SSRIs vs. TCAs in the treatment of panic disorder: a meta-analysis

OBJECTIVE: To compare the short-term efficacy of selective serotonin reuptake inhibitors (SSRIs) vs. tricyclic antidepressants (TCAs) in the treatment of panic disorder (PD) a meta-analysis was conducted. METHOD: Included were 43 studies (34 randomized, nine open), pertaining to 53 treatment conditions, 2367 patients at pretest and 1804 at post-test. Outcome was measured with the proportion of patients becoming panic-free, and with pre/post Cohen's d effect sizes, calculated for four clinical variables: panic, agoraphobia, depression, and general anxiety. RESULTS: There were no differences between SSRIs and TCAs on any of the effect sizes, indicating that both groups of antidepressants are equally effective in reducing panic symptoms, agoraphobic avoidance, depressive symptomatology and general anxiety. Also the percentage of patients free of panic attacks at post-test did not differ. The number of drop-outs, however, was significantly lower in the group of patients treated with SSRIs (18%) vs. TCAs (31%). CONCLUSION: SSRIs and TCAs are equal in efficacy in the treatment of panic disorder, but SSRIs are tolerated better.     

Antidepressant treatment is associated with a reduction in suicidal ideation and suicide attempts

Objective: To measure changes in suicidal behaviours during 6 months of treatment with antidepressants. Method: A group of depressed patients (n = 195) were assessed for suicidal behaviours in the 6 months prior to treatment. They were prospectively assessed for suicidal behaviours during 6 months of treatment with antidepressants. Results: Patients who made suicide attempts fell from 39 in the 6 months prior to treatment to 20 during treatment. Significant suicidal ideation reduced from 47% at baseline to 14% at 3 weeks remaining below this during the rest of the treatment. Twenty patients had emergent suicidal ideation; five of them had not experienced some level of suicidal behaviour in the 6 months prior to treatment. Conclusion: Suicide behaviours are common in depressed out‐patients. Antidepressant treatment is associated with a rapid and significant reduction in suicidal behaviours. The rate of emergent suicidal behaviour was low and the risk benefit ratio for antidepressants appears to favour their use.     

Discontinuing lithium maintenance treatment in bipolar disorders: risks and implications

Objective: To review research findings on clinical effects of discontinuing lithium maintenance treatment.
Methods: Data from studies reported since 1970 plus our recent findings were updated.
Results: Discontinuing lithium maintenance treatment led to marked increases of early affective morbidity and suicidal risk. Gradual discontinuation markedly reduced early recurrences of mania or depression, did so more in bipolar II than I disorder patients, and also tended to reduce suicidal risk. Similar effects were found in pregnant and nonpregnant women after lithium discontinuation. Long-term retreatment with lithium following discontinuation was only slightly less effective than in initial trials.
Conclusions: Recurrences increased sharply soon after discontinuing lithium, but were markedly limited and not merely delayed, by slow discontinuation. Similar reactions may follow discontinuation of other drugs, evidently as responses to long-term pharmacodynamic adaptations. Discontinuing treatment is not equivalent to not-treating. Post-discontinuation relapse risk has implications for the design, management, and interpretation of protocols involving discontinuation of long-term treatments that should be considered in both clinical management and research.     

Dual reuptake inhibitors incur lower rates of tachyphylaxis than selective serotonin reuptake inhibitors: a retrospective study

BACKGROUND: The notion that selective serotonin reuptake inhibitors (SSRIs) may be associated with higher relapse rates than other antidepressants during maintenance treatment (tachyphylaxis) has been discussed for years, but to date there is little or no empirical evidence confirming this phenomenon. In this study, we systematically assessed prior anti-depressant treatment history in a cohort of depressed patients who presented for outpatient psychiatric treatment. Rates of tachyphylaxis were compared in venlafaxine and tricyclic antidepressants (TCAs), which act as dual reuptake inhibitors, versus SSRIs. METHOD: 237 patients who presented for treatment at the Rhode Island Hospital Department of Psychiatry's outpatient practice and were diagnosed with DSM-IV major depressive disorder were interviewed with the semistructured Treatment Response to Antidepressant Questionnaire. This cohort reported having undergone 326 prior SSRI trials, 47 prior venlafaxine trials, and 35 prior trials with a TCA. Rates of tachyphylaxis as a function of antidepressant class were compared. RESULTS: Rates of tachyphylaxis were significantly lower (chi(2) = 6.77, df = 1, p = .01) with the dual reuptake inhibitors venlafaxine and TCAs (3 [3.7%] of 82) compared to rates of tachyphylaxis with SSRIs (46 [14.1%] of 326). CONCLUSION: These results provide preliminary evidence that dual reuptake inhibitors may incur lower rates of tachyphylaxis than SSRIs. By virtue of the retrospective and non-random design of the study, these results warrant confirmation.     

Exacerbation of cataplexy following gradual withdrawal of antidepressants: manifestation of probable protracted rebound cataplexy

BackgroundA double-blind, placebo-controlled sodium oxybate trial provided a unique opportunity to compare changes in cataplexy following gradual withdrawal from antidepressants in narcolepsy patients.MethodsOf 228 enrolled patients, 71 discontinued antidepressant therapy. Data from 57 patients were available for analysis: 37 patients discontinued tricyclic antidepressants (TCAs) and 20 discontinued selective serotonin reuptake inhibitors (SSRIs). The trial included a 21-day withdrawal phase followed by 18-day washout and 14-day single-blind treatment phases. Two additional weeks were permitted for withdrawal from fluoxetine due to its long half-life. Weekly cataplexy attacks were recorded throughout the trial. No historical data on the frequency of cataplexy prior to treatment with antidepressants was available.ResultsAmong the patients who were and were not withdrawn from antidepressants treatment, the median frequency of baseline weekly cataplexy was similar (17.5 vs. 14.0, respectively). As expected, significant between-group differences emerged by the end of the washout period (52.04 vs. 15.25, respectively; p < 0.05); however, the frequency of cataplexy events became similar again by the end of the trial (16.5 vs. 17.5, respectively).ConclusionsPatients gradually withdrawn from antidepressants experienced a significant increase in cataplexy, but eventually returned to their baseline frequency, comparable to previously untreated control patients. Compared to SSRIs, discontinuation from TCAs was associated with a greater increase in cataplexy attacks.     

Imiprmaine vs. Sertraline in Panic Disorder: 24-Week Treatment Completers

Despite the acknowledged favorable side effects profile of selective serotonin reuptake inhibitors (SSRIs), comparative studies have not found significant differences in efficacy between tricyclics (TCAs) such as imipramine and clomipramine, and SSRIs in the treatment of panic disorder. The present study focuses on treatment completers to inform patients who adhere to a recommended course of treatment on the possible differential patterns of improvement and of change in side effects between sertraline and imipramine. From an intent to treat consecutive sample of patients participating in the 24-week open phase protocolized treatment of a long-term controlled maintenance/discontinuation study, 20 imipramine completers and 16 sertraline completers with moderate to severe baseline symptomatology were compared using primarily repeated measures analysis of variance on measures of symptom severity, on 15 side effects systematically elicited using an inventory and on heart rate and weight. The results revealed greater early improvement with imipramine compared to sertraline but no enduring differences beyond week 8 of treatments. Side effects, in particular dry mouth, constipation, tremors, sweating, and cardiovascular complaints increased more in severity and were more frequent and persistent during imipramine than sertraline but, except for the 10 beats/min increase in heart rate, side effects were clinically insignificant at the end of both treatments. Change in sexual complaints and weight did not differ between the treatments. The more favorable side effect profile of SSRIs versus TCAs was demonstrated even in the best case scenario of treatment completers. The more rapid improvement with imipramine needs replication but, tentatively, it may be attributed to the greater motivational effects toward action observed with noradrenergic or dual action antidepressants compared to SSRIs.     

A systematic review of duloxetine and venlafaxine in major depression,including unpublished data

Schueler Y‐B, Koesters M, Wieseler B, Grouven U, Kromp M, Kerekes MF, Kreis J, Kaiser T, Becker T, Weinmann S. A systematic review of duloxetine and venlafaxine in major depression, including unpublished data. Objective: To determine the short‐term antidepressant efficacy and tolerability of duloxetine and venlafaxine vs. each other, placebo, selective serotonin reuptake inhibitors (SSRIs), and tri‐ and tetracyclic antidepressants (TCAs) in adults with major depression. Method: Meta‐analysis of randomised controlled trials identified through bibliographical databases and other sources, including unpublished manufacturer reports. Results: Fifty‐four studies including venlafaxine arms (n = 12 816), 14 including duloxetine arms (n = 4528), and two direct comparisons (n = 836) were analysed. Twenty‐three studies were previously unpublished. In the meta‐analysis, both duloxetine and venlafaxine showed superior efficacy (higher remission and response rates) and inferior tolerability (higher discontinuation rates due to adverse events) to placebo. Venlafaxine had superior efficacy in response rates but inferior tolerability to SSRIs (OR = 1.20, 95% CI 1.07–1.35 and 1.38, 95% CI 1.15–1.66, respectively), and no differences in efficacy and tolerability to TCAs. Duloxetine did not show any advantages over other antidepressants and was less well tolerated than SSRIs and venlafaxine (OR = 1.53, 95% CI 1.10–2.13 and OR 1.79, 95% CI 1.16–2.78, respectively). Conclusion: Rather than being a first‐line option, venlafaxine appears to be a valid alternative in patients who do not tolerate or respond to SSRIs or TCAs. Duloxetine does not seem to be indicated as a first‐line treatment.     

Are SSRIs better than TCAs? Comparison of SSRIs and TCAs: A meta-analysis

In this analysis we examined studies of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) to compare efficacy and drop-out rates. Frequency of reported side effects was also studied. Using Medline, we located 36 clinical trials of TCAs and SSRIs in a double-blind comparison. We performed a meta-analysis on these studies and on a subgroup of 21 studies that had more uniformly defined outcome criteria. The main outcome measures were efficacy for treatment completers and for the intention-to-treat group; drop-out rates due to adverse reactions and lack of efficacy; and reported side effects. Overall, the response rate to treatment for patients who completed a trial was 63.2% for SSRIs and 68.2% for TCAs (P = 0.038). For the intention-to-treat groups, these rates dropped to 48.0 and 48.6% (P, NS), respectively. Significantly more TCA-treated than SSRI-treated subjects dropped out due to either lack of efficacy or adverse reactions (30.0 vs. 24.7%, P = 0.01). Patients taking SSRIs experienced significantly more gastrointestinal problems and sexual dysfunction, whereas treatment with TCAs produced significantly more complaints of sedation, dizziness, and anticholinergic symptoms. Depression and Anxiety 6:10–18, 1997. © 1997 Wiley-Liss, Inc.     

Depression and pain: An appraisal of cost effectiveness and cost utility of antidepressants

BackgroundAlthough depression and chronic pain frequently co-occur, there is a lack of clarity in the literature regarding the cost-effectiveness and cost-utility of antidepressants in the presence of these two conditions. From the perspective of healthcare provider, the current study aims to compare the cost-effectiveness and cost-utility of antidepressants in a national cohort of depressed patients with and without comorbid pain conditions.MethodsAdult patients prescribed with antidepressants for depression were identified from the National Health Insurance Research Database in Taiwan (n = 96,501). By using remission as effectiveness measure and quality-adjusted life years (QALYs) as utility measure, the cost-effectiveness and cost-utility were compared across selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs), as well as by the presence of comorbid painful physical symptoms (PPS).ResultsSSRIs dominated SNRIs in both the cost-effectiveness and cost-utility regardless of comorbid PPS. In comparison with TCAs, SSRIs were likely to be the cost-effective option for patients without PPS. In patients with PPS, the cost-utility advantage for SSRIs over TCAs varied with threshold willingness-to-pay levels. Comorbid PPS may be considered an effect modifier of the cost-utility comparisons between SSRIs and TCAs.ConclusionsFor depressed patients without PPS, SSRIs are likely to be cost-effective in improving remission rates and QALYs compared to TCAs and SNRIs. However, to improve cost-utility in those with comorbid PPS, people need to choose between SSRIs and TCAs according to threshold willingness-to-pay levels. Future research is warranted to clarify the impacts of different pain conditions on the economic evaluations of pharmacological treatments in patients with depression.     

Selective serotonin reuptake inhibitor antidepressants and the risk of suicide: a controlled forensic database study of 14,857 suicides

OBJECTIVE: To test the hypothesis that selective serotonin reuptake inhibitor (SSRI) antidepressants may have a suicide emergent effect, particularly in children and adolescents. METHOD: Detections of different antidepressants in the forensic toxicological screening of 14 857 suicides were compared with those in 26,422 cases of deaths by accident or natural causes in Sweden 1992-2000. RESULTS: There were 3411 detections of antidepressants in the suicides and 1538 in the controls. SSRIs had lower odds ratios than the other antidepressants. In the 52 suicides under 15 years, no SSRIs were detected. In 15-19-year age group, SSRIs had lower relative risk in suicides compared with non-SSRIs. CONCLUSION: The hypothesis that treatment of depressed individuals with SSRIs leads to an increased risk of suicide was not supported by this analysis of the total suicidal outcome of the nationwide use of SSRIs in Sweden over a period of 9 years, either in adults or in children or adolescents.     

Clinical predictors of suicidal acts after major depression in bipolar disorder: a prospective study

Objective:  This study determined the clinical predictors of suicidal behavior during a 2-year follow-up of patients with bipolar disorder presenting with a major depressive episode (MDE).
Method:  Sixty four patients with DSM-III-R bipolar disorder were assessed at presentation for treatment of an MDE. Correlates of past suicidal behavior were determined by comparing patients with and without a history of suicide attempts using a t -test, Wilcoxon test or chi-squared test of independence on individual explanatory variables. Putative predictors of attempts during the follow-up period were tested separately using Cox proportional hazards regression analysis.
Results:  Twelve of 64 patients had at least one suicide attempt in the follow-up period, five of them attempted in the first 2 months and seven around or shortly after the 1-year follow-up visit. All attempters had a history of past suicide attempts. Most predictors of future suicidal behavior were correlates of past suicidal behavior. Family history of suicide acts and comorbid borderline personality disorder predicted early attempts, while younger age, high hostility scores, number of past attempts, subjective pessimism as reflected in depression and suicidal ideation, and few reported reasons for living predicted suicidal acts during the whole period.
Conclusion:  In this data set of bipolar patients we noted an intriguing picture of two clusters of suicide attempts. Hostility was the strongest risk factor. These findings may have implications in both the identification of at-risk patients and the timing of clinical interventions including aggressive pharmacotherapeutic prophylaxis to prevent relapse or recurrence of depressive symptomatology.     

Effects of antidepressant treatments on first-ECT seizure duration in depression

1. Current guidelines on the practice of Electroconvulsive Therapy (ECT) suggest that antidepressant medications should be discontinued prior to the course of therapy. However, the practice of withholding potentially helpful medication is debatable because the effects of these medications on seizure duration remain unclear. In particular, there is a lack of empirical knowledge about the effects of Selective Serotonin Reuptake Inhibitors (SSRIs) on ECT treatment. 2. Therefore, we investigated and compared the effects of SSRIs and tricyclic antidepressants (TCAs) on seizure duration after the first bilateral ECT treatment. 3. The diagnosis of major depressive disorder was made using the DSM-IV criteria. Both patient groups were age- and sex-matched. ECT was indicated for acute suicidal acts or refractoriness to medications. All patients had received antidepressant treatment for at least eight weeks and were receiving at least the recommended dose of medication. All patients were ECT treatment-na?ve and we measured the seizure duration after the first bilateral ECT treatment. 4. There was no significant difference between electrical charge applied to either group. Between the TCA and SSRI group the seizure duration was not significantly different: 33.2 seconds and 31.4 seconds respectively.     

The place for the tricyclic antidepressants in the treatment of depression.

OBJECTIVE: The new generation antidepressants have been an important advance in the treatment of depression. Since their introduction, their use has become widespread and the role of the older tricyclic antidepressants (TCAs) has been suggested only as a second-line choice. This assumption is questioned and the role of the TCAs as a first-line treatment for severe depression is discussed. METHOD: The relevant literature concerning the efficacy, tolerability and safety of the antidepressant drugs is reviewed, particularly those studies which compare the newer antidepressant agents with the TCAs. RESULTS: The newer agents are equally as efficient as the tricyclics in the treatment of mild to moderate depression. There are indications that the TCAs are more efficacious for severe depression. The tolerability of the drugs appear about equivalent in terms of discontinuation rates; however, the side effects are different and clinicians need to be mindful of drug interactions and the potential of the serotonin syndrome with the selective serotonin re-uptake inhibitors (SSRIs), problems not found with the TCAs. The TCAs are potentially lethal in overdose; however, appropriate clinical management appears to be a more important issue than the toxicity of the medication. CONCLUSIONS: The newer antidepressant agents are important advances in the treatment of depression. However, the TCAs still have an important place as the first-line treatment for patients with severe (melancholic/endogenous) depression.     

Risk of Suicidality in Depression with Serotonergic Antidepressants

Since depression is a risk factor for suicidal thoughts and behaviors, and since suicidal behaviors are associated with low serotonin activity, are selective serotonin reuptake inhibitors (SSRIs) more effective than other antidepressants in treating suicidality in depressed patients? There is inconclusive evidence for and against this hypothesis. However, all studies suggest that antidepressants are effective treatments of suicidal ideations and behaviors, and SSRIs have been shown to have prophylactic effects in preventing suicidal behaviors. Although some reports suggest that SSRIs might increase suicidal ideations and behaviors, the results of large, double-blind studies do not suggest a causal relationship between pharmacotherapy and the emergence of suicidality. Undertreatment of depression and therapeutic failure are more significant problems with the use of antidepressants in suicidal patients than the risk of using antidepressants in overdose. Prescribing inadequate doses of antidepressants is therefore a source of overlooked risk.     

Comorbid anxiety in bipolar disorder: does it have an independent effect on suicidality?

Objective:  Comorbid anxiety disorder is reported to increase suicidality in bipolar disorder. However, studies of the impact of anxiety disorders on suicidal behavior in mood disorders have shown mixed results. The presence of personality disorders, often comorbid with anxiety and bipolar disorders, may explain these inconsistencies. This study examined the impact of comorbid Cluster B personality disorder and anxiety disorder on suicidality in bipolar disorder.
Methods:  A total of 116 depressed bipolar patients with and without lifetime anxiety disorder were compared. Multiple regression analysis tested the association of comorbid anxiety disorder with past suicide attempts and severity of suicidal ideation, adjusting for the effect of Cluster B personality disorder. The specific effect of panic disorder was also explored.
Results:  Bipolar patients with and without anxiety disorders did not differ in the rate of past suicide attempt. Suicidal ideation was less severe in those with anxiety disorders. In multiple regression analysis, anxiety disorder was not associated with past suicide attempts or with the severity of suicidal ideation, whereas Cluster B personality disorder was associated with both. The results were comparable when comorbid panic disorder was examined.
Conclusions:  Comorbid Cluster B personality disorder appears to exert a stronger influence on suicidality than comorbid anxiety disorder in persons with bipolar disorder. Assessment of suicide risk in patients with bipolar disorder should include evaluation and treatment of Cluster B psychopathology.     

Suicide seasonality and antidepressants: a register‐based study in Sweden

Objective: Seasonality of completed suicides with a peak in spring and early summer is a well‐documented finding. The circannual serotonergic functioning is hypothesized to be central in this phenomenon. Antidepressant medications exert their pharmacological action mainly by regulating serotonin. Our aim is to study the amplitude of the seasonal effect among suicide victims positive for different classes of antidepressants or without any antidepressants at the time of death. Method: By using Swedish Registers, 12 448 suicides with forensic data for antidepressive medication and information on in‐patient‐treated mental disorder were identified during 1992–2003. Seasonality was estimated with a Poisson regression variant of the circular normal distribution of completed suicides. Results: Higher suicide seasonality was found for individuals treated with selective serotonin reuptake inhibitor (SSRIs) compared to those with other antidepressant treatment or without any antidepressant treatment. The finding is more evident for men and violent suicide methods and those without history of in‐patient treatment. Conclusion: Our results provide preliminary support for the serotonergic hypothesis of suicide seasonality and raise the question of a possible accentuation of the natural suicide seasonality in patients treated with SSRIs, a hypothesis that warrants further investigation.     

Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review

Objectives:  To update and extend comparisons of rates of suicides and suicide attempts among patients with major affective disorders with versus without long-term lithium treatment.
Methods:  Broad searching yielded 45 studies providing rates of suicidal acts during lithium treatment, including 34 also providing rates without lithium treatment. We scored study quality, tested between-study variance, and examined suicidal rates on versus off lithium by meta-analytic methods to determine risk ratios (RRs) and 95% confidence intervals (CI).
Results:  In 31 studies suitable for meta-analysis, involving a total of 85,229 person-years of risk-exposure, the overall risk of suicides and attempts was five times less among lithium-treated subjects than among those not treated with lithium (RR = 4.91, 95% CI 3.82–6.31, p < 0.0001). Similar effects were found with other meta-analytic methods, as well as for completed versus attempted suicide, and for bipolar versus major mood disorder patients. Studies with higher quality ratings, including randomized, controlled trials, involved shorter exposures with somewhat lesser lithium superiority. Omitting one very large study or those involving lithium-discontinuation had little effect on the results. The incidence-ratio of attempts-to-suicides increased 2.5 times with lithium-treatment, indicating reduced lethality of suicidal acts. There was no indication of bias toward reporting positive findings, nor were outcomes significantly influenced by publication-year or study size.
Conclusions:  Risks of completed and attempted suicide were consistently lower, by approximately 80%, during treatment of bipolar and other major affective disorder patients with lithium for an average of 18 months. These benefits were sustained in randomized as well as open clinical trials.