problematic in a significant fraction of individuals, we believe that minimizing the use of antidepressants for bipolar patients is desirable unless individual evidence suggests otherwise. FiguresReferencesCited byDetailsCited ByNone Volume 53Issue 10 October 2002Pages 1331-a-1331 Metrics PDF download History Published online 8 October 2014 Published in print 1 October 2002

Biological Perspectives

Adrenergic Receptors There are many adrenergic receptors in the human body. The appropriately named fight-or-flight response is a system of messages and codes that assists the body in dealing with crises requiring heightened levels of somatic activity (Martini, 1998). The sympathetic division of the autonomic nervous system (ANS) enables the body to handle this type of stress. Activation of the sympathetic nervous system stimulates membrane proteins known as adrenergic receptors. These receptors are sensitive to the catecholamines norepinephrine and epinephrine. Adrenergic receptors can be grouped into two main systems of the body: the central nervous system (CNS) and the peripheral nervous system. While the primary emphasis of this article is central functions, peripheral adrenergic receptor function is of interest due to adverse responses to psychotropic agents, which are mediated by these receptors. Central Adrenergic Receptors Norepinephrine (NE) is produced in the CNS. There are two central norepinephrine or noradrenergic systems. The first and best recognized NE system is found in a group of pontine pigmented neurons called the locus ceruleus. It contains about half the total number of norepinephrine-synthesizing neurons in the brain. The second NE system begins in the lateral tegmentum of the medulla. NE fibers from both the pons and the medulla travel pathways to synapse with adrenergic receptors in the spinal cord; brain stem, cerebellum, diencephalon, basal forebrain (i.e., the septum, amygdala, olfactory bulbs, and hippocampus), limbic area, and the cortex. Because NE plays an important role in the psychiatric realm of health, damage to this area of the brain can have serious repercussions, especially in disorders that have a mood component. In addition, because of the extensive connection that the locus ceruleus makes with the hippocampus and cortex, the adrenergic nervous system has been implicated in mechanisms that underlie cortical activation, learning, memory, and attention (Cameron, 1994). Depressive illness was first recognized as a biochemical phenomenon in 1965, when Schildkraut published an article describing what he called the catecholamine hypothesis of depression. Over the years, Schildkraut's hypothesis was broadened to the monoamine hypothesis (which included serotonin) and then to the monoamine receptor hypothesis of depression (Stahl, 1998). Stahl suggests it is not the increase in intrasynaptic monoamine availability that accounts for the effectiveness of antidepressants, but rather the changes (i.e., downregulation) in adrenergic receptors. In 1948 Alquist classified adrenergic responses and receptors into two overarching categories, alpha and beta (Insel, 1987), subsequently refined further to include alpha-l, alpha-2, beta-l, and beta-2. Alpha-1 and beta-1 receptors are located throughout the cerebrum and in the diencephalon. Depletion of NE, whether drug induced (e.g., reserpine) or idiopathic, has been associated consistently with an increase in both alpha-1 and beta-1 receptor sites. Long-term use of antidepressants downregulate alpha-1 and beta-1 receptors (a decrease in numbers and sensitivity). This change occurs after 2 to 4 weeks of therapy, or roughly about the same amount of time required for a clinical response to occur. Alpha-2 receptors are located in the cortex, limbic system, and locus ceruleus. Alpha-2 receptors serve as autoreceptors and, when stimulated, decrease the release of NE. While peripheral alpha-2 receptors are located presynaptically, centrally they are located postsynaptically. The mechanism by which they influence presynaptic neurons to release or not release NE from their postsynaptic position is not clear. Peripheral Adrenergic Receptors There are three primary neurotransmitters in the peripheral nervous system: NE, epinephrine, and acetylcholine (dopamine receptors play a less important role peripherally). …

Risks for Oral Health With the Use of Antidepressants

In this article, attention is focused on oral pathology, particularly dental caries, caused by hyposalivation as a consequence of (long-term) use of antidepressants. Changes in clinical psychiatric practice and increasing numbers of prescriptions of antidepressants in primary care and specialty care settings have made awareness of this risk even more relevant than in the past. Normal physiology of salivary glands and changes in the secretion of saliva during use of antidepressants are described. Monitoring, prevention, and treatment of hyposalivation induced by antidepressants are encouraged as an adjunct in the clinical management of depression.

Health economic evaluations of antidepressants: A review

In an era of constrained health care financing, clinicians are increasingly faced with considering the economic consequences in addition to the clinical outcomes associated with initiating a patient on antidepressant therapy. This has increased the demand for health economic studies comparing antidepressant use and associated health care expenditures in clinical practice. These health economics studies have used methods ranging from clinical trials to other types of analyses including prospective naturalistic trials or retrospective studies which may be less familiar to clinicians. Prospective and retrospective health economics studies performed in clinical practice complement the experience gained from clinical trials in assessing antidepressant use and economic outcomes in light of patient and provider behavior within the usual care environment of a complex health care system. Broadly considered, health economic studies of antidepressants have consistently found differences in clinical practice between the tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitors (SSRIs) as well as among the SSRIs. These differences relate to the pattern and duration of antidepressant use as well as total direct health care expenditures. Future health economic research studies in clinical practice should focus on the economic consequences of long-term antidepressant use as well as the impact of antidepressant use on indirect costs such as productivity and absenteeism.

Health economic evaluations of antidepressants: A review

In an era of constrained health care financing, clinicians are increasingly faced with considering the economic consequences in addition to the clinical outcomes associated with initiating a patient on antidepressant therapy. This has increased the demand for health economic studies comparing antidepressant use and associated health care expenditures in clinical practice. These health economics studies have used methods ranging from clinical trials to other types of analyses including prospective naturalistic trials or retrospective studies which may be less familiar to clinicians. Prospective and retrospective health economics studies performed in clinical practice complement the experience gained from clinical trials in assessing antidepressant use and economic outcomes in light of patient and provider behavior within the usual care environment of a complex health care system. Broadly considered, health economic studies of antidepressants have consistently found differences in clinical practice between the tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitors (SSRIs) as well as among the SSRIs. These differences relate to the pattern and duration of antidepressant use as well as total direct health care expenditures. Future health economic research studies in clinical practice should focus on the economic consequences of long-term antidepressant use as well as the impact of antidepressant use on indirect costs such as productivity and absenteeism. Depression and Anxiety 7:53–64, 1998. © 1998 Wiley-Liss, Inc.

P-12-33 - Polypharmacy: What is its role in the long-term use of antidepressants?

The genetic cytochrome P450 polymorphism is reported in factors affecting the individual response to drugs. The interindividual variation at steady-state levels or also in elimination of drugs, finds an explanation in genetic differences in the metabolism. In particular, activities of the P450-IID6 isoenzyme are related to the sparteine/debrisoquine oxidation polymorphism. Phenotyping such a system has been proposed to analyse variability in the tricyclic antidepressant level. To analyse clinical relevance of a pharmacogenetic approach, we studied the cytochrome P450 CYP2D6 genotypes and the clinical responses to clomipramine in 21 hospitalised patients who met DSM-III-R criteria for major depression. Three patients were predicted as poor metabolizers. We suggested a limitation of clomipramine (CMI) hydroxylation in poor metaboliser (PM) patients which is balanced by a desmethylation. The clinical efficacy pattern does not differ in poor metaboliser and early metaboliser patients. Firstly, there is no significant differences in the evolution of scores on MADRS and specific retardation scale into the two groups. Secondly, outcome of side effects does not occur more frequently in PM patients. Clinical relevance of such an approach needs further study.