title: The Use of Antidepressants for Physical and Psychological Symptoms in Cancer. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale Mirtazapine improves sleep and lowers anxiety and depression in cancer patients: superiority over imipramine Patient Health Questionnaire Anxiety and Depression Scale: Initial Validation in Three Clinical Trials A pilot study to evaluate symptom-oriented selection of antidepressants in patients with cancer. GRADE guidelines: 3. Rating the quality of evidence. An open-label, crossover trial of mirtazapine (15 and 30 mg) in cancer patients with pain and other distressing symptoms. Defining the clinically important difference in pain outcome measures An Open-Label Long-Term Naturalistic Study of Mirtazapine Treatment for Depression in Cancer Patients Phase II Trial of Mirtazapine for Cancer-Related Cachexia and Anorexia Effectiveness of mirtazapine for nausea and insomnia in cancer patients with depression. Mirtazapine for chronic breathlessness? A review of mechanistic insights and therapeutic potential
abstract: Cancer patients are commonly associated with various physical and psychological symptoms . In palliative setting , the aims are to relieve those symptoms , improve quality of life , and increase medication adherence among cancer patients . Antidepressants are generally accepted for the treatment of depression among patients with or without cancer . Some other potential benefits of the antidepressants have been reported in cancer patients . OBJECTIVE This study aims to review the use of antidepressants for physical and psychological symptoms in cancer patients . RESULTS Our findings showed the mixed result of positive and negative findings in various symptoms associated with cancer patients . These studies are categorised according to the hierarchy of evidence from high to low level , namely r and omised controlled trials , cohort studies , case-control studies , case series , case reports , as well as other type of publications . The majority of antidepressants used in cancer patients seem to be beneficial for the treatment of depression , anxiety , hot flashes and other symptoms such as sexual dysfunction , fatigue , nicotine dependence , vasomotor symptoms , executive functions , sleep problems , pruritus , as well as for hypochondriasis . While fluoxetine was found to be associated with the reduction of antiemetic property in ondansetron , mirtazapine was identified to be a good alternative in treating nausea and cachexia among cancer patients . CONCLUSION More research studies with adequate statistical power are warranted to vali date the use of antidepressants among cancer patients in treating these physical and psychological symptoms & NA ;  Pain intensity is frequently measured on an 11‐point pain intensity numerical rating scale ( PI‐NRS ) , where 0=no pain and 10=worst possible pain . However , it is difficult to interpret the clinical importance of changes from baseline on this scale ( such as a 1‐ or 2‐point change ) . To date , there are no data driven estimates for clinical ly important differences in pain intensity scales used for chronic pain studies . We have estimated a clinical ly important difference on this scale by relating it to global assessment s of change in multiple studies of chronic pain . Data on 2724 subjects from 10 recently completed placebo‐controlled clinical trials of pregabalin in diabetic neuropathy , postherpetic neuralgia , chronic low back pain , fibromyalgia , and osteoarthritis were used . The studies had similar design s and measurement instruments , including the PI‐NRS , collected in a daily diary , and the st and ard seven‐point patient global impression of change ( PGIC ) , collected at the endpoint . The changes in the PI‐NRS from baseline to the endpoint were compared to the PGIC for each subject . Categories of ‘ much improved ’ and ‘ very much improved ’ were used as determinants of a clinical ly important difference and the relationship to the PI‐NRS was explored using graphs , box plots , and sensitivity/specificity analyses . A consistent relationship between the change in PI‐NRS and the PGIC was demonstrated regardless of study , disease type , age , sex , study result , or treatment group . On average , a reduction of approximately two points or a reduction of approximately 30 % in the PI‐NRS represented a clinical ly important difference . The relationship between percent change and the PGIC was also consistent regardless of baseline pain , while higher baseline scores required larger raw changes to represent a clinical ly important difference . The application of these results to future studies may provide a st and ard definition of clinical ly important improvement in clinical trials of chronic pain therapies . Use of a st and ard outcome across chronic pain studies would greatly enhance the comparability , validity , and clinical applicability of these studies Goals of the workThis study aim ed to compare the effectiveness of mirtazapine and imipramine on not only the distressing symptoms of cancer patients such as pain , nausea , vomiting , appetite loss , and sleep disturbances  but also depressive and anxiety symptoms .  Material s and methods Fifty-three patients with cancer who were diagnosed with major depressive disorder , anxiety disorder , or adjustment disorder were included . Twenty patients on mirtazapine , 13 patients on imipramine , and 20 patients in the control group without medication were interviewed during three visits ( baseline , third week , and sixth week ) . Pain , nausea , vomiting , appetite loss , and sleep disturbances were evaluated with self- assessment single-symptom scales during each visit . The patients were also asked to complete the Hospital Anxiety Depression Scale ( HADS ) during each visit . Main results There were no significant differences among the three visits in the mirtazapine , imipramine , or control groups in terms of pain , nausea , vomiting , or appetite loss . For the initial , middle , and late insomnia , only the mirtazapine group showed improvements ( p = 0.001 , p = 0.001 , p = 0.003 ) . There were also significant differences in the mean total ( p = 0.03 ) , anxiety ( p = 0.003 ) , and depression ( p = 0.025 ) scores of HADS among the three visits for patients taking mirtazapine . There were no significant differences for HADS scores from the baseline to the end point for patients taking imipramine or control group patients . Conclusion Our findings suggest that mirtazapine is effective for resolving insomnia as well as anxiety and depressive symptoms in cancer patients . However , more systematic research , such as placebo-controlled studies , is needed Objective We examine the reliability and validity of the Patient Health Question naire Anxiety and Depression Scale (PHQ-ADS)—which combines the nine-item Patient Health Question naire depression scale and seven-item Generalized Anxiety Disorder scale — as a composite measure of depression and anxiety . Methods Baseline data from 896 patients enrolled in two primary -care based trials of chronic pain and one oncology- practice –based trial of depression and pain were analyzed . The internal reliability , st and ard error of measurement , and convergent , construct , and factor structure validity , as well as sensitivity to change of the PHQ-ADS were examined . Results The PHQ-ADS demonstrated high internal reliability ( Cronbach & agr ; values of .8 to .9 ) in all three trials . PHQ-ADS scores can range from 0 to 48 ( with higher scores indicating more severe depression/anxiety ) , and the estimated st and ard error of measurement was approximately 3 to 4 points . The PHQ-ADS showed strong convergent ( most correlations , 0.7–0.8 range ) and construct ( most correlations , 0.4–0.6 range ) validity when examining its association with other mental health , quality of life , and disability measures . PHQ-ADS cutpoints of 10 , 20 , and 30 indicated mild , moderate , and severe levels of depression/anxiety , respectively . Bifactor analysis showed sufficient unidimensionality of the PHQ-ADS score . PHQ-ADS change scores at 3 months differentiated ( p < .0001 ) between individuals classified as worse , stable , or improved by a reference measure , providing preliminary evidence for sensitivity to change . Conclusions The PHQ-ADS may be a reliable and valid composite measure of depression and anxiety which , if vali date d in other population s , could be useful as a single measure for jointly assessing two of the most common psychological conditions in clinical practice and research . Trial Registration : Clinical trials.gov Identifier : NCT00926588 ( SCOPE ) ; NCT00386243 ( ESCAPE ) ; NCT00313573 ( INCPAD ) BACKGROUND Major depressive disorder ( MDD ) is a common and debilitating illness in patients with cancer . However , the optimal treatment of depression in these patients remains uncertain , with limited evidence to support the use of pharmacologic therapy . We conducted a pilot study to evaluate the feasibility of an antidepressant clinical trial in the oncology population and the process of symptom-oriented selection of antidepressants ( citalopram or mirtazapine ) in patients with cancer and MDD . METHODS This was a single center , two-arm , nonr and omized , open-label , nine-week pilot study of mirtazapine or citalopram in cancer patients with MDD . The primary endpoint was the feasibility to recruit and to retain patients . Secondary outcomes included changes in Patient Health Question naire-9 ( PHQ-9 ) ( depression ) , Functional Assessment of Cancer Therapy-General ( FACT-G ) ( quality of life ) , Functional Assessment of Chronic Illness Therapy-Fatigue ( FACIT-Fatigue ) ( fatigue ) , and Pittsburgh Sleep Quality Index ( PSQI ) ( sleep ) . We conducted descriptive statistics and responder analyses . RESULTS Of 21 patients , 18 ( 86 % ) successfully completed the study . An average of 2.8 subjects were enrolled per month . Mean scores on the PHQ-9 improved overall by 6.4 points ( 95 % confidence interval [ CI ] 3.6 - 9.2 ) . Additionally , mean FACT-G , FACIT-Fatigue , and PSQI scores improved in both study arms . CONCLUSION Conducting antidepressant clinical trials is challenging in the oncology population . We approached but did not meet our feasibility goals . Depression and quality of life ( QOL ) scores improved with both mirtazapine and citalopram , but evidence -based pharmacologic treatments for depression in cancer patients are needed This article introduces the approach of GRADE to rating  quality of evidence .  GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence We performed a pilot open-label , crossover trial of mirtazapine ( 15 and 30 mg at night ) in advanced cancer patients with pain and other distressing symptoms . Twenty patients completed the trial and sixteen dropped out . Following a baseline assessment , patients completed a one-week observation period and were then r and omized to a starting dose of either 15 mg or 30 mg of mirtazapine given at bedtime . After three weeks , subjects were switched to the alternate dose and followed by an additional three-week period , completing the treatment . The average age of the completers was 60.2 years and consisted of 7 women and 13 men . The majority were Caucasian ( n = 18 , 90 % ) and married ( n = 18 , 90 % ) . The drop-out group did not significantly differ from the completers based on age , gender , race , marital status , or tumor type . We examined the impact of mirtazapine therapy on patients ' levels of depression , pain intensity , appetite , insomnia , weight , and overall quality of life . A series of repeated measures ANOVAs were conducted to compare the completers ' status at Weeks 1 , 4 , and 7 compared to baseline and to examine the interaction with starting dose and baseline observations . Scores on the Zung self-rating Depression Scale ( F = 8.20 , P < 0.05 ) and the Functional Assessment of Cancer Therapy - General Measure ( F = 5.73 , P < 0.05 ) were significantly improved at study end ( Week 7 ) and were not dependent on mirtazapine dosage . Patients ' weights were significantly higher at both Week 4 and Week 7 , independent of dosage . Trend level differences were found on Memorial Pain Assessment Card items for pain , pain relief , and mood and on numeric rating scales measuring nausea , anxiety , insomnia , and appetite . This open-label pilot study suggests that mirtazapine may be effective for improving multiple symptoms , depression and quality of life in patients with advanced cancer . A controlled trial of this drug would be valuable & NA ; The purpose of this study was to determine the levels of change on st and ard pain scales that represent clinical ly important differences to patients . Data from analgesic studies are often difficult to interpret because the clinical importance of the results is not obvious . Differences between groups , as summarized by a change in mean values over time , can be difficult to apply to clinical care . Baseline scores vary widely and group mean differences could reflect large changes in a few patients , small changes in many patients , or any combination of these outcomes . Determination of the proportion of patients who have a clinical ly important improvement in their pain would provide a more interpretable result with direct clinical implication s. However , determining a clinical ly important outcome requires information about the degree of change over time that is clinical ly important . Data from the titration phase of a multiple cross‐over r and omized clinical trial of oral transmucosal fentanyl citrate ( OTFC )  for the treatment of cancer‐related breakthrough pain were re‐analyzed to examine the differences in pain scores between treatment episodes that did and did not yield adequate pain relief . The scales evaluated were absolute pain intensity difference ( PID , 0–10 scale ) , percentage pain intensity difference ( PID% , 0–100 % scale ) , pain relief ( PR , 0 ( none ) , 1 ( slight ) , 2 ( moderate ) , 3 ( lots ) , 4 ( complete ) ) , sum of the pain intensity difference ( SPID over 60 min ) , percentage of maximum total pain relief ( % Max TOTPAR over 60 min ) , and global medication performance ( 0 ( poor ) , 1 ( fair ) , 2 ( good ) , 3 ( very good ) , 4 ( excellent ) ) . Adequate relief was defined by the patient 's decision not to use another dose of opioid medication as a rescue , in addition to the study medication , to treat each painful episode . One hundred thirty OTFC naive patients contributed data on 1268 episodes of breakthrough pain . The scales that were converted to a percentage change yielded the best accuracy in predicting adequate relief , with balanced sensitivity and specificity . The best cut‐off point for both the % Max TOTPAR and the PID% was 33 % . The best cut‐off points for the absolute scales were absolute pain intensity difference of 2 , pain relief of 2 ( moderate ) , and SPID of 2 . The global medication performance of 2 ( good ) had excellent values as well . This study presents data ‐derived cut‐off points for the changes in several pain scales , each reflecting the clinical ly important improvement for patients treating breakthrough cancer pain episodes with OTFC . Confirmation in other patient population s and different pain syndromes will be needed . The use of consistent clinical ly important cut‐off points as the primary outcome in future pain therapy clinical trials will enhance their validity , comparability , and clinical applicability Abstract Background : Depression is quite common among cancer patients . It has yet to be determined which antidepressant is the most effective in cancer patients with depression . Methods : The present study included 21 consecutive depressed oncology patients of whom 19 were followed up for 6 months . All patients initially received mirtazapine 15 mg/day and the dose was increased in the absence of significant treatment response and adverse effects . Results : Depressive symptoms diminished at the end of month 1 and this improvement was maintained for the remaining 23 weeks of the study . Mean 17-item Hamilton Rating Scale for Depression ( HAM-D-17 ) scores fell significantly from 21.4 ± 4.9 at baseline to 6.5 ± 3.2 at the end of the first month of treatment ( p < 0.001 ) . Among the 19 patients who were followed up , five reported at least one adverse effect during treatment ; however , the vast majority of these adverse effects were described as mild to moderate . Conclusion : This prospect i ve , open-label study provides preliminary evidence regarding the efficacy , safety and tolerability  of mirtazapine treatment in cancer patients with depression . Relatively low doses of mirtazapine appeared to be safe and effective for treating cancer patients undergoing radiotherapy and /or chemotherapy , and the reduction in the severity of depressive symptoms was maintained until the end of the 24-week treatment period We performed an open-label single-institution phase II trial of mirtazapine ( 15 - 30 mg by mouth [ po ] every day [ qd ] ) , a tetracyclic antidepressant that may lead to weight gain , for 8 weeks in nondepressed patients with cancer-related cachexia/anorexia ( CRCA ) . The primary end point was the proportion of patients who gained ≥1 kg at week 4 . Secondary end points were quality of life and appetite . From June 2006 to July 2007 , 17 of 58 eligible patients were enrolled . On intention-to-treat analysis at week 4 , 4 of 17 patients ( 24 % ) gained 1 kg or more , 1 patient maintained weight ( gain of 400 g ) and 2 patients lost weight ( 800 g and 1.2 kg ) ; 24 % and 6 % improved appetite and health-related quality of life ( HQOL ) , respectively . Mirtazapine is a promising agent for the treatment of CRCA AIMS The purpose of the present paper was to evaluate the effectiveness of mirtazapine orally disintegrating tablets for nausea and sleep disturbance , which are common and distressing symptoms of cancer . METHODS This was a 4-week , prospect i ve , open-labeled study of cancer patients . Assessment s were performed at baseline and on days 1 , 3 , 5 , 7 , 14 , and 28 . Primary outcome measures were the Clinical Global Impression scale for nausea/vomiting and the Chonnam National University Hospital-Leeds Sleep Evaluation Question naire ( C-LSEQ ) including total amount of night sleep time . The secondary outcome measures consisted of pain items in the 36-item Short Form Health Survey , the Montgomery-Asberg Depression Rating Scale ( MADRS ) , and the EuroQoL (EQ)-5D .  Forty-two cancer patients were enrolled . RESULTS Those with nausea ( n = 28 ) improved significantly from day 1 . The total night sleep time and each item on the C-LSEQ improved from days 1 - 5 . The scores on the MADRS and the depression/anxiety dimension and visual analog scale of EQ-5D improved significantly from the first week . Pain measures also improved from day 1 . Exacerbation of sleepiness developed in approximately one-third of subjects during the initial few days , but disappeared gradually . CONCLUSION In the present study mirtazapine rapidly improved nausea , sleep disturbance , pain and quality of life , as well as depression in cancer patients .  Mirtazapine may be an effective treatment option in managing cancer patients with multiple distressing symptoms , including nausea and sleep disturbance ABSTRACT Introduction :  Chronic breathlessness  is a common and distressing symptom of advanced disease with few effective treatments . Central nervous system mechanisms are important in respiratory sensation and control . Consequently , drugs which may modify processing and perception of afferent information in the brain may have a role . Antidepressants have been proposed ; however , current evidence is limited . Of potentially suitable antidepressants , mirtazapine is an attractive option given its tolerability profile , low cost , and wide availability , along with additional potential benefits . Areas covered : The paper provides an overview of the physiology of breathlessness , with an emphasis on central mechanisms , particularly the role of fear circuits and the associated neurotransmitters . It provides a potential rationale for how mirtazapine may improve chronic breathlessness and quality of life in patients with advanced disease . The evidence was identified by a literature search performed in PubMed through to October 2018 . Expert opinion : Currently , there is insufficient evidence to support the routine use of antidepressants for chronic breathlessness in advanced disease . Mirtazapine is a promising c and i date to pursue , with definitive r and omized controlled trials required to determine its efficacy and safety in this setting
target: However , mirtazapine showed effectiveness in treating depression , anxiety , sleep disorders , emesis and neuropathic pain .
  Across all studies , mirtazapine is safe to use , with drowsiness and dizziness the most common side-effects .
background: Cancer patients often experience multiple distressing symptoms which are challenging to manage .
  It would therefore be helpful to find a treatment that alleviates more than one symptom , to avoid polypharmacy : mirtazapine has been used in several studies for this purpose .
  The objective of this study was to assess the effectiveness and safety of mirtazapine in alleviating one or more frequently encountered cancer-related symptoms .