[The efficacy of antidepressants in the treatment of chronic noncancer pain--a review]

[Article in Polish]

Miller A, Rabe-Jablonska J.

Z Centralnego Szpitala Klinicznego Uniwersytetu Medycznego w Lodzi.

Antidepressants are often applied in the treatment of chronic pain. Analgesic action of tricyclic antidepressants (TCAs) has been extensively studied and proven. TCAs are associated with a number of adverse effects which are inconvenient for patients. The newer antidepressants have fewer side effects and equivalent efficacy on mood disorders. This article reviews the available publications (mainly placebo-controlled trials) concerning the efficacy of these medications in the treatment of chronic pain. The data regarding selective serotonin reuptake inhibitors (SSRI) are conflicting. Trazodone (a serotonin-reuptake inhibitor as well as a postsynaptic serotonin receptor antagonist) does not appear to be effective for the treatment of chronic pain. No placebo-controlled studies are available for noradrenergic and specific serotoninergic antidepressant (NaSSA)--mirtazapine and noradrenaline reuptake inhibitor (NaRI)--reboxetine. Bupropion, a noradrenaline and dopamine-reuptake inhibitor appears to be effective in the treatment of neuropathic pain. Venlafaxine--selective serotonin and noradrenergic reuptake inhibitors (SNRI) was shown to be effective in the treatment of different kinds of pain. Duloxetine (SNRI) is effective in relieving both the emotional and painful physical symptoms of depression. Additional randomized, controlled trials are necessary to fully evaluate the role of new antidepressants in the treatment of chronic pain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15771151&dopt=Abstract antidepressant




Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects.

Hoshaw BA, Malberg JE, Lucki I.

Department of Psychiatry, University of Pennsylvania, 415 Curie Boulevard, Room 538, Philadelphia, PA 19104, USA.

Drug development research has identified neurotrophic factors as a downstream target of chronic antidepressant treatments. In order to study their antidepressant-like effects, two neurotrophic factors, brain-derived neurotrophic factor and insulin-like growth factor I, were examined in the rat modified forced swimming test after a single icv administration. Both neurotrophins produced antidepressant-like behavioral effects in the modified rat forced swimming test, reducing immobility and increasing swimming. In contrast to currently used antidepressants, which produce acute effects in the forced swimming test, the effects of the neurotrophins were unusually long lasting and persisted at least 6 days after the treatment. Neither neurotrophic factor had an effect on locomotor activity. The results support a role for neurotrophic factors mediating the behavioral effects of antidepressant drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15777771&dopt=Abstract antidepressant




Agitated "unipolar" depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy.

Akiskal HS, Benazzi F, Perugi G, Rihmer Z.

Department of Psychiatry and International Mood Center, University of California, La Jolla, CA, USA.

BACKGROUND: The nosologic status of agitated depression is unresolved. Are they unipolar (UP) or bipolar (BP)? Are they mixed states? Even more controversial is the notion that antidepressants might play some role in the suicidality of such patients () [Akiskal, H.S., Mallya, G., 1987. Criteria for the "soft" bipolar spectrum: treatment implications. Psychopharmacol Bull. 23, 68-73]. METHODS: After excluding all patients with history of hypomanic episodes occurring outside the frame of a major depressive episode (MDE), even those with a shorter duration of hypomanic symptoms than stipulated in DSM-IV, the remaining consecutive 254 unipolar major depressive disorder (MDD) private adult (>21 years old) outpatients were interviewed (off psychoactive drugs for 2 weeks) with the Structured Clinical Interview for DSM-IV (SCID-CV), the Hypomania Interview Guide (HIGH-C), and the Family History Screen. Intra-MDE hypomanic symptoms were systematically assessed, with >/=3 such symptoms required for a diagnosis of depressive mixed state (DMX). Agitated depression was defined as an MDE with HIGH-C psychomotor agitation score >/=2. Logistic regression was used to study associations and control for confounding variables. RESULTS: In this strictly defined unipolar sample, agitated depression was present in 19.7%. Compared with its non-agitated counterpart, it had significantly fewer recurrences, less chronicity, higher rate of family history for bipolar disorder, and DMX; and, among the intra-depressive non-euphoric hypomanic symptoms (in decreasing order of frequency), distractibility, racing/crowded thoughts, irritable mood, talkativeness, and risky behavior. The most striking finding was the robust association between agitated depression and DMX (OR=36.9). Furthermore, patients with psychomotor agitation had significantly higher rate of weight loss and suicidal ideation. Of DMX symptoms, we found an association between suicidal ideation, psychomotor activation, and racing thoughts. Agitated depression was tested by forward stepwise logistic regression versus all variables significantly different in the pairwise comparisons, yielding DMX, talkativeness, and suicidal ideation as the independent significant positive predictors. LIMITATIONS: No suicidal ideation scale was used. CONCLUSIONS: Agitated depression emerges as a distinct affective syndrome with weight loss, pressure of speech, racing thoughts and suicidal ideation. Psychomotor activation and racing thoughts during MDD independently predicted suicidal ideation. In this "unipolar" MDD sample, agitated depression had a strong clustering of intra-episode non-euphoric hypomanic symptoms (i.e. DMX) which, coupled with its association with bipolar family history, support its link with the bipolar spectrum. Agitated depression is therefore best regarded as "pseudo-unipolar." These findings overall accord with classical German concepts of agitated depression as a mixed state. Given that these patients are typically activated along the lines of risk-taking behavior, Kraepelin's rubric of "excited (mixed) depression" appears to us the preferred terminology over "agitated depression". CLINICAL IMPLICATIONS: The data reported herein, placed in the setting of the literature reviewed in the discussion suggest that the reports of increased risk of suicidal ideation and/or behavior in some depressed patients treated by antidepressant monotherapy or combinations thereof might be attributed to baseline psychomotor activation/agitation as part of an unrecognized bipolar mixed state. Whether antidepressants induce de novo suicidality in MDD cannot be answered without adequately powered prospective double-blind studies, unlikely to be conducted because of ethical constraints. Nonetheless, we submit that agitated, activated, or otherwise excited depressions (which we consider as depressive mixed states) overlap considerably with the so-called antidepressant "activation syndrome." Furthermore, the rare occurrence of suicidality on antidepressants should not obscure the fact that the advent of the new antidepressants is associated with worldwide decline in suicide rates. We finally wish to point out that our formal nosology (i.e. DSM-IV and ICD-10), in its failure to recognize the bipolar nature of depressive mixed states, thereby fails to shield pseudo-unipolar patients from antidepressant monotherapy, which is inappropriate for such patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15780694&dopt=Abstract antidepressant




Antidepressant Use During Pregnancy and the Rates of Spontaneous Abortions: A Meta-Analysis (May).

Hemels ME, Einarson A, Koren G, Lanctot KL, Einarson TR.

MSc Student, Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Motherisk Program, Hospital For Sick Children, Toronto.

BACKGROUND: Due to the high prevalence of depression in women of childbearing age and coupled with the fact that approximately 50% of the pregnancies are unplanned, there is a high chance that these women have been exposed to antidepressants in early pregnancy. OBJECTIVE: To determine baseline rates of spontaneous abortions (SAs) and whether antidepressants increase those rates. METHODS: Rates of SAs in women taking antidepressants compared with non-depressed women were combined into a relative risk using a random effects model. MEDLINE, EMBASE, Healthstar, Toxline, Psychlit, Cochrane database, and Reprotox were searched for studies published in any language from 1966 to 2003. Key words used to identify articles included pregnancy outcome, abortion, miscarriage, spontaneous, antidepressant, depression, and the generic names of each antidepressant and class. Bibliographies, review articles, and reference lists from studies were also used to identify potential articles expected to provide evidence of safety of antidepressants in pregnancy. RESULTS: Of 15 potential articles, 6 cohort studies of 3567 women (1534 exposed, 2033 nonexposed) provided extractable data. All matched on important confounders. Tests found no heterogeneity (chi(2) 3.13; p = 0.98), and all quality scores were adequate (>50%). The baseline SA rate (95% CI) was 8.7% (7.5% to 9.9%; n = 2033). For antidepressants, the rate was 12.4% (10.8% to 14.1%; n = 1534), significantly increased by 3.9% (1.9% to 6.0%); RR was 1.45 (1.19 to 1.77; n = 3567). No differences were found among antidepressant classes. CONCLUSIONS: Maternal exposure to antidepressants may be associated with increased risk for SA; however, depression itself cannot be ruled out.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15784808&dopt=Abstract antidepressant




Depression symptoms and antidepressant medicine use in Diabetes Prevention Program participants.

Rubin RR, Knowler WC, Ma Y, Marrero DG, Edelstein SL, Walker EA, Garfield SA, Fisher EB; Diabetes Prevention Program Research Group.

Diabetes Prevention Program Coordinating Center, Biostatistics Center, 6110 Executive Boulevard, Suite 750, Rockville, MD 20852, USA.

OBJECTIVE: To assess depression markers (symptoms and antidepressant medicine use) in Diabetes Prevention Program (DPP) participants and to determine whether changes in depression markers during the course of the study were associated with treatment arm, weight change, physical activity level, or participant demographic characteristics. RESEARCH DESIGN AND METHODS: DPP participants (n = 3,187) in three treatment arms (intensive lifestyle, metformin, and placebo) completed the Beck Depression Inventory (BDI) and reported on use of antidepressant medicines at randomization and subsequently at each annual visit (average duration in study 3.2 years). RESULTS: On study entry, 10.3% of participants had BDI scores > or =11, which was used as a threshold for mild depression, 5.7% took antidepressant medicines, and 0.9% had both depression markers. During the DPP, the proportion of participants with elevated BDI scores declined (from 10.3% at baseline to 8.4% at year 3), while the proportion taking antidepressant medicines increased (from 5.7% at baseline to 8.7% at year 3), leaving the proportion with either marker unchanged. These time trends were not significantly associated with the DPP treatment arm. Depression markers throughout the study were associated with some participant demographic factors, adjusted for other factors. Men were less likely to have elevated depression scores and less likely to use antidepressant medicine at baseline (9.0% of men and 17.9% of women had at least one marker of depression) and throughout the study (P <0.0001). Those with more education were less likely to have elevated symptom scores (P = 0.0007) but more likely to be taking antidepressant medicine (P = 0.002). Non-Hispanic white participants were less likely than African Americans to have BDI scores > or =11 (P = 0.03), but white participants were more likely to be taking antidepressant medicine than any other racial/ethnic group (P <0.0001). CONCLUSIONS: DPP participation was not associated with changes in levels of depression. Countervailing trends in the proportion of DPP participants with elevated depression symptoms and the proportion taking antidepressant medicine resulted in no significant change in the proportion with either marker. The finding that those taking antidepressant medicine often do not have elevated depression symptoms indicates the value of assessing both markers when estimating overall depression rates.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15793181&dopt=Abstract antidepressant




[Mechanisms of antidepressants and serotonin (5-HT)-induced glial cell line-derived neurotrophic factor (GDNF) releases in rat C6 gliobrastoma cells]

[Article in Japanese]

Hisaoka K, Takebayashi M, Nishida A, Tsuchioka M, Yamawaki S, Nakata Y.

Institute of Clinical Research, National Hospital Organization Kure Medical Center, 3-1 Aoyama, Kure, 737-0023, Japan. hisaokak kure-nh.go.jp

Recent studies show that neuronal and glial plasticity are important for the therapeutic action of antidepressants. Here, we demonstrated that amitriptyline, a tricyclic antidepressant, significantly increased GDNF mRNA and GDNF release in C6 cells. Furthermore, different classes of antidepressants increased GDNF release, but non-antidepressant psychotropic drugs did not. The amitriptyline-induced GDNF release was completely inhibited by U0126, a mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor, but was not inhibited by H-89, a protein kinase A inhibitor or calphostin C, a protein kinase C inhibitor. These results suggest that the amitriptyline-induced GDNF release may be regulated through a MEK/MAPK pathway. Next, we examined the effects of monoamines on GDNF release, because antidepressants are known to increase monoamines. 5-HT increased GDNF mRNA and GDNF release, but noradrenaline and dopamine did not. The 5-HT-induced GDNF release was partially, but significantly, blocked by ketanserin, a 5-HT2A receptor antagonist. The 5-HT-induced GDNF release was completely inhibited by U0126, but was not inhibited by H-89 or calphostin C. These results suggest that the 5-HT-induced GDNF release was mediated through a MEK/MAPK pathway and, at least, 5-HT2A receptors. GDNF, as well as other neurotrophic factors, may contribute to explain the therapeutic action of antidepressants and suggest a novel strategy of pharmacological intervention.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15796067&dopt=Abstract antidepressant




Predictors of antidepressant use among older adults: have they changed over time?

Blazer DG, Hybels CF, Fillenbaum GG, Pieper CF.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 3003, Durham, NC 27710. Blaze001 mc.duke.edu.

OBJECTIVE: Antidepressant use increased substantially among older adults with the introduction of the new-generation medications such as the selective serotonin reuptake inhibitors. The authors analyzed data from two follow-up intervals-1986-1987 to 1989-1990 (interval 1) and 1992-1993 to 1996-1997 (interval 2)-from a community-based cohort of 4,162 older adults to determine predictors of future antidepressant use. METHOD: Information on antidepressant use, demographic and health characteristics, and categories of depressive symptoms-positive affect, negative affect, somatic complaints, and interpersonal problems-were obtained. Logistic regression was used to control simultaneously for multiple variables predicting antidepressant use during the two intervals. Repeated-measures logistic regression (with generalized estimating equations) was employed to model the probability of antidepressant use, with adjustment for the effect of time. RESULTS: Prior antidepressant use and white race were strong predictors of future use during both intervals. Negative affect was the only additional significant predictor of use during interval 1. In contrast, low positive affect scores, cognitive impairment, and poorer health were additional significant predictors during interval 2. In a repeated-measures model, race, prior antidepressant use, poor health, low positive affect scores, and somatic complaints varied as predictors over time. Negative affect and cognitive impairment were consistent predictors over time. CONCLUSIONS: The predictors of antidepressant use by older adults changed over time, with health-related measures of quality of life, such as positive affect, health status, and somatic complaints, becoming more prominent as predictors of use.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15800142&dopt=Abstract antidepressant




Is combination olanzapine and antidepressant medication associated with a more rapid response trajectory than antidepressant alone?

Parker G, Brotchie H, Parker K.

Black Dog Institute, Prince of Wales Hospital, Randwick, Australia 2031. g.parker unsw.edu.au.

OBJECTIVE: The authors' goal was to determine if prescription of antidepressant medication plus olanzapine initiates a more rapid response than prescription of antidepressant alone. METHOD: Twenty patients with major depression were studied. For 2 weeks the patients were blindly assigned to receive antidepressant plus olanzapine or antidepressant plus placebo. After 2 weeks, olanzapine augmentation was initiated for patients who did not improve with placebo augmentation. Response to medication was measured primarily by Hamilton Depression Rating Scale score. Other measures were the CORE, Clinical Global Impression, Beck Depression Inventory, and Daily Rating Schedule. RESULTS: Hamilton depression scores improved nonsignificantly in response to olanzapine combination therapy, but that trend was not evident on any secondary measure. Four patients who did not improve while receiving antidepressant and placebo showed rapid remission following late olanzapine augmentation. CONCLUSIONS: Failure to demonstrate any benefit from initial combination therapy may reflect an underpowered rather than a negative study. The distinct impact of late olanzapine augmentation suggests that pretreatment with an antidepressant may be required to facilitate a rapid antidepressant response to combined treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15800157&dopt=Abstract antidepressant