Some people with bipolar disorder may have milder symptoms than others. For example, hypomanic episodes may make an individual feel very good and productive; they may not feel like anything is wrong. However, family and friends may notice the mood swings and changes in activity levels as unusual behavior, and depressive episodes may follow hypomanic episodes.
Although recent studies have shown that immunological processes play an important role in the pathophysiology of mood disorders, immune activation may only be present in specific subgroups of patients. Our study aimed to examine whether immune activation was associated with (a) the presence of manic symptoms and (b) the onset of manic symptoms during 2 years of follow-up in depressed patients. Patients with a depressive disorder at baseline (N=957) and healthy controls (N=430) were selected from the Netherlands Study of Depression and Anxiety. Assessments included lifetime manic symptoms at baseline and two-year follow up, as well as C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) at baseline. Within depressed patients, immune activation was not related to the presence or absence of lifetime manic symptoms at baseline. However, CRP levels were strongly elevated in depressed men who developed manic symptoms compared with those who did not develop manic symptoms over 2 years (P
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Therefore, the present study aimed to examine whether immune activation was associated with (a) the presence of manic symptoms and (b) the onset of manic symptoms during 2 years of follow-up in patients with a depressive disorder. To avoid the limitations of previous studies, this study included a large sample of currently depressed patients (N=939) in whom manic symptoms were thoroughly assessed, as well as healthy controls (N=430). Because previous research has found sex differences in the association between inflammatory markers and depressive disorders,6, 19 the results for men and women were shown separately. In addition, we were able to explore the role of potential confounders, such as sociodemographics, childhood trauma,32 lifestyle factors and disease-related factors. This is important, as these factors are related to inflammatory markers13, 14, 15, 16, 17, 33, 34 as well as depression with and without manic symptoms.18, 35, 36 Furthermore, we have explored the additive effect of the different inflammatory markers, which, to our knowledge, no other study has done before.
For the present study, we used data from the baseline (cross-sectional analyses) as well as 2-year follow-up (prospective analyses) assessment (overall response rate: 87.1%; see Lamers et al.38 also for determinants of non-response). During the baseline interview, the presence of depressive (major depressive disorder, dysthymia) and anxiety disorders (social phobia, generalized anxiety disorder, panic disorder and agoraphobia) was established using the Composite International Diagnostic Interview (CIDI) according to DSM-IV criteria.39 The CIDI is a highly reliable instrument with high inter-rater reliability rates.40 The severity of depression was measured by the 28-item self-report Inventory of Depressive symptoms (IDS).41 To detect the presence of lifetime manic symptoms, the Mood Disorder Questionnaire (MDQ)42 was used at baseline as well as 2-year follow-up. The MDQ is a 15-item self-report questionnaire comprising 13 dichotomous items on the lifetime presence or absence of manic symptoms as well as two additional questions regarding the clustering of symptoms in time and severity of related problems. We considered manic symptoms to be present when a patient reported seven or more positive answers from the thirteen items, irrespective of the answers on the two additional questions. Our group recently showed that this strategy is adequate in detecting a recent (hypo)manic episode (sensitivity=0.83 and specificity=0.82).43
Figure 1 shows the flow chart presenting the procedures to select participants for our cross-sectional and prospective analyses. For the cross-sectional analyses (based on the baseline assessment), the following groups were distinguished: (a) healthy controls (reference group I: N=430) without any lifetime depressive or anxiety disorder, without depressive symptoms (IDS score lower than 14) and without manic symptoms (MDQ score lower than 7); (b) patients with a current (
From a clinical point of view, it is important to examine whether immune activation predicts the development of manic symptomatology in patients with depression. The identification of manic symptomatology is often delayed in clinical practice,66 which is problematic as depressed patients with manic symptoms are usually more therapy-resistant28 and are more likely to commit suicide attempts.29 This clinical relevance of bipolarity in unipolar depression has motivated the DSM-5 work group to include bipolar disorders not only but also a mixed features specifier for major depressive disorder in the new version of the DSM.27 This emphasizes the importance of the search for a biomarker that can detect a predisposition for bipolar disorder and it is tempting, but not completely appropriate, to consider CRP as such a biomarker. Interestingly, recent findings suggest that patients with high inflammatory activity may respond less to antidepressants and better to anti-inflammatory medication.67, 68, 69 Depression is a heterogeneous concept and studies investigating immune activation in mood disorders are important to further differentiate particular subgroups in which immune activation plays an etiological role or has clinical implications. It is likely that the monocyte-T-cell theory of mood disorders does not apply to all depressed patients, and our findings add to this rapidly growing body of literature by showing that higher levels of inflammatory markers are found among depressed men who are more at risk to become bipolar.
Adequate understanding, timely diagnosis, and effective short- and long-term treatment of depressive episodes in BD patients are critically important but remarkably insufficiently resolved (Baldessarini et al. 2010c). Clinical significance of bipolar depression is underscored by strong association with overall morbidity, other co-occurring psychiatric conditions (notably anxiety and substance-abuse disorders), disability, and excess mortality owing largely to suicide in young patients and intercurrent medical illness in older patients (Ösby et al. 2001, 2018; Tondo et al. 2014, 2016; Baldessarini et al. 2020).
BD patients commonly fear, seek to avoid, to report, and to seek clinical help for depression. Contrarily, they may not recognize moderate increases of mood, energy, activity, or libido as hypomanic symptoms as clinically relevant, and may even prefer such states. Diagnostic uncertainty is especially likely early in the illness-course and without corroborating information from a family member or close friend (Vöhringer and Perlis 2016).
As noted, depressive, dysthymic, and mixed states account for the majority of illness-burden in BD, and are strongly predicted by initial depressive, mixed, or anxious episodes (Goodwin and Jamison 2007; Yildiz et al. 2015; Forte et al. 2015; Baldessarini et al. 2014, 2019a). Remarkably few treatments are proved to be highly and consistently effective in acute episodes of bipolar depression, and there is even less evidence supporting substantial long-term protection from recurrences (Table 4). In particular, there is continued controversy about the value and risks of antidepressant drugs in bipolar depression (Pacchiarotti et al. 2013; McGirr et al. 2016). Lack of highly effective treatments encourages widespread drug-combinations and other off-label treatments largely untested for effectiveness and safety.
Several anticonvulsants have been used widely for BD, based on secure evidence of short-term antimanic effects (carbamazepine and valproate) or long-term reduction of risk of depressive recurrences (lamotrigine) (Baldessarini 2013; Geddes and Miklowitz 2013; Reinares et al. 2013). Such treatment choices are encouraged by seeming simpler than treatment with lithium (Baldessarini 2013; Vázquez et al. 2014). For divalproex monotherapy, 4 small trials suggest possible value in acute bipolar depression (Table 4), but it remains FDA-unapproved for depression or long-term treatment in BD. Evidence that lamotrigine is effective in acute bipolar depression rests on pooling inconsistent data, including from individually failed trials vs. placebo (Table 4) (Solmi et al. 2016). Lamotrigine is FDA-approved only for long-term prophylaxis in BD, with partial effectiveness against recurrences of depression but little efficacy against acute or recurrent mania (Frye et al. 2011; Baldessarini 2013). Moreover, slow dose-increases to avoid potentially serious dermatological reactions limit practicality of off-label use of lamotrigine in acute bipolar depression. Evidence concerning carbamazepine for short- or long-term use for bipolar depression is very limited (Table 4), and controlled trials for other anticonvulsants in BD are lacking (Reinares et al. 2013; Selle et al. 2014).
SGAs, including cariprazine, lurasidone, olanzapine-fluoxetine, and quetiapine are currently the only FDA-approved medicines for short-term treatment of acute depressive episodes in BD (Baldessarini 2013; Selle et al. 2014; Earley et al. 2019; Ragguett and McIntyre 2019). Of these, only quetiapine has outperformed placebo consistently in several trials, with similar results for doses of 300 vs. 600 mg/day, and only the lower dose is FDA-approved (McElroy et al. 2010). Olanzapine-fluoxetine was superior to placebo, whereas olanzapine alone was less effective (Tohen et al. 2003). Unsurprisingly, as both olanzapine and quetiapine are antimanic, they have yielded somewhat lower risks of mood-switching than placebo (Selle et al. 2014). Most of these responses in acute bipolar depression have been modest (Table 4), and possible long-term protective effects require further study. Of note, beneficial effects in bipolar depression are not a class-effect of all SGAs (Taylor et al. 2014). In effective doses, antipsychotics risk adverse effects that include excessive sedation as well as distressing restlessness (akathisia) (Brown et al. 2006; Tamayo et al. 2010). Although risks of tardive dyskinesia with most SGAs are far lower than with FGAs (Tarsy et al. 2010; Carbon et al. 2017), their greatly increasing use and broadening indications may risk increased numbers of cases of even this uncommon adverse outcome (Pompili et al. 2016). Moreover, risks of weight-gain, type-2 diabetes, and other features of metabolic syndrome (hyperlipidemia, hypertension) are encountered with some SGAs (particularly olanzapine and quetiapine), sometimes rapidly (Centorrino et al. 2012; Baldessarini 2013; Vázquez et al. 2015). These medically important adverse effects tend to limit the potential value of SGAs for prophylactic treatment against recurrences of bipolar depression (Vázquez et al. 2014, 2015; Fountoulakis et al. 2017). In summary, cariprazine, lurasidone, and quetiapine, as well as olanzapine-fluoxetine are effective in acute bipolar depression, though with some risks, and they need further testing for long-term, prophylactic effects against bipolar depression. 2ff7e9595c
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