Selective serotonin reuptake inhibitors for migraine prophylaxis. Antidepressant treatment of chronic tension-type headache: a comparison between fluoxetine and desipramine. A non-selective (amitriptyline), but not a selective (citalopram), serotonin reuptake inhibitor is effective in the prophylactic treatment of chronic tension-type headache. (S)-(+)-mecamylamine (TC-5214): a neuronal nicotinic receptor modulator enters phase III trials as an adjunct treatment for Major Depressive Disorder (MDD). Sertraline in chronic tension-type headache. A randomised, double-blind study in adults with major depressive disorder with an inadequate response to a single course of selective serotonin reuptake inhibitor or serotonin–noradrenaline reuptake inhibitor treatment switched to vortioxetine or agomelatine† Chronic Enhancement of Serotonin Facilitates Excitatory Transcranial Direct Current Stimulation-Induced Neuroplasticity Use of benzodiazepines and selective serotonin reuptake inhibitors in middle-aged and older adults with anxiety disorders: a longitudinal and prospective study. Chronic tension-type headache, mood depression and serotonin: therapeutic effects of fluvoxamine and mianserine. Sertraline versus amitriptyline in the prophylactic therapy of non-depressed chronic tension-type headache patients Analgesic effect of amitriptyline in chronic tension-type headache is not directly related to serotonin reuptake inhibition Randomized double-blind comparison of serotonergic (Citalopram) versus noradrenergic (Reboxetine) reuptake inhibitors in outpatients with somatoform, DSM-IV-TR pain disorder. S-Fluoxetine in the Prophylaxis of Migraine: A Phase II Double-Blind Randomized Placebo-Controlled Study S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Efficacy of Noradrenergic and Serotonergic Antidepressants in Chronic Back Pain: A Preliminary Concentration-Controlled Trial Selective Serotonergic (SSRI) Versus Noradrenergic (SNRI) Reuptake Inhibitors with and without Acetylsalicylic Acid in Major Depressive Disorder. Serotonin precursors in chronic primary headache. A double-blind cross-over study with L-5-hydroxytryptophan vs. placebo.
The objective of this study was to assess the efficacy of sertraline in migraine prophylaxis . Other selective serotonin reuptake inhibitors have been studied for migraine prophylaxis , but this is the first report with sertraline .  Twenty-seven subjects were enrolled and baseline assessment of migraine frequency and severity were measured over a 4-week period . Subjects were then r and omized to receive placebo or sertraline in a double-blind fashion with headache frequency and severity measured over an 8-week period . Subjects completed a daily diary reporting the occurrence , severity , and degree of impairment associated with migraine . The headache index , a composite measure of migraine frequency and severity , scores did not significantly improve between assessment s at baseline ( 20.8 + /- 14.88 ) , 8 weeks ( 17.6 + /- 12.27 ) , and 12 weeks ( 16.7 + /- 6.38 ) in the treatment group ( n=6 ) ( P=0.956 ) . This finding is compared to other studies with the serotonin selective reuptake inhibitors , fluoxetine , fluvoxamine , and paroxetine . The authors believe that the selective serotonin reuptake inhibitors are not as effective as conventional migraine prophylaxis medications such as beta-blockers , tricyclic antidepressants , or divalproex sodium , but that in patients with comorbid depression who have failed conventional therapy selective serotonin reuptake inhibitors may be effective Amitriptyline , which is a noradrenaline reuptake and 5-HT reuptake inhibitor , has an established role in the management of  chronic tension-type headaches .  In a single-blind study , patients with chronic tension-type headache were r and omized to either fluoxetine 20 mg ( a selective 5-HT reuptake inhibitor ) or desipramine 75 mg ( a selective noradrenaline reuptake inhibitor ) and followed for 12 weeks to compare the effectiveness of the two drugs in improving headache , and to assess whether pain control is related to changes in depression . Patients were evaluated at weekly intervals on an analog pain-rating scale and at 4-weekly intervals on the Montgomery and Asberg Depression Rating Scale ( MADRS ) , the MOS general health status question naire ( SF36 ) , the Hospital Anxiety and Depression Scale ( HADS ) , and a side effects checklist .  Eighteen patients were r and omized to take fluoxetine and 19 to take desipramine . Of the 25 patients who completed the trial , 12 were on  fluoxetine and 13 were on desipramine . There was no significant difference between the two groups at baseline nor in change of pain ; reduction in use of analgesic medication ; nor change in the HADS , MADRS , or SF36 scores at 12 weeks , but 72 % of patients who completed the study improved , and this improvement almost exactly mirrored the improvement on the MADRS . The results from this trial are compatible with the notion that the beneficial effect of antidepressants in  chronic tension-type headache  is indirect , mediated by an effect on depression , and not more , dependent on serotonin reuptake inhibition than noradrenaline reuptake inhibition OBJECTIVES : Although the tricyclic antidepressant amitriptyline is extensively used in the prophylactic treatment of chronic tension-type headache , only few studies have investigated the efficacy of this treatment and the results are contradictory . In addition , the new selective serotonin reuptake inhibiting antidepressants , which are widely used in depression and of potential value in pain management , have never been investigated in a placebo controlled study of tension-type headache . The aim was to evaluate the efficacy of amitriptyline and of the selective serotonin reuptake inhibitor citalopram in chronic tension-type headache . METHODS : Forty non-depressed patients with chronic tension type headache were included in a 32 week , double blind , placebo controlled , three-way crossover study . RESULTS : Thirty four patients completed the trial .  Amitriptyline reduced area under the headache curve by 30 % compared with placebo ( P = 0.002 ) , whereas citalopram had no significant effect ( P = 0.68 ) . Explanatory analyses showed that amitriptyline significantly reduced the duration of headache ( P = 0.01 ) , headache frequency ( P = 0.01 ) , and intake of analgesics ( P = 0.02 ) but not headache intensity ( P = 0.12 ) . CONCLUSION : Although amitriptyline did not eliminate the headache , it provided a clinical ly important reduction of headache in the majority of otherwise treatment resistant patients . The differential effect of amitriptyline and citalopram indicates that mechanisms other than inhibition of serotonin reuptake are involved in the analgesic effect of the tricyclic antidepressants . Amitriptyline , but not citalopram , is valuable in the prophylactic treatment of chronic tension type headache Major Depressive Disorder ( MDD ) is a common illness that affects > 40 million people worldwide , and antidepressants are one of the top 5 leading classes of pharmaceuticals with annual sales in excess of $ 20 billion ( 1,2 ) . The current st and ard of care focuses on serotonin−norepinephrine reuptake inhibitors ( SNRI ) and selective serotonin reuptake inhibitors ( SSRI ) ; however , patients often respond poorly . In fact , the National Institute of Mental Health conducted a large-scale STAR*D study and found that 63 % of patients did not achieve remission with the SSRI Citalopram ( 1,3−5 ) . Citalopram was originally developed in Lundbeck in the late 1980s and sold as a racemate . Lundbeck , in collaboration with Forest Laboratories , has recently released an up date d version called Escitalopram ( also known as Lexapro ) , which is the single (S)-enantiomer of the racemic Citalopram , which provided new patent life . In 2009 , Lexapro garnered ∼$2.7 billion in sales in the US ( Figure ​(Figure1)1 ) ( 2 ) . Figure 1 Structures of Citalopram , Escitalopram , and TC-5214 . An alternative hypothesis for depression emerged over 30 years ago and suggests that a cholinergic imbalance ( hypercholinergic tone ) is a major factor in depression , and both clinical and pre clinical studies have implicated neuronal nicotinic cholinergic receptors ( NNRs ) rather than muscarinic receptors ( 5 ) . On the basis of these data , AstraZeneca and Targacept have explored the role of NNR antagonism in depressive disorders and recently announced the initiation of a phase III trial of TC-5214 , (S)-(+)-mecamylamine , as an adjunct therapy with Citalopram . TC-5214 is a low molecular weight ( 167.3 as free base , 203.8 as the HCl salt ) , basic ( pKa = 11.5 ) compound , freely soluble in water . While TC-5214 displays modest selectivity among the NNRs , its antidepressive properties are presumed to be the result of inhibition of the α4β2 NNRs . Pre clinical ly , TC-5214 demonstrated robust efficacy in rodent models of depression ( forced swim and behavioral despair ) and anxiety ( social interaction and light/dark chamber ) . The (S)-enantiomer showed a superior preclincial safety profile compared to that of either the racemic compound or the (R)-enantiomer . Furthermore , TC-5214 was well tolerated in both acute and chronic toxicity tests , displayed no mutagenic potential , and possessed pharmacokinetic properties suitable for development ( 3−5 ) . In 2009 , Targacept conducted a double blind , placebo controlled phase IIb trial in MMD patients with TC-5214  , as an adjunct treatment with Citalopram demonstrated superiority to placebo in both primary and secondary outcome measures ( 3−5 ) . This positive outcome led to a license agreement in December of 2009 with AstraZeneca for the global development and commercialization of TC-5214 . On June 23 , 2010 , AstraZeneca and Targacept announced the enrollment of the first patients in the phase III trial of TC-4214 . Coined the Renaissance Program , the trial will include two fixed dose and two flexible dose phase III studies of TC-5214 as an adjunct treatment for patients with poor response to st and ard SSRI or SNRI therapy . Each fixed dose and flexible dose phase III study will employ an initial open label phase wherein patients diagnosed with MDD receive one of seven marketed SSRIs or SNRIs for eight weeks to assess therapeutic response . Patients that respond poorly will then be r and omized into a double blind , placebo controlled second phase to receive a fixed or a flexible dose of TC-5214 or placebo , twice daily , while continuing the SSRI or SNRI therapy . A change from double blind baseline for TC-5214 on the Montgomery−Asberg Depression Rating Scale ( MADRS ) as compared to placebo is the primary outcome measure . The program will also include a double blind , placebo controlled study for long-term safety . The companies plan completion of the trial in time to file an IND with the FDA in late 2012 ( 3−5 ) . MMD is the leading cause of disability in the US for people 15−44 , and the burden for MDD in the US in 2000 was in excess of $ 83 billion ( 6 ) . When broken down , the workplace burden for lost time is ∼62 % , treatment costs account for ∼31 % , and suicide related costs average 7 % ( 6 ) . For those suffering from MDD with poor response to SSRIs and SNRIs , the phase III data is anxiously awaited OBJECTIVES To study the effect of Sertraline , a selective serotonin reuptake inhibitor in  chronic tension type headache ( CTTH ) in a double blind placebo controlled r and omized trial . MATERIAL AND METHODS The study design was a double blind placebo controlled r and omized study of 50 patients , over a period of 10 weeks including run-in period of two weeks , treatment period four weeks , and follow-up four weeks . The diagnosis of CTTH was based on criteria given by International Headache Society ( IHS ) . The overall response was grade d in terms of headache index , analgesic intake per week and percentage reduction in headache frequency using chi-square and ' t ' test . Anxiety and depression was assessed using Hamilton Rating Scale . RESULTS The mean analgesic intake per week declined from 4.34 + /- 0.736 tab/week to 1.07 + /- 0.592 tab/week in sertraline group ( p < 0.01 ) while reduction in placebo group was not significant ( 3.98 + /- 0.729 tab/week to 2.94 + /- 0.665 tab/week ) ( p > 0.05 ) . The reduction in headache index and percentage reduction in frequency of headache was not significant in drug treatment group . Side effects were seen in 24.4 % of patients nausea , nervousness and dizziness being the commonest . CONCLUSION The drug treatment group showed a significant decline in analgesic intake per week . The study result shows that sertraline can be a useful alternative to amitryptiline in those patients who fail to respond or can not tolerate it Objective This r and omised , double-blind , 12-week study compared efficacy and tolerability of flexible-dose treatment with vortioxetine ( 10–20 mg/day ) versus agomelatine ( 25–50 mg/day ) in major depressive disorder patients with inadequate response to selective serotonin reuptake inhibitor (SSRI)/serotonin – noradrenaline reuptake inhibitor ( SNRI ) monotherapy . Methods Patients were switched directly from SSRI/SNRI to vortioxetine or agomelatine . Primary endpoint was change from baseline to week 8 in the Montgomery – Åsberg Depression Rating Scale ( MADRS ) total score analysed by mixed model for repeated measurements , using a noninferiority test followed by a superiority test . Secondary endpoints included response and remission rates , anxiety symptoms ( Hamilton Anxiety Rating Scale ) , Clinical Global Impression , overall functioning ( Sheehan Disability Scale ) , health-related quality of life ( EuroQol 5 Dimensions ) , productivity ( work limitation question naire ) and family functioning ( Depression and Family Functioning Scale ) . Results Primary endpoint noninferiority was established and vortioxetine ( n = 252 ) was superior to agomelatine ( n = 241 ) by 2.2 MADRS points ( p < 0.01 ) . Vortioxetine was also significantly superior in response and remission rates at weeks 8 and 12 ; MADRS , Hamilton Anxiety Rating Scale , Clinical Global Impression , Sheehan Disability Scale and EuroQol 5 Dimensions scores at week 4 onwards ; work limitation question naire at week 8 and Depression and Family Functioning Scale at weeks 8 and 12 . Fewer patients withdrew because of adverse events with vortioxetine ( 5.9 % vs 9.5 % ) . Adverse events ( incidence ≥5 % ) were nausea , headache , dizziness and somnolence . Conclusions Vortioxetine was noninferior and significantly superior to agomelatine in major depressive disorder patients with previous inadequate response to a single course of SSRI/SNRI monotherapy . Vortioxetine was safe and well tolerated Serotonin affects memory formation via modulating long-term potentiation ( LTP ) and depression ( LTD ) . Accordingly , acute selective serotonin reuptake inhibitor ( SSRI ) administration enhanced LTP-like plasticity induced by transcranial direct current stimulation ( tDCS ) in humans . However , it usually takes some time for SSRI to reduce clinical symptoms such as anxiety , negative mood , and related symptoms of depression and anxiety disorders . This might be related to an at least partially different effect of chronic serotonergic enhancement on plasticity , as compared with single-dose medication . Here we explored the impact of chronic application of the SSRI citalopram ( CIT ) on plasticity induced by tDCS in healthy humans in a partially double-blinded , placebo (PLC)-controlled , r and omized crossover study . Furthermore , we explored the dependency of plasticity induction from the glutamatergic system via N-methyl-D-aspartate receptor antagonism . Twelve healthy subjects received  PLC medication , combined with anodal or cathodal tDCS of the primary motor cortex . Afterwards , the same subjects took CIT ( 20 mg/day ) consecutively for 35 days . During this period , four additional interventions were performed ( CIT and PLC medication with anodal/cathodal tDCS , CIT and dextromethorphan ( 150 mg ) with anodal/cathodal tDCS ) . Plasticity was monitored by motor-evoked potential amplitudes elicited by transcranial magnetic stimulation . Chronic application of CIT increased and prolonged the LTP-like plasticity induced by anodal tDCS for over 24 h , and converted cathodal tDCS-induced LTD-like plasticity into facilitation . These effects were abolished by dextromethorphan . Chronic serotonergic enhancement results in a strengthening of LTP-like glutamatergic plasticity , which might partially explain the therapeutic impact of SSRIs in depression and other neuropsychiatric diseases OBJECTIVE The purpose of this study was to examine the use of benzodiazepines ( BZs ) and selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors ( SSRIs/SNRIs ) over nine years of follow-up in middle-aged and older adults with diagnoses of panic disorder with or without agoraphobia , social phobia , or generalized anxiety disorder . SETTING AND PARTICIPANTS Participants in this study were enrolled in the Harvard/Brown Anxiety Research Project ( HARP ) . HARP is a naturalistic , longitudinal , multisite study of adults with anxiety disorders who are recruited from psychiatric setting s. The analytic sample consisted of 51 participants with anxiety disorders who were 55 to 70 years old at baseline and a younger cohort of 211 participants added for comparative analysis . DESIGN The authors examined patterns of medication use ( BZs and SSRIs/SNRIs ) in participants with anxiety disorders as they aged , by assessing the proportion of participants taking these medications using generalized estimating equation modeling . MEASUREMENTS The present data were derived from the structured diagnostic interview administered at enrollment using a combination of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders , Third Edition-R Non-Affective Disorder , Patient Version , Research Diagnostic Criteria Schedule for Affective Disorders-Lifetime , and subsequent follow-up interviews over a nine-year period using the Longitudinal Interval Follow-up Evaluation-Pharmacia & Upjohn to assess the weekly course of disorders to indicate syndrome severity and document medication use by specific type and dose on a weekly basis . RESULTS Findings showed that rates of BZ use were high among both the older ( 53 % at baseline ) and the younger ( 57.4 % ) age groups and did not significantly decrease over time , after controlling for time in episode of their anxiety disorders . There was a statistically significant increase in  SSRI/SNRI use over time in both groups . At the beginning of the study , 18 % of the older group and 21 % of the younger group were using SSRIs/SNRIs ; however , at the end of the study , the rates increased to 35 % and 43 % , respectively . CONCLUSIONS Although there was an increase in  SSRI/SNRI use in older participants with anxiety disorders over the course of study , at nine years of follow-up , only 35 % of participants were utilizing SSRI/SNRI medication , while more than one-half of the same participants were continuing to use BZs . To the authors ' knowledge , there are no r and omized clinical trials that have addressed comparative efficacy and safety of BZs and SSRIs/SNRIs in this population . However , there is documented evidence of adverse effects of chronic BZ use and the risk of developing dependency in older population Forty out- patients affected by chronic tension-type headache were selected according to the diagnostic criteria of International Headache Society ( IHS ) Headache Classification Committee . In a controlled trial patients received placebo for a four-week baseline period , then they were r and omized in double-blind fashion to therapy with mianserine ( 30 - 60 mg/day ) of fluvoxamine ( 50 - 100 mg/day ) for another eight-week period . Frequency of headache , pain severity and analgesic consumption were evaluated using a self-monitoring system . Mood depression was evaluated at 0 , 4 and 8 weeks by using Zung 's Self-Rating Depression Scale and Hamilton Rating Scale for Depression . Both drugs were beneficial in the treatment of chronic tension-type headache .  Non-depressed subjects with more severe headache responded best to fluvoxamine , whereas mianserine was more effective in the treatment of depressed patients with moderate headache . These results suggest that central serotoninergic neurotransmission can play a role in the pathophysiology of chronic tension-type headache also in non-depressed patients Abstract Patients with chronic tension- type headache ( CTTH ) are the most difficult to treat . Tricyclic antidepressants are the first-line therapeutic agents , but their anticholinergic side effects limit their usage . Selective serotonin reuptake inhibitors ( SSRI ) with fewer side effects than tricyclic antidepressants have also been used in treatment of CTTH , but the results are conflicting . In this study , prophylactic action of sertraline in treatment of nondepressed patients with CTTH was investigated and compared with amitriptyline in a prospect i ve , r and omized , open label , parallel-group study . A 4-week baseline period was followed by a 12-week treatment period with either 50 mg sertraline  ( n=41 patients ) or 25 mg amitriptyline  ( n=44 patients ) . Efficacies of treatments were determined by using a headache diary , in which patients recorded the occurrence , number , intensity and duration of headaches in days , analgesic drug consumption and any adverse events . Both drugs reduced headache symptoms and analgesic drug consumption at the first , second and third months of treatment compared to baseline values . There was significant superiority of amitriptyline in the headache symptoms and drug consumption reductions versus sertraline at the second and third months of treatment . Side effects were more favorable in the sertraline-treated patients , but dropouts were similar in both groups . These results suggest that both drugs were effective in the treatment of non-depressed patients with CTTH , but in comparison between groups , amitriptyline was more effective than sertraline & NA ; The tricyclic antidepressant amitriptyline is the only documented and most widely used prophylactic drug for  chronic tension‐type headache ( CTTH ) . However , it is not fully clarified whether the serotonin ( 5‐HT ) reuptake inhibition plays a major role for the analgesic effect of amitriptyline . To explore the importance of 5‐HT reuptake inhibition for mechanism of action of the analgesic effect of amitriptyline we investigated platelet 5‐HT levels during preventive treatment of CTTH with amitriptyline , the selective serotonin reuptake inhibitor citalopram , and placebo .  Thirty‐four patients with CTTH were given preventive treatment with amitriptyline 75 mg/day , the selective 5‐HT reuptake inhibitor citalopram 20 mg/day , and placebo in a 32‐week , double‐blind , placebo‐controlled , three‐way crossover trial . Blood sample s were collected in the last week of each treatment period . Platelet 5‐HT was used as a measure of 5‐HT reuptake inhibition and determined by high performance liquid chromatography . Area under the headache curve was 308 ( 157–715 ) ( median with quartiles in parentheses ) with amitriptyline and significantly lower than 377 ( 158–1121 ) with citalopram ( P=0.04 ) , and 441 ( 178–1408 ) with placebo ( P=0.002 ) . There was no difference between citalopram and placebo ( P=0.23 ) . Platelet 5‐HT was 0.4 (0.3–0.7) × 10−18 mol/platelet with citalopram , which was significantly lower than 1.7 (1.2–2.4) × 10−18 mol/platelet with amitriptyline ( P<0.001 ) , and 3.5 (2.8–4.3) × 10−18 mol/platelet with placebo ( P<0.001 ) . The lower platelet 5‐HT during treatment with citalopram than amitriptyline indicates that 5‐HT reuptake was most effectively inhibited by citalopram . In contrast , amitriptyline was most effective in reduction of headache . This suggests that the analgesic effect of amitriptyline in CTTH is not solely due to 5‐HT reuptake inhibition and that other mechanisms such as norepinephrine reuptake inhibition , NMDA receptor antagonism , blockade of muscarinic receptors and ion channels should be addressed in the future research OBJECTIVES Whether the effect of tricyclic antidepressants on Pain Disorder arises from their noradrenergic or serotonergic actions or both remains unclear . We compared the selective serotonin reuptake inhibitor ( SSRI ) citalopram and the noradrenergic reuptake inhibitor ( NARI ) reboxetine in out patients with Pain Disorder . We also distinguished the drugs ' analgesic and antidepressant effects . METHODS In this 8-week , r and omized double-blind study , 35 patients with a DSM-IV-TR diagnosis of Pain Disorder were r and omly assigned to receive either citalopram 40 mg/day ( N=17 patients ) or reboxetine 8 mg/day ( N=18 ) . The  Present Pain Intensity ( PPI ) scale and the Total Pain Rating Index ( tPRI ) of the McGill Pain Question naire were used to measure the effect on pain symptoms . Changes in the Zung Self-Rating Depression Scale ( Zung-D ) scores were evaluated to monitor a possible antidepressant effect . For all patients who had at least one assessment , an intent-to-treat analysis was performed . RESULTS No significant differences were found in the demographic variables or clinical characteristics of the two treatment groups . In the citalopram group , PPI and tPRI scores measured at baseline decreased after treatment ( tPRI : 41.9 vs. 30.0 , p=.004 ; PPI : 3.5 vs. 2.8 , p=.045 ) whereas in the reboxetine group differences were not statistically significant ( tPRI : 35.2 vs. 31.5 ; PPI : 3.7 vs. 3.1 ) . The Zung-D showed no significant changes between baseline and endpoint assessment in either group . CONCLUSIONS Our study suggests that the SSRI citalopram may have a moderate analgesic effect in patients with Pain Disorder , and that this analgesic activity appears to be not correlated to changes in depressive scores . If confirmed in a larger sample , this evidence suggests that patients who are intolerant or resistant to tricyclic antidepressants , may be treated with SSRIs S-fluoxetine is the long-acting enantiomer of the racemic antidepressant serotonin reuptake inhibitor .  Sixty-five patients needing migraine prophylaxis were recruited into a phase II , double-blind , placebo-controlled trial . After a 1-month placebo run-in , 53 patients met entry criteria with regard to attack frequency and were r and omized , 27 to S-fluoxetine and 26 to matching placebo .  Three failed to start treatment and mere were 17 early discontinuations , 9 from S-fluoxetine , 8 from placebo , at similar times and for similar reasons . The primary efficacy variable was attack frequency and analysis compared decline-from-baseline in the two groups . This was earlier and greater ( 1.7 attacks/28 days , or 52 % ) on active therapy than on placebo ( 1.1 attacks/28 days , or 27 % ) , and statistically significant in month 2 ( F=4.93 ; p=0.033 ) and month 4 ( F=4.55 ; p=0.041 ) . As secondary measures of efficacy , migraine-days per month and Patient 's Global Impression of Disease Severity coherently reflected the changes in attack frequency . Mean attack severity and acute medication use ( doses per attack ) were unaltered by either treatment . There were no serious adverse events . Withdrawals for adverse events were four from each group but none was considered causally related . The finding of greater efficacy of S-fluoxetine than of placebo should be interpreted conservatively , since the analysis in the final month was made on only half of the entered patients . It supports progression to phase III evaluation , which was the purpose of the study OBJECTIVE Despite the progressive increase in the number of antidepressants , many patients with major depressive disorder continue to be symptomatic . Clearly , there is an urgent need to develop better tolerated and more effective treatments for this disorder . The use of S-adenosyl methionine ( SAMe ) , a naturally occurring molecule that serves as a methyl donor in human cellular metabolism , as adjunctive treatment for antidepressant nonresponders with major depressive disorder represents one such effort toward novel pharmacotherapy development . METHOD Participants were 73 serotonin reuptake inhibitor ( SRI ) nonresponders with major depressive disorder enrolled in a 6-week , double-blind , r and omized trial of adjunctive oral SAMe ( target dose : 800 mg/twice daily ) . Patients continued to receive their SRI treatment at a stable dose throughout the 6-week trial . The primary outcome measure for the study was the response rates according to the 17-item Hamilton Depression Rating Scale ( HAM-D ) . RESULTS The HAM-D response and remission rates were higher for patients treated with adjunctive SAMe ( 36.1 % and 25.8 % , respectively ) than adjunctive placebo ( 17.6 % versus 11.7 % , respectively ) . The number needed to treat for response and remission was approximately one in six and one in seven , respectively . There was no statistically significant difference in the proportion of SAMe- versus placebo-treated patients who discontinued the trial for any reason ( 20.6 % versus 29.5 % , respectively ) , due to adverse events ( 5.1 % versus 8.8 % , respectively ) , or due to inefficacy ( 5.1 % versus 11.7 % , respectively ) . CONCLUSIONS These preliminary results suggest that SAMe can be an effective , well-tolerated , and safe adjunctive treatment strategy for SRI nonresponders with major depressive disorder and warrant replication Objective : Although antidepressants are widely prescribed as analgesics in chronic back pain , their clinical pharmacology is not well established . Norepinephrine transporter blockade seems to be essential for analgesia , but optimal concentrations are unknown . Fixed-dose studies of serotonin reuptake inhibitors are generally negative , but such studies can not be interpreted clearly because efficacy might be detected if concentration-response relationships were known . We evaluated ( 1 ) the feasibility of conducting a controlled-concentration study of a norepinephrine ( desipramine ) and a serotonin reuptake ( fluoxetine ) inhibitor and ( 2 ) the relationship between achieved concentrations and analgesic response . Methods : This single-center , 12-week , double-blind , prospect i ve , controlled-concentration study r and omized 121 chronic back pain patients without major depression to active placebo ( benztropine mesylate )  or  to predetermined low , medium , or high concentrations of desipramine ( targets were 50 , 110 , and 150 ng/mL , respectively ) or fluoxetine ( targets were 100 , 200 , and 400 ng/mL , respectively ) . Of these , 83 completed the trial : 38 withdrew primarily due to side effects . Results : Manipulation check revealed significant overlap of assigned and achieved concentrations related to drug intolerability . Completers ' analysis of achieved concentrations revealed reduction in pain intensity was significantly greater for low-concentration desipramine ( < 60 ng/mL , mean Descriptor Differential Scale [ DDS ] , 4.5 ) compared with placebo ( DDS 6.2 ) , higher concentrations of desipramine ( > 60 ng/mL , DDS 7.9 ) , and all concentrations of fluoxetine ( P < 0.05 , DDS 7.1 ) . Significant improvement in everyday function mirrored findings for pain intensity . Conclusions : Preliminary evidence for a low-concentration " therapeutic window " for noradrenergic analgesia may warrant additional study BACKGROUND Antidepressant medication efficacy remains a major research challenge . Here , we explored four questions : whether noradrenergic antidepressants are more effective than serotonergic antidepressants ; whether the addition of 100 mg acetylsalicylic acid ( ASA ) changes antidepressant efficacy ; whether the long-term efficacy differs depending on the antidepressant and the addition of ASA ; and whether serum levels of brain-derived neurotrophic factor ( BDNF ) are clinical ly informative . SUBJECTS AND METHODS In a two-year study , forty people with major depressive disorder were r and omly assigned to groups that received an SSRI ( escitalopram ) or an SNRI ( duloxetine ) , each group received concomitant ASA ( 100 mg ) or a placebo . Sociodemographic data were recorded and patients under went regular assessment s with the Hamilton depression scale ( HDS ) and clinical global impression ( CGI ) scale . Serum levels of BDNF were measured four times per year . RESULTS There was no significant difference in efficacy between the two antidepressants or between antidepressant treatment with and without ASA . However , subgroup comparisons revealed that the duloxetine + ASA ( DASA ) subgroup showed a more rapid improvement in HDS score as early as 2 months ( t=-3.114 , p=0.01 ) , in CGI score at 5 months ( t=-2.119 , p=0.05 ) , and a better remission rate ( χ2=6.296 , p 0.012 ) than the escitalopram + placebo ( EP ) subgroup . Serum BDNF before treatment was also higher in the DASA subgroup than in the EP subgroup ( t=3.713 ; p=0.002 ) . CONCLUSION This suggest two hypotheses : either a noradrenergic agent combined with ASA is more effective in treating depression than a serotonergic agent alone , or the level of serum BDNF before treatment is a precursor marker of the response to antidepressants . Further research is needed to test these hypotheses Serotonin ( 5-HT ) plays a crucial role in mediating the descending pain inhibitory systems and in the pathophysiology of migraine . Previous studies regarding the use of 5-Hydroxytryptophan ( 5-HTP ) , the active precursor of 5-HT , in the treatment of Chronic Primary Headache ( CPH ) have been inconclusive so far . In order to assess the efficacy of the serotonin active precursor in chronic headache prophylaxis , a double-blind cross-over study has been carried out in 31 patients with CPH , comparing L-5-HTP to placebo . Clinical syndromes included : ( a ) migraine ( 16 patients ) ; ( b ) mixed headache ( 6 patients ) ; ( c ) psychogenic headache ( 5 patients ) ; ( d ) muscle contraction headache ( 4 patients ) .  L-5-HTP was administered for two months at daily doses of 400 mg p.o . The reduction in severity and frequency of headache in patients taking the active drug and placebo was noted . Mood patterns were also taken into consideration . L-5-HTP proved to be more effective than placebo in reducing both headache frequency and severity , but the difference was not statistically significant . Favourable responses ( greater than 50 % average reduction in headache symptoms ) were obtained in 48 % of the cases after the second month of treatment . No significant difference in therapeutic response was observed as related to different clinical syndromes , except for psychogenic headache patients , who responded poorly to the active drug . Side effects , experienced in 19 % of the cases , were generally mild and transient . We conclude that L-5-HTP is a medication of moderate efficacy and remarkable safety , providing us with another alternative approach to CPH prophylaxis
Two studies compared SSRIs or SNRIs versus amitriptyline and found no evidence for a difference in terms of migraine frequency ( st and ardised mean difference ( SMD ) 0.04 , 95 % confidence interval ( CI ) -0.72 to 0.80 ; I(2 ) = 72 % ) , or other secondary outcomes such as migraine intensity and duration .SSRIs  or SNRIs were generally more tolerable than tricyclics .
Since the last version of this review , the new included studies have not added high quality evidence to support the use of SSRIs or venlafaxine as preventive drugs for migraine .
There is no evidence to consider SSRIs or venlafaxine as more effective than placebo or amitriptyline in reducing migraine frequency , intensity , and duration over two to three months of treatment .
Our conclusion is that the use of SSRIs and SNRIs for migraine prophylaxis is not supported by evidence
BACKGROUND This is an up date d version of the original Cochrane review published in 2005 on selective serotonin reuptake inhibitors ( SSRIs ) for preventing  migraine and tension-type headache .
Another up date d review is under development to cover tension-type headache .
Migraine is a common disorder .
The chronic forms are associated with disability and have a high economic impact .
In view of discoveries about the role of serotonin and other neurotransmitters in pain mechanisms , selective serotonin reuptake inhibitors ( SSRIs ) and serotonin-norepinephrine reuptake inhibitors ( SNRIs ) have been evaluated for the prevention of migraine .
OBJECTIVES To determine the efficacy and tolerability of SSRIs and SNRIs compared to placebo and other active interventions in the prevention of episodic and chronic migraine in adults .