Anti-Depressants and Chemical Depression

Premise

I ought to outline my premise and my intent:

– Antidepressants, while not always useful, are often more useful than placebo alone

– Chemicals and neurotransmitters do play a part in depression

– Psychotherapy is the best means to alleviating any mental disorder

– It is often a good idea to interplay psychotherapy with drugs in order to maintain coherence in psychotherapy

I will not try to propose my own propositions and thoughts but simply let the evidence speak for itself.  This is an exercise in database usage and journal utilization.

Chemical Depression

 “Inhibition of serotonergic raphe neurons is mediated by somatodendritic 5-HT1A autoreceptors, which may be increased in depressed patients. We report an association of the C(-1019)G 5-HT1A promoter polymorphism with major depression and suicide in separate cohorts. In depressed patients, the homozygous G(-1019) allele was enriched twofold versus controls (p = 0.0017 and 0.0006 for G/G genotype and G allele distribution, respectively), and in completed suicide cases the G(-1019) allele was enriched fourfold (p = 0.002 and 0.00008 for G/G genotype and G allele distribution, respectively). The C(-1019) allele was part of a 26 bp imperfect palindrome that bound transcription factors nuclear NUDR [nuclear deformed epidermal autoregulatory factor (DEAF-1)]/suppressin and Hairy/Enhancer-of-split-5 (Drosophila) (Hes5) to repress 5-HT1A or heterologous promoters, whereas the G(-1019) allele abolished repression by NUDR, but only partially impaired Hes5-mediated repression. Recombinant NUDR bound specifically to the 26 bp palindrome, and endogenous NUDR was present in the major protein-DNA complex from raphe nuclear extracts. Stable expression of NUDR in raphe cells reduced levels of endogenous 5-HT1A protein and binding. NUDR protein was colocalized with 5-HT1A receptors in serotonergic raphe cells, hippocampal and cortical neurons, and adult brain regions including raphe nuclei, indicating a role in regulating 5-HT1A autoreceptor expression. Our data indicate that NUDR is a repressor of the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter polymorphism. We suggest a novel transcriptional model in which the G(-1019) allele derepresses 5-HT1A autoreceptor expression to reduce serotonergic neurotransmission, predisposing to depression and suicide.”

+ Impaired Repression at a 5-Hydroxytryptamine 1A Receptor Gene Polymorphism Associated with Major Depression and Suicide

– Journal of Neuroscience; http://www.jneurosci.org/cgi/content/full/23/25/8788?maxtoshow=&HITS=10&hits=10

“The neuroanatomical correlates of depression remain unclear. Functional imaging data have associated depression with abnormal patterns of activity in prefrontal cortex (PFC), including the ventromedial (vmPFC) and dorsolateral (dlPFC) sectors. If vmPFC and dlPFC are critical neural substrates for the pathogenesis of depression, then damage to either area should affect the expression of depressive symptoms. Using patients with brain lesions we show that, relative to nonfrontal lesions, bilateral vmPFC lesions are associated with markedly low levels of depression, whereas bilateral dorsal PFC lesions (involving dorsomedial and dorsolateral areas in both hemispheres) are associated with substantially higher levels of depression. These findings demonstrate that vmPFC and dorsal PFC are critically and causally involved in depression, although with very different roles: vmPFC damage confers resistance to depression, whereas dorsal PFC damage confers vulnerability.”

+ Distinct Regions of Prefrontal Cortex Mediate Resistance and Vulnerability to Depression

– Journal of Neuroscience; http://www.jneurosci.org/cgi/content/full/28/47/12341?maxtoshow=&HITS=10&hits=10

“Long-term depression (LTD) at the corticostriatal synapse is postsynaptically induced but presynaptically expressed, the depression being a result of retrograde endocannabinoid signaling that activates presynaptic cannabinoid CB1 receptors and reduces the probability of glutamate release. To study the role of protein synthesis in striatal LTD, we used a striatum-only preparation in which the presynaptic cell body is cut off, leaving intact only its axons, whose terminals synapse on medium spiny neurons. LTD (duration >150 min) was induced in this preparation, thus providing evidence that transcription in the presynaptic cell nucleus is not necessary for this form of plasticity. The maintenance of striatal LTD, however, was blocked by bath application of protein translation inhibitors but not by the same inhibitors loaded into the postsynaptic cell. These results suggest that local translation is critical for the expression of striatal LTD, distinguishing this form of mammalian synaptic plasticity from other forms that require postsynaptic protein synthesis. Possible roles of axonal or glial translation in striatal LTD are considered.”

+ The Role of Protein Synthesis in Striatal Long-Term Depression

– Journal of Neuroscience; http://www.jneurosci.org/cgi/content/full/26/46/11811?maxtoshow=&HITS=10&hits=10

Antidepressants and Placebo

“The authors provided a very informative commentary on publication bias and antidepressant efficacy. They made clear that the modest advantage of drug over placebo in reported clinical trials is reduced when unreported clinical trials are included in data analysis. The robust placebo response, particularly in less severely depressed subjects, deserves emphasis when considering clinical implications. “

+ Carpenter, William, T. Jr. (2009). Placebo effect in depression. The American Journal of Psychiatry, 166(8), 935.

“We assessed the efficacy of continuation treatment with antidepressants in a meta-analysis of relapse prevention studies in the five principal anxiety disorders, to explore the benefit of continuation treatment in each disorder, and their relative efficacy across these disorders. METHOD: Double-blind placebo-controlled studies with relapse prevention designs in Panic Disorder, Generalized Anxiety Disorder, Social Phobia, Post-Traumatic Stress Disorder and Obsessive–Compulsive Disorder were identified in a systematic literature search. The primary efficacy comparison was relapse rates between active and placebo arms calculated as odds ratios (ORs) using Review Manager version 5.0. Relapse data were also used to calculate relative risk (RR), risk difference (RD) and number needed to treat (NNT). RESULTS: Twenty-two relapse prevention trials were identified for these 5 disorders. Continuation antidepressant treatment produced robust treatment effects for each disorder, however the magnitude varied by indication. The greatest treatment effect was noted for GAD (pooled OR 0.20), whereas the pooled ORs for PD and OCD were for almost 2-fold higher (0.35 and 0.38 respectively). RR, RD and NNT showed similar statistically significant trends. LIMITATIONS: This study cannot identify an optimal duration of therapy. This analysis only examined studies testing monoamine reuptake inhibiting antidepressants, and therefore these results might not be generalizable to other classes of antianxiety agents. CONCLUSIONS: This meta-analysis underscores the importance of continuation treatment following acute response in all 5 anxiety disorders, however the relative efficacy of continuation antidepressant treatment appears to vary by disorder.”

+ Donovan, Mary Rocco, Glue, Paul, Kolluri Sheela, Emire Birol. (2009). Comparative efficacy of anitdepressants in preventing relapse in anxiety disorders – a meta-analysis. Journal of Affective Disorders, (np).

“Psychotherapy and antidepressant medications are the two preeminent treatment choices for depression. This article puts each of these treatments into perspective by presenting an overview of what is currently known about their effectiveness either singly or in combination. Discussion of placebos, common factors among therapies, relapse rates, depression severity, patient treatment preferences and exaggerations in pharmaceutical advertising provide guidance for clinicians in deciding on the best course of treatment. Overall, research reveals the importance of psychosocial factors, no matter what the mode of treatment, and the need for fostering a collaborative bond between clinicians and their patients. We argue that empirical evidence points to making psychotherapy the initial treatment choice for most cases of depression. “

+ Greenberg, Roger P., Goldman, Eliabeth Davis. (2009). Antidepressants, psychotherapy or their combination; Weighing options for depression treatments. Journal of Contemporary Psychotherapy, 39(2), 83-91.

“We evaluated the effects of a selective serotonin reuptake inhibitor, paroxetine, on treating tinnitus. Tinnitus patients stratified for the presence of depression and anxiety were studied retrospectively. Fifty-six patients were observed for more than 6 months. They were initially treated with paroxetine only at a dose of 10 mg/day for 2–4 weeks; thereafter, the dose was increased to 20 mg/day. Tinnitus distress was evaluated with the Tinnitus Handicap Inventory (THI) and with visual analog scales (VASs) for tinnitus loudness and annoyance. Depression and anxiety were measured with the Self-Rating Depression Scale (SDS) and the trait section of the State-Trait Anxiety Inventory (STAI). The patients were grouped according to their SDS and STAI scores, and each variable was compared at baseline and the 6-month followup. Changes among these variables were also examined to determine whether reduced tinnitus distress was related to the improvement of depression or anxiety. Patients with both depression and anxiety showed better results (decrease in THI, VASs, SDS and STAI scores) than patients with anxiety alone, or patients without depression and anxiety. In patients with depression and anxiety, changes in tinnitus variables and changes in depression and anxiety scores were strongly correlated. In other patients, however, changes in tinnitus variables and changes in depression and anxiety scores were not correlated. These results suggest that paroxetine is effective in treating distressed tinnitus patients with depression and anxiety by reducing their tinnitus severity as well as their depression and anxiety.”

+ Oishi, Naoki, Kanzaki, Sho, ShindenShinden, Seiichi, Saito, Hideyuki, Inoue, Yashurio, Ogawa, Karou. (2010). Effects of selective serotnonin reuptake inhibitor on treating tinnitus in pateints stratified for presence of depression or anxiety. Audiology and Neurotology, 15(30), 187-193.

“Four serotonin-related genes including guanine nucleotide binding protein beta polypeptide 3 (GNB3), 5-hydroxytryptamine receptor 1A (HTR1A; serotonin receptor 1A), 5-hydroxytryptamine receptor 2A (HTR2A; serotonin receptor 2A), and solute carrier family 6 member 4 (SLC6A4; serotonin neurotransmitter transporter) have been suggested to be candidate genes for influencing antidepressant treatment outcome. The aim of this study was to explore whether interaction among these genes could contribute to the pharmacogenomics of short-term antidepressant response in a Taiwanese population with major depressive disorder (MDD). Methods: Included in this study were 101 MDD patients who were treated with antidepressants, 35 of whom were rapid responders and 66 non-responders after 2 weeks of treatment. We genotyped four single nucleotide polymorphisms (SNPs), including GNB3 rs5443 (C825T), HTR1A rs6295 (C-1019G), HTR2A rs6311 (T102C), and SLC6A4 rs25533, and employed the generalized multifactor dimensionality reduction (GMDR) method to investigate gene–gene interactions. Results: Single-locus analyses showed the GNB3 rs5443 polymorphism to be associated with short-term antidepressant treatment outcome (P-value=0.029). We did not correct for multiple testing in these multiple exploratory analyses. Finally, the GMDR approach identified a significant gene–gene interaction (P-value= 0.025) involving GNB3 and HTR2A, as well as a significant 3-locus model (P-value=0.015) among GNB3, HTR2A, and SLC6A4. Conclusions: These results support the hypothesis that GNB3, HTR2A, and SLC6A4 may play a role in the outcome of short-term antidepressant treatment for MDD in an interactive manner. Future research with independent replication using large sample sizes is needed to confirm the functions of the candidate genes identified in this study as being involved in short-term antidepressant treatment response.”

+ Lin, Eugene1; Chen, Po See2; Chang, Hui Hua3; Gean, Po-Wu4; Tsai, Hsin Chun2; Yang, Yen Kuang2; Lu, Ru-Band2. (2009). Interaction of serotonin-related genes affects short-term antidepressant response in major depressive disorder. Progress in Neuro-Psychopharmacology & Biological Psychiatry. Vol 33(7), Oct 1, 2009, pp. 1167-1172.

“Improvements in placebo groups of antidepressant trials account for a major part of the expected drug effects. We aimed to determine overall effect sizes of placebo and drug effects in antidepressant trials, and to analyze whether the placebo effect in antidepressant trials also occurs for patient self-perception, general psychopathology, and quality of life. Methods: Search terms covered different variants of pharmacotherapy for patients with depressive disorders from January 1980 to December 2005 in the databases Medline/Pubmed, PsycINFO and CENTRAL, a.o. We included RCTs with a placebo group and an antidepressant group in people with depression. Results: We computed within group effect sizes for several outcome variables and integrated them using random-effect models. A total of 96 studies were included. Mean effect size in the placebo group for primary outcome variables was d=1.69 (95% CI=1.54–1.84) compared to 2.50 in the drug group (95% CI=2.30–2.69). There was a major difference between placebo effect sizes assessed with observer ratings (d=1.85, 95% CI=1.69–2.01) versus patient self-perception (d=0.67; 95% CI=0.49–0.85). The effect sizes in placebo groups in 2005 were more than twice as great as those in 1980, but only for observer ratings, not for patient self-ratings. The result was partly due to increased homogeneity of samples of recently published trials. Conclusions: The placebo effect accounted for 68% of the effect in the drug groups. Whereas clinical trials need to control the placebo effect, clinical practice should attempt to use its full power. “

+ Rief, Winfried1; Nestoriuc, Yvonne1; Weiss, Sarah1; Welzel, Eva1; Barsky, Arthur J.2; Hofmann, Stefan G.3. (2009). Meta-analysis of the placebo response in antidepressant trials. Journal of Affective Disorders. Vol 118(1-3), Nov 2009, pp. 1-8

Conclusions

This conclusion, from Donovan, et. al. best surmises the stance on antidepressants, “…the importance of continuation treatment following acute response in all 5 anxiety disorders, however the relative efficacy of continuation antidepressant treatment appears to vary by disorder”. While it is no debating that placebo effect does play a role in therapy, it is also evident that antidepressants can significantly help, past placebo, in therapy. It is not the fact that antidepressants are never useful and always placebo.

Depression, along with other mental disorders, do have a significant biological cause. In this case, somatodendritic 5-HT1A autoreceptors facilitating serontonal neurotransmitters and antagonists are significantly proven to play a role in depression and anxiety.

I encourage anyone to find any contrary evidence, but it must be from a scientific journal. Several of the above are meta-analysis which are the best qualified forms of evidence and to reply to such with a news paper article is as intellectual as responding to an existentialistic proposition with a candy cane.

What do you think..?

~

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