Although we cannot entirely rule out the role of these underlying secular trends on our results, the fact that on average subjects were followed for less than 1 year suggests that such effects were probably small. Furthermore, we introduced a variety of measures into our analyses to adjust for confounding, particularly of illness severity, given that the earlier the age at onset, the more severe the illness course is likely to be, and the greater the illness severity, the higher the risk of conversion.
Despite these efforts, some residual confounding may well have persisted. Residual confounding and sample size considerations may explain the lack of a clear conversion age effect for TCAs, in contrast to SSRIs and other antidepressants. Alternatively, the lack of TCA effect modification may not be an artifact. It has been demonstrated that TCAs are no better than placebo in the treatment of depression in children and adolescents, 37 , 38 a negative finding not likely due to failed studies, given an adequately powered recent study.
Children and adolescents younger than 15 years, especially those treated with SSRIs or other antidepressants, are at heightened risk of manic conversion, cautions to be evaluated clinically, scientifically, and ethically 43 in the context of a growing evidence base for their use.
Despite this important caveat, judicious prescription practices and thorough risk-benefit analysis at the level of the individual patient are warranted for the age-specific use of antidepressant agents. Caution and restraint may be especially pertinent when treating children whose symptoms are not a major source of impairment, those with a strong family history of bipolar disorder, or those who have not yet tried and failed psychotherapeutic interventions of proven efficacy.
It has long been known that antidepressant medications can precipitate mania in vulnerable individuals, but little is known about the effects of age on this clinical phenomenon. Differing response and adverse effect profiles according to developmental stage have been clinically described for antidepressant medications, and a preclinical body of literature suggests that the prepubertal as opposed to the adult response to serotonergic and noradrenergic probes can dramatically differ from each other.
This study replicates earlier although still inconclusive findings that antidepressant drug therapy can induce manic conversion among vulnerable individuals and that antidepressant categories differ in their manic induction propensities highest for TCAs and the other antidepressants and lowest for SSRIs. To the best of our knowledge, this is the first study to specifically address age effects on antidepressant-induced mania.
Until clinical and prospective studies confirm or refute these findings, judicious prescription practices may be especially pertinent when treating children whose symptoms are not a major source of impairment, those with a strong family history of bipolar disorder, or those who have not yet tried and failed psychotherapeutic interventions of proven efficacy.
Martin Yale. Arch Pediatr Adolesc Med. Coronavirus Resource Center. Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy Continue.
Save Preferences. Privacy Policy Terms of Use. Twitter Facebook. This Issue. Citations View Metrics. August Study population. Ascertainment of diagnoses, exposures, covariates, and outcomes. Statistical analysis. View Large Download. What This Study Adds. Kline NS Clinical experience with iproniazid Marsilid. J Clin Exp Psychopathol. Arch Gen Psychiatry.
Bunney WE Jr Drug therapy and psychobiological research advances in the psychoses in the past decade. Am J Psychiatry. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders: report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate—imipramine combination.
Peet M Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Psychiatry. Fava GA Can long-term treatment with antidepressant drugs worsen the course of depression? There are no credible reasons to worry about the proposed treatment exacerbating the disorder.
I am ignoring the potential issue of worsening suicidality in adolescents and young adults treated with antidepressants since it is both controversial and infrequently seen.
Likely or possible TEAS should be considered if hypomanic symptoms not meeting syndromal criteria emerge within 12 weeks of antidepressant initiation or dose increase. Varied terms have been ascribed to this phenomenon including: induction of rapid cycling, roughening the course of the disorder, cycle acceleration, increased affective lability and so forth. The core phenomenon expressed by all these terms is an increase in mood shifts per unit time Miklowitz and Gitlin This may manifest by a true cycle acceleration—i.
Over the last decade, a number of reviews and meta-analyses have examined the relative small research literature on the efficacy of antidepressants in bipolar depression. Studies in this area included studies with either only bipolar I or a combination of bipolar I and bipolar II patients.
The data on treating bipolar II depression specifically will be reviewed below. Both narrative reviews Licht et al. Considering either response, remission or both, two of these meta-analyses found no significant efficacy of antidepressants in bipolar depression Sidor and MacQueen ; McGirr et al.
Finally, a meta-analysis which compared antidepressants for bipolar depression to separate studies on antidepressants in unipolar depression found comparable efficacy Vasquez et al. Most, but not all bipolar subjects in the studies included within the meta-analyses were on mood stabilizers.
Thus, the studies primarily examined the additive efficacy of antidepressants as opposed to antidepressant monotherapy. In the only double-blind, placebo-controlled study published in the last 30 years, paroxetine monotherapy was not more effective than placebo in treating bipolar I and II depression McElroy et al.
Of note, the most recent meta-analysis in this area found efficacy when antidepressants were added to second generation antipsychotics but not when added to classic mood stabilizers lithium or anticonvulsants. Whether this reflects additive efficacy from the SGAs or some other factor is unknown. Thus, the only reasonable conclusion would be that, with the relative paucity of data available, the effectiveness of antidepressants, whether prescribed as monotherapy or adjunctive to mood stabilizers for bipolar depression is still unproven Gitlin Most of the same reviews and meta-analyses also examined switch rates comparing antidepressants to placebo.
Of note, in the only monotherapy study using paroxetine as the antidepressant McElroy et al. Although far from certain, it is likely that different antidepressant classes confer different vulnerability to switching Peet ; Gijsman et al. Tricyclics are generally considered to have the highest switch rate while selective serotonin reuptake inhibitors SSRIs and bupropion confer the lowest risk. Whether this increased risk is shared with other SNRIs such as duloxetine and desmethylvenlafaxine is unknown.
Switch rates with monoamine oxidase MAO inhibitors are generally considered to be less than with tricyclics although data supporting this are not available Himmelhoch et al.
Surprisingly, definitive evidence from large studies and meta-analyses that mood stabilizers diminish the risk of TEAS is lacking Sachs et al. As described above, aside from TEAS, cycle acceleration, first described decades ago, comprises the other major clinical concern when antidepressants are prescribed to bipolar patients. A number of studies from the tricyclic era seemed to suggest a link between antidepressant use and cycle acceleration Wehr and Goodwin ; Kukopulos et al.
It is less clear whether this phenomenon is seen in any consistent way with more modern antidepressants-SSRIs, bupropion, SNRIs-especially if the patient is also on mood stabilizers Bauer et al. In one study using modern antidepressants, an association was found between prescription of antidepressants and rapid cycling Schneck et al. However, as noted earlier by Coryell et al. Overall, only some of the prospective studies demonstrate a link between rapid cycling and antidepressant use Carvalho et al.
The studies reviewed above examined either bipolar I depression or a mixture of bipolar I and II patients. As noted, bipolar II disorder may be far more dominated by depression compared to bipolar I patients Judd et al. Additionally, whether all mild hypomanias need to be treated is debatable Parker Thus, switches with bipolar II patients are both less frequent and milder, diminishing the risk of antidepressant treatment considerably.
A corollary question is whether bipolar II depression can be safely and effectively treated with antidepressant monotherapy. A handful of recent studies have suggested both efficacy and safety of antidepressant monotherapy in short term studies in this population.
Amsterdam and Brunswick ; Amsterdam and Shults ; Amsterdam et al. In a recent study comparing venlafaxine to lithium, the SNRI showed greater efficacy with no differences in switch rates both in the acute study 12 weeks and during a 6 month continuation study Amsterdam et al. This is particularly noteworthy given that two prior studies Vieta et al.
In the largest double-blind, controlled study, no efficacy differences were seen in bipolar II depressed patients randomized to sertraline, lithium, or lithium plus sertraline for 16 weeks Altshuler et al. Additionally, no differences in switch rates were seen across the three groups. Also consistent with evidence from earlier studies, no switches to formal mania were seen among this bipolar II population. In subgroup analyses in two studies, safety i. Practice guidelines generally recommend only short term treatment with antidepressants in bipolar individuals Yatham et al.
This paucity of data is particularly unfortunate given the evidence that a substantial proportion of bipolar patients treated in the community have antidepressants as part of their maintenance regimen Grande et al. Naturalistic studies suggested that a subgroup of patients that responded to a mood stabilizer plus an antidepressant did better if the antidepressant was included as part of a maintenance regimen, with lower depressive relapse rates and no increase in manic switches compared to the cohort whose antidepressants were withdrawn Altshuler et al.
In a long term 1—3 years randomized study, continued antidepressant treatment with mood stabilizers was associated with somewhat less severe depressive symptoms and a mildly delayed time to depressive relapse with no difference in depressive episode prevalence Ghaemi et al. Of note, the antidepressant continuation group showed no increase in switch rates compared to those whose antidepressants were withdrawn.
However, increased cycling was observed in the subgroup of rapid cyclers treated with long term antidepressants 1. Contrary to prediction, bipolar I patients showed a better long term response to maintenance antidepressants compared to bipolar IIs Vohringer et al.
Shorter studies 4—6 months and longer term studies 6—24 months showed similar findings. In this study, bipolar II patients who were short term responders to fluoxetine were randomly and blindly assigned to 1 year of treatment with either continued fluoxetine, lithium or placebo.
Those subjects who continued on fluoxetine had fewer depressive relapses. There were no significant differences in a priori defined hypomanic episodes or mean mania rating scores across the three treatment groups. No consistent evidence has demonstrated cycle acceleration in bipolar patients on modern antidepressants especially with mood stabilizer co-treatment.
A subset of bipolar patients, both bipolar I and II, will need a maintenance regimen of mood stabilizers plus antidepressants and will not show mood instability with this regimen. The key questions should not be simple dichotomous choices: are antidepressants effective for bipolar depression? Rather, the right questions should be: For which bipolar patients will antidepressants be helpful?
Table 1 shows the risk factors for antidepressant-induced mania TEAS. Antidepressants can inadvertently activate dopaminergic pathways. SNRIs may also increase inhibition of noradrenaline uptake. Although all classes of antidepressants may potentially induce hypomania or mania, some classes carry more risk than others.
Table 1. However, the majority of studies support the concept that AAH more closely resembles an intrinsic bipolar disorder. The authors compare the quality of depressive episodes in patients who have experienced AAH, noting similar rates of melancholic and psychotic features as well as depression severity across AAH and BP groups. The authors suggest that one of the explanations for AAH in individuals with unipolar depression is that underlying BP was never accurate.
However, if there are risk factors suggestive of an underlying bipolar disorder, then consideration could be given to pursuing or adding a mood stabilizer. There is a dose-dependent relationship between antidepressants and the emergence or remission of hypomania, so some research suggests dose reduction or discontinuation with close observation and monitoring for emergence ether of further depression or mood elevation.
Even in the context of ongoing hypomania, the dose should be reduced gradually to offset potential withdrawal effect that may exacerbate the elevated state. The use of mood stabilizing agents is controversial. Thus the initial diagnosis must be carefully evaluated. Use of a mood stabilizer prior to future antidepressant trials may reduce the risk of further AAH.
Atypical antipsychotics can be used in combination with antidepressant dose reduction, and may be informed by hypomania severity as measured by the Young Mania Rating Scale [YMRS]. Pharmaceutical Press, National Institute for Health and Care Excellence. CG90 Depression: the treatment and management of depression in adults. Stata Statistical Software: Release Bipolar Disord ; 10 — Age effects on antidepressant-induced manic conversion.
Arch Pediatr Adolesc Med ; — J Clin Psychopharmacol ; 26 — The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer. Danjou P, Hackett D. Safety and tolerance profile of venlafaxine. Int Clin Psychopharmacol ; 10 Suppl 2 — The safety and tolerability of venlafaxine hydrochloride: analysis of the clinical trials database. J Clin Psychopharmacol ; 16 S—9S.
Possible venlafaxine-induced mania. J Clin Psychopharmacol ; 19 —5. Venlafaxine-associated mania. J Clin Psychopharmacol ; 21 — Peet M. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Psychiatry ; — Benazzi F. Antidepressant-associated hypomania in outpatient depression: a case study in private practice.
J Affect Disord ; 46 —7. Ramasubbu R. Dose-response relationship of selective serotonin reuptake inhibitors treatment-emergent hypomania in depressive disorders. Acta Psychiatr Scand ; —9. Effectiveness and safety of long-term antidepressant treatment in bipolar disorder. J Clin Psychiatry ; 62 —9. Antidepressant treatment in bipolar versus unipolar depression.
Am J Psychiatry ; —5. Culpepper L. Misdiagnosis of bipolar depression in primary care practices. J Clin Psychiatry ; 75 :e05 Antidepressant drugs for neuropathic pain-an overview of Cochrane reviews. Cochrane Library , Evidence-based guidelines for treating bipolar disorder: revised second edition—recommendations from the British Association for Psychopharmacology.
J Psychopharmacol ; 23 —
0コメント