Sub-threshold depression and antidepressants use in a community sample: searching anxiety and finding bipolar disorder

Patients with mild-to-moderate, chronic or episodic dysthymia and anxiety may not benefit greatly from antidepressant treatment [1]. According to this study, antidepressants have limited short-term efficacy in unipolar depressive disorders and even less in acute bipolar depression. Moreover their long-term prophylactic effectiveness in recurrent unipolar major depression remains uncertain and is doubtful in bipolar depression [1]. These limitations may, in part, reflect the excessively broad concept of unipolar depression. The current subtyping of depression is based on the DSM-IV-TR categorical division of bipolar and depressive disorders. Current evidence, however, supports a dimensional approach to depression, as a continuum/spectrum of overlapping disorders, ranging from bipolar I depression to major depressive disorder [2].

Treatment-refractory depression may reflect failure to distinguish depressive conditions, particularly in bipolar disorder, that are inherently less responsive to antidepressants. Antidepressants probably should be avoided in bipolar depression, mixed manic-depressive states, and in neurotic depression. Expectations of beneficial effects of antidepressant treatments for specific types of patients with symptoms of depression or anxiety require critical re-evaluation.

The characteristics of the enrolled sample by age, sex and the rate of non-interviewed have been already published [3]. No significant statistical differences were found between the interviewed sub-samples and the randomized sub-samples according to age and sex [3].

A total sample of 3389 subjects was enrolled (57.7% female).

Comorbidity with PD or GAD is also associated with the use of antidepressant drugs. Re-calculating the weight of the association between MDQ positivity and antidepressants use, standardizing by having a diagnosis of PD or GAD, the significance of association disappears (χ² = 1.6 (1df), p = 0.2, OR = 2.6). Thus, the basis for taking antidepressants is the anxiety disorder and MDQ positivity is probably occurring as a confounding factor.

The study indicates that around 5% of people in the community have SD and that SD is higher in women than in men (5.5 vs 2%). People with SD have a lifetime prevalence of manic and hypomanic episodes detected by MDQ (7.3%). This frequency falls in the middle, between people without depression (DE or SD) at the time of interview (2.4%) and people with DE (27.3%). If we consider that SD is more prevalent than DE in the community (5% vs 2.4%), the relevance of MDQ positivity at the community level is quite similar in DE (MDQ positivity 0.4% of the whole community sample) and in SD (MDQ positivity 0.3% of the sample). This is an interesting point because it is intuitive that the identification of a previous manic or hypomanic episode should be easiest in people with a clear diagnosis of DE.

For the purpose of this study we decided to compare the lifetime prevalence of MDQ Positivity in people showing symptoms of DE without a lifetime diagnosis of DE and in people with DE at the time of interview. Our purpose is to define how much is of clinical and public health relevance if a person with depressive symptoms at the time of a hypothetical clinical contact but without prior diagnosis of depressive episode has manic or hypomanic lifetime episode and how much this phenomenon may be related with the antidepressants use. In this sense the definition of SD as people having a HAM-D score of > 10 is an operational choice for detecting people without diagnosis of DE but with a relevant depressive symptomatology that may result in antidepressant prescription.

We take into account that the diagnosis of Mania and Hypomania by SCID may be too restrictive [13] and we also use the MDQ positivity to measure the "bipolarity spectrum". The under recognition of BD in people with DE is not the specific objective of this study; this topic has been addressed in another study using the same database [14].

The results of our community study show that people with SD use largely the first- (14.6%) and the second-line antidepressants (5.1%), as well as BDZ (24.1%). The consumption of antidepressants is similar in people with SD and DE, only smaller for the first-line antidepressants but higher for all other medications than in people without depressive symptoms. The use of antidepressants in SD is more significant with comorbidity factors PD or GAD as per treatment guidelines, indicating antidepressants as the first-line of treatment for PD [15, 16] and GAD [17].

Nevertheless in our community sample, the diagnoses of PD or GAD are strictly associated with MDQ positivity. This is expected given the recent findings in a recent study [18] determining any confounding relationship between MDQ positivity and antidepressant use in people with SD. In fact, antidepressants are frequently used in the sub-sample with a previous manic or hypomanic episode, detected by MDQ, with a high risk for developing BD (even without a DE).

European guidelines exert a more flexible attitude towards the use of antidepressants, whereas currently published American guidelines explicitly do not recommend antidepressants in the treatment of bipolar depression, unless the depressive episode is severe [26]. Our study indicates that antidepressants are broadly used (20% of people) in a large community subsample with SD and is strictly associated with bipolar disorders with the possible induction of mood-cycling in the sub-sample.

Question arises as to whether or not subjects with SD treated with antidepressants need to be further treated. This issue requires some examination of our results in light of results reported in recent literature. First, according to the hypothesis proposed by Ghaemi [1], our study indicate that the antidepressant use does not appear to be associated with improvement in the quality of life of people with SD; this is in contrast to people with DE in whom the use of first-line of antidepressants appears to be associated with a better quality of life. This finding needs to be confirmed by further studies, nonetheless, the results are in agreement with the findings of a recent review of clinical randomized trials, which suggest that there is no clinically significant difference between antidepressants and placebo in patients with minor depression [27].

Second, subject with SD and positivity for MDQ include: a) people with manic episode, fulfilling the criteria for Bipolar Disorders; people with hypomanic episode (not meeting the criteria for manic episode) including, b) people with cyclothymic disorder (the essential features of cyclothymic disorder is a chronic, fluctuating mood disturbance involving numerous periods of hypomanic and depressive symptoms), and/or c) people with hypomanic episode who do not meet the criteria for cyclothymic disorder (they should be classified as Bipolar Disorder Not Otherwise Specified).

As with Bipolar Disorder, use of antidepressants in cyclothymic disorder is typically not recommended, unless they're combined with a mood stabilizer. As with bipolar disorder, taking antidepressants alone can trigger potentially dangerous manic episodes. Patients with cyclothymia may switch to type II illness when treated with antidepressants [28]. Some evidence indicates that cyclothymia may be also associated with high risk for switch to rapid cyclicity [29]. Concerning the risk about switch to mania in people with SD and singular/isolated episode of hypomania using antidepressants, some studies suggest a similar risk in Bipolar Disorder Not Otherwise Specified than in other Bipolar Disordes [30]. Thus, people with SD and mania/hypomania detected by MDQ positivity are in a group where the use of antidepressants alone is counterindicated. In our study, this sub-sample is represented by 7.3% of the total SD in the community.

Third, a strong association between MDQ positivity, SD and anxiety disorders as Panic Disorder and Generalized Anxiety Disorders was found in our study. In these Anxiety disorders, antidepressants are an efficacious treatment and SSRI, as previous cited, are indicated as the first choice for treatment as per most treatment guidelines for anxiety disorders [15–17, 31]. Nevertheless it was be found that co-morbidity with anxiety spectrum disorders and anxiety disorders is associated with rapid switching [32], thus the use of AD alone (without mood stabilizers) in people with SD, MDQ positivity and anxiety disorders may be an option to be considered with extreme caution. Therefore, the use of antidepressants in SD and Anxiety disorders must be preceded by an efficacious screening for mania/hypomania.

Fourth, a large number of studies have found that counseling and psychosocial therapies in sub threshold depression is highly effective, at least in the short-term [33]. Similarly a brief psychological therapies were effective for anxiety [33]. Thus, antidepressants do not appear to have significant advantages for treating SD, and, it may even be dangerous if used in people with SD and MDQ positivity. Our results, together with the results of the recent above cited systematic review [27], suggest that antidepressants should not be considered for treatment of individuals with SD.

Our study appears to suggest a greater caution in prescribing antidepressants to people with SD, especially antidepressants with higher risk to induce mania, particularly to people with concomitant anxiety disorders. In SD, a well-designed assessment to evaluate the presence of previous manic or hypomanic symptoms should be mandatory before prescribing antidepressants.