1 1. Summary
Different depressive episodes can occur in the life of a patient and they can be ascribed to a bipolar or a unipolar disorder. Many researchers have studied different subtypes of depressive episodes and the new DSM-5 classification have defined different specifiers for clinical and therapeutic implications.
About anxious distress specifier, until now there are only retrospective studies and relationship with bipolar spectrum are not investigated.
Studies indicate that the anxious distress specifier is common in major depressive episodes and identifies a subpopulation in MDD with greater morbidity, lower remission rates, long duration of disease, social, occupational impairment and suicidal ideation. Studies show also that the specifier is associated with poor outcome with single therapies, more side effects of antidepressants and more use of antipsychotics (Fava et al 2006; Wu et al., 2013).
Furthermore studies about the specifiers of the new DSM-5 classification have investigated also the specifier with mixed features. They suggest that anxiety with distractibility, psychomotor agitation and irritability (excluded in “mixed features” because overlapping symptoms in mania and depression) may
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In the new DSM-5 classification is unclear how anxious distress specifier as expression of a mood episode with severe anxiety or agitation, differs from the classical definition of mixed features specifier.
Thus patients with subsyndromal mixed symptoms with anxiety or psychomotor agitation can be diagnosed using the “with anxious distress” specifier and not “with mixed feature” in DSM-5, leaving a portion of patients
with mixed features not specified and with inadequate treatment (Shim et al., 2016).
The aim of the study was to assess the presence of anxious distress in a sample of 241 outpatients with major depressive episode in MDD, BD-I or BD-II, and to evaluate the longitudinal predictive validity of the specifier for clinical outcome. The sample was followed for a period of at least 12 weeks and naturalistically treated on mood stabilizers (lithium salts or anti-epileptics drugs), antidepressants and antipsychotics. Patients have been followed at Section of Psychiatry, Department of Clinical and Experimental Medicine, University of Pisa and at the Istituto di Psicopatologia in Rome. Patient enrollment criteria were age 18-65 years and meeting DSM-5 criteria for MDD, BD-I or BD-II or Koukopoulos’s criteria for mixed attenuated episodes. To assess diagnosis and symptomatology we used the following instruments: SCID-5, SIMD, HDRS, YMRS, CGI, GAF and Brief TEMPS-M.
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In the sample 142 patients (58.9%) had a depressive episode with anxious distress specifier and compared with patients without the specifier, there were not significant differences in socio-demographic characteristics except for marital status because a higher number of patients with anxious distress were married.
Patients with major depressive episode with anxious distress specifier had diagnosis of BD-II, familiarity for bipolar disorders, previous hypomanic episodes, seasonal pattern, mixed features according to Koukopoulos’s criteria. Moreover they had higher scores of YMRS, HDRS, CGI-s and they were more treated with SSRI and antipsychotics. Response after twelve weeks indicated more anxiety and higher YMRS score. Regarding the time from baseline to twelve weeks there was a significant reduction of HDRS score in the two groups but a significant reduction of scores of YMRS only in the group without anxious distress. In the group with anxious distress there was a reduction of YMRS score until eight weeks and after an increase.
After we have divided the sample in three groups: the first group without mixed features (DSM-5 and Koukopouls’s criteria) and anxious distress, the second group only with anxious distress and a third group with mixed features (DSM-5 and Koukopoulos’s criteria) and anxious distress. The response from baseline to twelve weeks for the group with only anxious distress was in a significant reduction of HDRS score and a significant increase of YMRS score. Patients with anxious distress were more treated with antidepressants,
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SSRI and associations of two antidepressants. Thus the treatment response suggesting a relationship with bipolar spectrum was present even if patients with anxious distress were separated by patients with DSM-5 mixed features and also with mixed attenuated features.
There are limitations of this study that can be considered.
The most important limitations are the small sample and the short duration of the follow-up.
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2. Introduction
Major depression is a heterogeneous disorder both in the transverse that in the longitudinal course. Different episodes can occur in the life of a patient so a major depressive episode can be ascribed to a bipolar or a unipolar disorder. Many definitions of types of major depression have been described over the years and then various specifiers in the DSM-5. The research on different specifiers of major depression has been carried out with the aim of more appropriate therapeutic strategies.
Many studies have investigated the different presentations of major depression in particular “mixed features” but also other specifiers such as “anxious distress”.
In the new DSM-5 classification is unclear how anxious distress specifier (as the classical expression of a mood episode with severe anxiety or agitation) differs from the mixed features specifier or how the specifier integrates the mixed anxiety and depressive disorder in DSM-IV-TR. High levels of anxiety or psychomotor agitation included in the “anxious distress” specifier in DSM-5 are also significant clinical characteristics in “mixed features” but they are excluded because lacked specificity since common across many disorders, in not mixed depressive episodes and in both poles of mood episodes. Relations
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among psychomotor agitation, anxiety and depression remain unclear in depression with mixed features (Shim et al., 2016).
Studies inquire the validity of excluding these symptoms as a criterion of mixed features in DSM-5.
Anxiety in fact is associated with depression in manic patients and with mania in depressed patients and less in pure mania (Swann et al., 2009).
Symptoms such as psychomotor agitation and anxiety are significant characteristics described in most classic mixed states and also in Kraepelin’s description of mild excited depression (although not all depressive episodes with psychomotor agitation are “with mixed features”) (Benazzi et al., 2006).
Anxiety in fact is associated with specific depressive factors playing a significant role in the core clinical features of mixed depression (Sato et al., 2005).
Moreover severe anxiety is also a core symptom of mania with mixed features characterized often by somatic and physic anxiety (Cassidy, 2010). In mania anxiety is limited to mixed features while in depression it may be present also in not mixed features (Swann et al., 1993).
Studies suggest that anxiety along with distractibility, psychomotor agitation and irritability (excluded in “mixed features” because overlapping symptoms
in mania and depression) may contribute to fractionate mixed presentations (Sato et al., 2002). In fact anxiety symptoms could lead to different patterns of
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symptoms occurring in mixed states, identifying different subtypes of mixed presentations (Malhi et al., 2016). Psychomotor agitation and distractibility are probable core features of mixed mania (Targum et al., 2016, Malhi et al., 2016), while irritability is related to non melancholic depression (admixture of depressive and anxiety symptoms) (Malhi et al., 2016).
These subtypes differ in terms of clinical phenomenology, but also disease course, comorbidity, and treatment response (Malhi et al., 2017).
Furthermore patterns of these symptoms may distinguish mixed states and mixed phases. A transitory mixed phase can be also the result of a switch in which manic symptoms emerge in depressive state after treatment (e.g. with antidepressants) and can be understood as a true mixed presentation (Malhi et al., 2015)
Patients with subsyndromal mixed symptoms with anxiety or psychomotor agitation can be diagnosed using the “with anxious distress” specifier and not “with mixed feature” in DSM-5, leaving a portion of patients with mixed features not specified and with inadequate treatment (Shim et al., 2016).
Moreover atypical features (such as mood lability, hostility, activation, biographical instability, multiple anxiety comorbidities, and suicidal tendencies) are more probable in bipolar depression compared to unipolar depression and significantly more present in women (Benazzi 2003; Akiskal 2005). In the same way also psychomotor agitation, racing or crowded
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thoughts and irritability are the most common subsyndromal manic symptoms in bipolar major depressive episodes (Benazzi et al., 2005, Balazs et al., 2006, Goldberg et al., 2009).
Anxiety levels during mood episodes correlate with more probability of a severe course of affective disease and treatment not response (Baek et al., 2015). This is very important for planning treatments, predict treatment effects and prognosis of these patients (Shim et al., 2016).
2.1“Mixed features” in major depression
Researchers in the past have given different definitions to depression with mixed features. Emil Kraepelin was the first to define mixed state as “various combinations of the symptoms characteristic of both the manic and depressive phases” (Kraepelin 1904). In DSM (DSM-IV) (American Psychiatric
Association 1994) and (DSM-IV-TR) (American Psychiatric Association 2000), mixed episodes were defined with the full criteria for both manic and depressive episodes that had to be satisfied concurrently, each day, and for at least 1 week. Clinically, the DSM definitions were limited because some symptoms, (such elation and depression) cannot co-occur and there is not the distinction of the primary mood state (Malhi et al., 2017)
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Subsequently Benazzi (2001) suggested that a depressive mixed state occurs in bipolar II depression when at least 2 Hypomanic symptoms manifest in the context of a major depressive episode. Furthermore there were studied Hostile depression (major depressive episode with irritability) and Agitated depression, that emerged as mixed states related to the bipolar spectrum. (Benazzi et al., 2005 and Akiskal 2005). Afterwards Koukopoulos distinguished depressive episodes in “agitated depression” (mixed depression with psychomotor agitation) and “mixed depression” with own criteria (defined for the first time in 1992) (Koukopoulos et al., 2014; Faedda et al.,2015).
DSM-5 lead to a more dimensional approach eliminating the category of mixed episodes that has been replaced by the mixed features specifier. In DSM-5 mixed features are defined by the presence of at least three nonoverlapping opposite-pole symptoms in the context of hypo/manic and depressive episodes in bipolar disorder (BD) I and II and major depressive disorder (MDD). Some studies have investigated the validity and the clinical significance of DSM-5 mixed features specifier in major depressive episode (MDE) (Zimmerman et al., 2014; Miller et al., 2016).
To evaluate the clinical significance of manic features in depressed patients, has been developed a self-report measure that estimate the DSM-5 mixed features specifier and it is a subscale of the Clinically Useful Depression
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Outcome Scale (CUDOS-M). The scores are resulted significantly higher in hypomanic patients than depressed patients, and patients with bipolar depression than patients with Major depressive disorder (Zimmerman et al., 2014).
Results from the Mood Disorders Collaborative Project (IMDCP) indicate that approximately 25% and 35% of adults with MDD and BD-I/II respectively, presenting with an MDE meet the DSM-5 criteria for “mixed features” (McIntyre 2014; Miller et al., 2016). It is reported that this group have greater illness burden, comorbidities (e.g. anxiety disorders, substance abuse), and greater functional impairment (McIntyre et al., 2016).
These Results from IMDCP are replicated and extended by investigators from the Stanley Foundation Bipolar Network (SFBN). They assess also that subthreshold hypomania has a more prevalence (43,5%) compared to DSM-5 definition and are significantly more women than men. The specifier predicts a more severe course of bipolar illness (Miller et al., 2016).
Furthermore in many studies the most frequent manic/hypomanic symptoms are irritability, mood lability, distractibility, psychomotor agitation, impulsivity, aggression, racing thoughts and pressure to keep talking. Euphoria, grandiosity and hypersexuality are less represented (May et al., 2006; Goldberg et., al 2009; Fiedorowicz et al., 2011; Miller et al., 2016). Symptoms of distractibility, irritability, psychomotor agitation, anxiety and
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other neurovegetative symptoms (weight loss or gain, insomnia or hypersomnia) that are overlapping symptoms in mania and depression have been excluded from the “mixed features” in DSM-5 for low specificity. Many
studies (such as Judd et al., 2012, Pae et al., 2012, Targum et al., 2016) have examined patients with at least 1 (or 2/3 concurrent) manic symptom and have reported higher prevalence of these symptoms compared with other manic symptoms in MDD and BD patients (such as the co-occurrence of self esteem or grandiosity). Talkativeness and flight of ideas are endorsed by 65% of patients and a decreased need for sleep by 40% of patients. 60% of patients are endorsed irritability and distractibility (Targum et al., 2016).
These results suggest in fact that they are important symptoms of mixed features and that excluding them the remained criteria are not sufficiently sensitive to identify this condition. Overlapping symptoms are important also to distinguish between mixed manic and mixed depressive state (Psychomotor agitation is a more characteristic feature of mixed mania) (Malhi et al., 2016).
Koukopoulos (2013) also suggest that 3rd and 4th criterion of the DSM-5 mixed specifier (pressure to keep talking, and flight of ideas) are frequently in mixed depression but the other five criteria are extremely rare. Excitatory symptoms of mixed depression are qualitatively different from typical manic/hypomanic symptoms. In fact patients with mixed depression lack expansiveness, easy performance or activities showing pain with lamentations
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and risk of suicide. It is important to diagnose these patients for adequate treatments, in fact antidepressants can worse the agitation and increase the risk of suicide (Koukopoulos et al., 2013).
Mixed depression defined by Koukopoulos presented three symptoms among agitation, racing/crowded thoughts, irritability, absence of retardation, talkativeness, dramatic description of suffering, mood lability and early insomnia (Koukopolous et al., 2007). These criteria had been later validated also by a study (Sani et al., 2014), and they demonstrate to capture not only DSM-based manic symptoms, but also psychic excitation in general (Koukopoulos 1992; Koukopoulos et al., 2006). Patients with mixed depression are male, younger, less educated, with a history of substance abuse and have received psychiatric treatment at an earlier age. They are clinically more severe, develop rapid cycling course with fewer hospitalizations, have less BD type I, have more mixed depressive episodes and more lifetime depressive episodes (Sani et al., 2014).
Using a definition that includes irritability, psychic or psychomotor agitation as central features of mixed depression, the prevalence changes from 0-12% to 33-47% (Koukopolous et al., 2007; Angst et al., 2011). More inclusive approaches are related to increased statistical power and lower rates of antidepressant use compared to DSM-5 mixed features definition (Kim et al., 2016). Mixed features in major depressive episodes are associated with family
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history of mania, more duration episodes, atypical features, early onset, and lifetime comorbidity with anxiety, alcohol and substance use disorders, attention deficit hyperactivity disorder and borderline personality disorder (Perugi et al., 2015). There is also an association with several illness characteristics of bipolar disorders such as anxiety disorder comorbidity and irritability. Addictionally there is an increasing of bipolar II subtypes (compared to pure depression). Mood elevation symptoms during bipolar depression are associated with more frequent history of suicide attempts and treatment-emergent mood elevation with antidepressants (Swann et al., 2007; Balazs et al., 2006, Frye et al., 2009, Goldberg et al., 2009; Swann 2017).
The frequency of mixed syndromes is more common in bipolar than unipolar depressive episodes (Benazzi, 2003; Sato et al., 2003; Benazzi et al., 2006; Angst et al., 2011). MDD patients with agitation have more probability to have mood switches, suggesting that psychomotor agitation in MDD may be a marker of BD (Koukopoulos et al., 2005, Vieta, 2015). Psychomotor agitation is the manic/hypomanic symptom that is reported most frequently in both patients with BP and with MDD (Takeshima et al., 2015).
These symptoms are generally experienced with a great distress for the patient, leading to increased risk of suicidality (Balazs et al., 2006, Baldessarini et al., 2012). In fact bipolar patients with mixed states have been shown to have a higher risk of suicide (Vieta et al., 2014). Mixed depressive
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episodes are three times more common in BD type II compared with unipolar depression, and they contribute to the increased risk of suicide reported in BD type II compared to unipolar depression (Benazzi et al., 2007; Cassidy et al., 2001).
Mixed states can be also understood as a spectrum of states that mostly show poor hyperactivities in mood, thinking and volition with a gradation from typical depressive symptoms to typical manic symptoms (Bertschy et al., 2007).
Moreover patients with a previous mixed episode have a shorter interepisode intervals, suicide attempts and higher comorbidity with substance misuse (specially alcohol abuse) than non-mixed patients (Akiskal et al., 2006, Hantouche et al., 2006; Valenti et al., 2011).
Onset polarity of first episode identify distinct subgroups of bipolar disorder, which present different symptomatology, illness course, comorbidity, and prognosis (Goodwin et al., 2007; Carvalho et al., 2014). Depressive onset is the most frequent type of onset (up to 66% of case) (Daban et al., 2006; Baldessarini et al., 2013). Patients with mixed onset are more frequently female, have subsequent mixed and depressive episodes with a higher frequency, low rates of remission, high suicide-attempt rates, comorbidity (anxiety, substances, medical), a rapid cycling course, were prone to substance
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abuse and poor response to treatment (Baldesserini et al., 2010; Azorin et al., 2011; Gonzales et al., 2011; Tundo et al., 2015).
In different studies about bipolar disorder mixed depression has a prevalence from 21% to 76% depending on setting, type of population and the use of a broad or narrow definition of mixed states (Marneros et al., 2005; Undurraga et al., 2012, Shim et al., 2016,). Although studies report that there is no difference between prevalence of mixed depression based on gender other studies show a significantly more prevalence among women (Akiskal et al., 2006, Benazzi et al., 2007)
Mixed depression has been associated with adverse clinical outcomes, younger onset age, and longer episode duration (Goldberg et al., 2009; Judd et al., 2012). Co-occurring manic symptoms have been associated with an increased risk of suicidal behavior, more depressive episodes, less response to treatment, more atypical features of depression and increased familial risk of bipolar disorder (Sato et al., 2003; Benazzi, 2004; Olgiati et al., 2006). Patients with mixed depression have a more severe illness course and a longer time to achieve remission compared to pure states (Shim et al., 2013).
Mixed features predict less favorable outcomes of affective illness and the diagnosis is of crucial importance mostly in depressive episodes, because an inappropriate treatment can worse symptoms. In fact the use of antidepressant monotherapy without stabilizers or antipsychotics can increase manic
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symptoms severity, risk of non-response, activation syndrome, switch and suicidality (Goodwin et al., 2007; Angst et al., 2009).
2.2 The “anxious distress specifier” in major depression.
Although depression and anxiety are traditionally conceptualized as two independent disorders, they are highly co-morbid with rates ranging from 40%–50% (Sanderson et al., 1999, Fava et al., 2000; Zimmerman et al., 2002).
Studies indicate that anxiety symptoms and disorders are common in patients with major depressive disorder (MDD) (Schaffer et al. 2012) and are correlated with a less favorable clinical outcome. In fact higher levels of anxiety correlate with a lower probability of remission and a longer time to achieve remission (Fava et al. 2008).
Patients have greater depression severity, chronicity, less recurrence (Gasperz 2017) (chronicity is negatively associated with recurrence), greater functional impairment, more suicidal ideation, self harm and complete suicide (Fawcett 2001; Fava et al 2004; Fava et al., 2006; Seo et al., 2011; Goldberg 2012).
Moreover they have also worse treatment outcomes (VanValkenburg et al.1984; Joffe et al. 1993), more treatment side effects, with lower rates of
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treatment compliance (Fava et al., 2008; Wu et al., 2013; Ionescu et al., 2014). Clinicians and researchers have conceptualized the idea of mixed anxiety and depressive states in several different ways. The ICD-10 was the first to introduce the diagnosis of “mixed anxiety-depression” in 1992 in response to
increasing evidence that co-morbid anxiety and depression were prevalent in patients who did not meet full criteria for either disorder (World health Organization 1992). ICD-10 requires the presence of mild symptoms of both anxiety and depression that are not severe enough to qualify for either full diagnosis. Than in DSM-IV trials provided insufficient evidence to include anxious depression as an official Axis I diagnosis. In fact mixed anxiety depressive disorder was included as an area for further research in the DSM-IV’s Appendix (American Psychiatric Association 1994; Zimbarg 1994) and
the final criteria did not require the presence of both anxiety and depressive symptoms (Ionescu et al., 2013).
Recently DSM-5 adds the specifier “with anxious distress” and defines high levels of anxiety symptoms that do not meet the full criteria for any of the disorders in the diagnostic category (Shim et al., 2016).
Anxious distress specifier in DSM-5 is defined as the presence of at least two of the following symptoms during the majority of days of a major depressive episode or persistent depressive disorder: (a) feeling keyed up or tense; (b) feeling unusually restless; (c) difficulty concentrating because of worry; (d)
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fear that something awful might happen; (e) feeling that the individual might lose control of himself or herself. The specifier is graded as mild, moderate, moderate-severe and severe if two, three, four or five symptoms are present. The fourth grade requires psychomotor agitation (American Psychiatric Association 2013).
Until now studies on the anxious distress specifier validity are all retrospective studies without prospective ones (McIntyre et al., 2016, Gaspersz et al., 2017, Shim et al 2016) and relationships with bipolar spectrum are not investigated. Some studies show that the anxious distress specifier is a common clinical presentation in patients with MDD (with a prevalence of 54%-59%) (McIntyre et al., 2016; Gaspersz et al., 2017,) without differences in socio-demographic variables. Patients have greater severity of the disease, a higher number of hospitalizations, higher rates of suicidal ideation, greater depressive symptom severity, greater work impairment, decreased quality of life, and greater self-reported cognitive impairment. In MDD cognitive impairment is often a prevalent, pervasive and durable feature. Anxiety negatively affects measures of cognitive function in MDD that mediate unfavorable illness presentation, course, and treatment outcomes (McIntyre et al., 2013).
Other studies have shown that the DSM-5 anxious distress specifier is a reliable measure, with significant discriminant validity (Zimmerman et al., 2014; Zimmerman et al., 2017; Gaspersz et al., 2017).
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To evaluate the clinical significance of anxiety in depressed patients, has been developed a subscale that test the DSM-5 anxious distress specifier, included in the Clinically Useful Depression Outcome Scale (CUDOS-A). This self-report measure shows high scores in patients with symptoms of anxiety or a comorbid anxiety disorder measuring poorer psychosocial functioning and quality of life (Zimmerman et al., 2014).
A limitation of this study is the lack of instruments assessing the DSM-5 specifier and also other studies have supported the validity of the specifier with proxy items on various scales (McIntyre et al., 2016, Gaspersz et al., 2017).
Recently has been developed a clinical interview that assess the features of anxious distress specifier, the DSM-5 Anxious distress specifier interview (DADSI). The scale is correlated more with anxiety than with depression and irritability and with a current anxiety disorder. This is found to be a reliable and valid measure of anxiety symptoms in depressed patients and of severity of the features (Zimmerman et al., 2017).
There has been also examined the longitudinal predictive validity of the “anxious distress specifier” in patients with MDD and the validation against DSM IV based comorbid anxiety disorder diagnoses (Gaspersz et al., 2017). The specifier, operationalized in the studies as the presence of proxy items, is significantly predictive of chronicity, time of remission of MDD, depression
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severity and suicidal ideation. One fifth of patients with MDD with the specifier has no anxiety disorders, while half of the MDD patients without the specifier has an anxiety disorder. In the specifier four items are typical for generalized anxiety disorder and one for panic but the specifier does not distinguish better these two anxiety disorders (Uher et al.,2014). The specifier is in fact a more generic marker of anxiety. DSM-5 anxious distress specifier is clinically significant and valid in identifying comorbid anxiety features and comorbid anxiety disorders that are related to worse clinical outcomes and that are not taken within the DSM anxiety disorder diagnoses (Fawcett, 2013; Konstantakopoulos 2013). In fact the specifier predicts all longitudinal outcomes outperforming the presence of DSM IV based anxiety disorders. The specifier may have particular importance in primary care, for time and expertise limitations in psychiatric assessment (Gaspersz et al.,2017).
DSM-5 anxious distress specifier in depressed patients is longitudinally predictive also of poor treatment outcome with greater depression severity, lower remission rates (in patients on adequate antidepressant treatment) and greater frequency of side effects. In depressed patients with anxiety a greater responsiveness to changes in the body during antidepressant treatment lead to more side effects. Side effects lead also to less compliance to antidepressant treatment with chronicity or recurrence of the disorder (Gaspersz et al.,2017). Some studies find that BDNF rs7124442 TT genotype predicts a worse
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antidepressant response after 6 weeks in persons with anxious depression (Domschke et al., 2010b; Ionescu et al., 2013).
Anxious depression may be associated with a dysfunction of the HPA-axis (Meller et al., 1995; Cameron, 2006; Leonard 2009) and may be a chronic inflammatory phenomenon, sharing common pathophysiological pathways with inflammatory states (Camacho, 2013).
Studies have showed that levels of circulating monocytes are elevated in patients with MDD, bipolar disorders and schizophrenia correlated to an increased expression of immune genes and overproduction of monocyte and macrophage-related cytokines (Beumer et al., 2012). Severe anxiety and also psychomotor agitation (conditions of chronic stress) decrease the sensitivity of patients to anti-inflammatory activity, with an impaired capacity to moderate the inflammatory response under stressful conditions (Miller et al., 2005). Unipolar depressive disorder patients with moderate or severe anxious distress have a higher level of immune activation such as CRP levels and monocyte counts than patients with mild anxious distress (Shim et al., 2016). Furthermore higher levels of inflammatory markers are associated with more suicidality, a poor treatment response to antidepressant therapy and a higher use of second generation antipsychotics (Benazzi et al 2005; O’Brien et al 2006; Fava et al., 2008; Yoshimura et al., 2009; Shim et al.,2016).
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The specifier is predictive of more suicidal thoughts (Baek et al., 2015) that are often associated with inadequate treatment response in MDD (Zisook et al., 2009; Courtet et al., 2014;).
The anxious distress specifier identifies a subpopulation in MDD with greater morbidity, lower remission rates, long duration of disease, social, occupational impairment and poor outcomes with single therapies (Fava et al 2006; Wu et al., 2013). This underline the need of integrated and combined psycho-pharmacological strategies. However if this specifier can help with treatment can be argued because no specific treatment is developed for this specifier (McIntyre et al., 2016).
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3. Aims of the study
The aim of the study was to assess the presence of anxious distress specifier in a sample of 241 outpatients with major depressive episode in MDD, BD-I or BD-II and to evaluate the longitudinal predictive validity of the specifier for clinical outcome. The sample was followed for a period of at least 12 weeks and naturalistically treated with mood stabilizers (lithium salts or anti-epileptics drugs), antidepressants and antipsychotics.
Based on the currently available findings, we hypothesized that:
- Patients with anxious distress specifier have a worst outcome than patients without the specifier.
-The presence of anxious distress specifier during a depressive episode could suggest a bipolar course.
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4. Materials and methods
4.1 Subjects
A sample of 241 patients with major depressive episode was recruited at the Section of Psychiatry, Department of Clinical and Experimental Medicine, University of Pisa, Italy and at the Istituto di Psicopatologia in Rome, Italy during a period of about one year and longitudinally followed up for a period of at least twelve weeks.
Patient enrollment criteria were age 18-65 years and meeting DSM-5 criteria for Major depressive episode in type I and II Bipolar Disorder and Major Depressive Disorder (APA 2013). Exclusion criteria were the presence of medical or neurological conditions inducing mood disorders.
4.2 Procedure
The Structured Clinical Interview for DSM 5 (SCID-5) (First M.B. et al. 2015) was used to interview all patients.
The Semi-structured Interview for Mood Disorder (Cassano et al., 1987) was used to collect the participants' demographic and retrospective clinical data.
Diagnosis of Major depressive episode was formulated according to DSM-5 criteria (APA, 2013) and were screened the specifiers with anxious distress, melancholic, psychotic, mixed and atypical features, peri-partum onset and
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seasonal pattern. The diagnosis of mixed attenuated episodes was assessed by Koukopoulos’s criteria (Koukopoulos 1992), which have been validated by Benazzi et al., 2004 and by Sani et al., 2014.
Treatment was chosen by the senior clinicians (AT, LM) based upon the international guidelines and the clinical experience at the time of patient’s enrollment (Yathan et al., 2013; NICE 2014; Goodwin et al., 2016).
Patients were treated with antidepressants (81.3%), Lithium (23.7%), Valproic acid (31.1%), Carbamazepine (12.4%), Lamotrigine (5.0%), atypical antipsychotics (33.6%) and typical antipsychotics (2.5%).
Patients were evaluated at baseline and in a follow-up at four, eight and twelve weeks.
With the purpose to evaluate the impact of anxious distress specifier on demographic and clinical features and its role in treatment response, we divided patients into two groups, those with anxious distress and those without anxious distress.
Considering the large overlap between anxious distress and attenuated mixed features we divided the sample in three groups: the first without mixed features (DSM-5 and Koukopoulos’s criteria) and anxious distress, the second with only anxious distress and the third with mixed features (DSM-5 and Kokoupoulos’s criteria) and anxious distress. The comparison of three groups
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had the purpose to evaluate the response to treatment of the three groups and the role of “anxious distress” in the prospective course.
All patients gave written informed consent for data collection and for their use in anonymous and aggregate form, and the local ethical committees approved the research project.
4.3 Assessment Tools
The diagnostic and symptomatology assessments were performed with the following tools:
• Structured Clinical Interview for DSM-5, SCID 5 (First, M.B. et al. 2015):
This interview is used for the diagnosis of disorders according to the DSM 5 criteria.
The SCID 5 consists of ten modules containing each question to investigate the presence of symptoms-criteria for different diagnostic categories.
Each module is independent and can be used separately from the other according to specific searches.
The SCID 5 must be used by interviewers with good clinical experience and who have undergone adequate training.
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The interview is organized according to the diagnostic categories of DSM-5: the sequence of questions follows the structure of this manual and the different items explore the diagnostic criteria.
For this study the form relating to Mood Disorders was mainly used in order to adequately recruit patients with Major Depressive Episode and properly diagnose the different specifiers, and the previous illness episodes.
• Semi-structured Interview for Mood Disorders (SIMD) (Cassano et al.
1987):
The SIMD-R is a semi-structured diagnostic interview for assessment of mood disorders.
It systematically collects information on different familiar, demographics, medical history and clinical aspects.
This interview has been developed to gather systematic information on family history, previous episode number and polarity, suicide attempts (current and lifetime), and psychotic symptoms of any polarity.
Thanks to this tool it was also possible checking the main affective diagnosis and the type of mood episodecurrently in progress.
Whenever possible, collateral clinical data, including information obtained from other informants as well as any available past medical records, were used to support patient information, to corroborate the onset age and polarity of the participants' illness episodes.
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These criteria are designed by Koukopoulos and validated by Benazzi et al. (2004) and by Sani et al. (2014).
In our study these criteria were used for defining mixed attenuated depression; it was defined as a major depressive episode plus three or more of the following eight symptoms: inner tension/agitation, racing or crowded thoughts, irritability or unprovoked feeling of rage, absence of signs of retardation, talkativeness, dramatic description of suffering or frequent spells of weeping, mood lability or marked reactivity, early insomnia.
• Hamilton Rating Scale for Depression (HAM-D) (Hamilton 1960) • Young Mania Rating Scale (YMRS) (Young et al., 1978)
• Clinical Global Impression (CGI) (Guy 1976)
• Global Assessment of functioning (GAF) (American psychiatric
association 1994)
• Brief TEMPS-M temperament questionnaire (Erfurth et al, 2005)
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4.4 Statistical analysis
Statistical analysis was conducted using IBM SPSS Statistics Version 21. Chi-square test or two-tailed Fisher’s exact test was used, when appropriate, to compare categorical variables.
Independent student’s T-test and One-way ANOVA were utilized respectively to compare two and three groups on parametric variables.
A mixed design ANOVA was utilized to study changes from baseline to twelve weeks.
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5. Results
The study included 241 patients, with a mean age of 47.7±13.6, 74.7% were females, 48.5% were occupied, with a mean of years of education of 13.4±4.1.
In the sample 31 patients (12.9%) had a diagnosis of BP-I, 87 patients (36.1%) of BIP-II, 42 patients (17.4%) of major depressive disorder (single episode), 81 patients (33.6%) of recurrent major depression.
About the specifiers of major depressive episodes, 142 patients (58.9% of the sample) had a depressive episode with “anxious distress”, 40 (16.6%) with “melancholic features”, 16 (6.6%) with “psychotic features”, 7 (2.9%) with “peri-partum onset”, 52 (21.6%) with “seasonal pattern”, 16 (6.6%) with “atypical features”. Only 6 (2.5%) of patients had a depressive episode with “mixed features” according to DSM-5 while 117 (48.5%) of patients had mixed attenuated depression according to Koukopoulos’s criteria.
In table 1 are showed results from the comparison of demographic and clinical characteristics of patients with (142) and without (99) “anxious distress”.
Patients in the two groups did not differ significantly in gender distribution, mean age, years of education and work.
The two groups differed significantly in marital status: the number of married patients was higher in the group with anxious distress while single patients were higher in the group without anxious distress (p .032). Separated or widowed patients did not differ in the two groups.
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Comparing diagnosis distribution in the two groups, BD-II was higher in the group with anxious distress while recurrent MDD was higher in the group without this specifier (p .015). BD-I and MDD (single episode) did not significantly differ in the two groups (see Table 1).
The two groups did not significantly differ in the specifiers with melancholic features, with psychotic features, with peri-partum onset, with atypical features and with DSM-5 mixed features. The two groups differed significantly in the specifier with seasonal pattern (p .003) and with mixed features according with Koukopoulos’s criteria (p<0.001) that were higher in the group with anxious distress.
They did not significantly differ in DSM-5 severity of index episode, duration of index episode and lifetime delusions (see Table 2).
Between two groups there were no significant differences in number of comorbidities and in the type of comorbidities except for Generalized anxiety disorder that was higher in the group with anxious distress (p .007) and for the abuse of cocaine that was higher in the group without anxious distress (p .034) (see Table 3).
The two groups did not differ significantly in types of temperament.
Moreover they differed significantly in family history, that was higher for bipolar disorder in the group with anxious distress while in the other group
32
was higher for depression (p .004). The two groups did not significantly differ in family history for anxiety disorders and psychosis (see Table 4).
The two groups did not differ significantly in mean age of onset, polarity of onset, length of illness and the total number of previous episodes. There were not significant differences in type of previous episodes except for the mean number of previous hypomanic episodes that was higher in the group with anxious distress (p .017). Furthermore the two groups did not significantly differ in suicide attempts, hospitalizations and switch (Table 5).
The two groups differed significantly also in symptomatology at baseline, in fact scores of HDRS (p. 005), YMRS (p .004) and CGI-s (p. 021) were higher in the group with anxious distress compared to the other group. The two groups did not differ in scores of GAF (Figure 1,2).
About therapies prescribed at baseline the two groups differed significantly in the use of Selective serotonin reuptake inhibitor (SSRIs) (p .004), typical antipsychotics (FGA) (p .044) and atypical antipsychotics (SGA) (p .038), that was higher in the group with anxious distress, while Tricyclic antidepressants (TCAs) were more utilized in the second group (p .034). The two groups did not significantly differ in the use of Lithium, Antiepileptics, other antidepressants, rates of antidepressants and associations of two antidepressants (see Table 6).
33
About the clinical response after twelve weeks, the two groups differed significantly in compliance (p .002) and anxiety symptoms (p .034) that were higher in the group with anxious distress. The two groups did not significantly differ in rates of drop out, suicide attempts, admissions, switch induced, remission, 50% of response and remission (CGI-s and CGI-i≤2) (see Table 7).
About symptomatology after twelve weeks of treatment the two groups differed significantly in median scores of YMRS (p .006) that were higher in the group with anxious distress. The two groups did not significantly differ in scores of HDRS, CGI and GAF (Figure 3,4).
In prospective course there was a significantly reduction of HDRS scores in the group with anxious distress and in the group without anxious distress from baseline to twelve weeks (p<0.001) (Figure 5).
About median scores of YMRS there was a reduction in the two groups from baseline to week 12 but the difference was statistically significant only in the group without anxious distress (p<0.001). In the group with anxious distress there was a reduction until eight weeks and after there was an increase of scores that at twelve weeks was 1.6±3.3 (Figure 6).
From the comparison of three groups: the first was without mixed features (DSM-5 and koukopoulos’s criteria) and anxious distress, the second with only anxious distress and the third with mixed features (DSM-5 and Koukopoulos’s criteria) and anxious distress.
34
There was a reduction from baseline to week 12 of the YMRS score in the first and the third group with a difference that was significant only in the third group (p<0.001). On the contrary in the group with anxious distress there was an increase of YMRS score with a difference that was significant (p<0.05) (see Figure 7).
HDRS score significantly decreased from baseline to week 12 in the three groups (Figure 8).
About therapies prescribed at baseline the three groups differed significantly in the use of antidepressants that was higher in the group with anxious distress and in the group without anxious distress and mixed features (p .004) than in the third group. The groups differed significantly in the use of SSRIs that was higher in the group with anxious distress (p .009) than in the other groups.
They differed significantly also in TCAs that were more used in the group without anxious distress and mixed features (DSM-5 and Koukopoulos’s criteria) than in the other groups (p .015). The groups differed significantly in the association of two antidepressants that was higher in the group with anxious distress than in the group with mixed features (p .026). The three groups differed significantly also in the use of antiepileptics and of atypical antipsychotics that was higher in the group with mixed features and anxious distress than in the other groups (p .001). The groups did not differ in the use of Lithium, other antidepressants and typical antipsychotics (see Table 8).
35
6. Discussion and conclusions
Our study shows that in a sample of 241 patients with major depressive episodes in MDD, BP-I, BP-II, the anxious distress specifier was present in 58.9% of the sample in line with studies that indicate the prevalence of the specifier in 50-59% of samples of MDD (McIntyre et al., 2016, Shim et al., 2016, Gaspersz et al., 2017).
Comparing the groups with anxious distress specifier and without anxious distress, they did not differ significantly in socio-demographic characteristics such as gender, age, years of education and work: this is supported by other studies (McIntyre at al., 2016; Shim et al., 2016).
In our study the two groups differed significantly only for marital status, in fact the number of married patients was higher in the group with anxious distress. In an other study (Gaspersz et al., 2017), in a sample of 1080 patients with MDD there were no sociodemofraphic differences except for fewer years of education for patients with anxious distress.
In our study comparing the two groups for diagnosis distribution, we found that anxious distress correlated with bipolar II disorder, while the number of patients with MDD was higher in the group without anxious distress.
Moreover family history for bipolar disorder was higher in the group with anxious distress, that had also seasonal pattern more frequently and higher
36
number of patients with mixed features according to Koukopoulos’s criteria. Furthermore the group with anxious distress had more previous hypomanic episodes. These data may suggest a relationship with bipolar spectrum.
About comorbidities there was not difference in the number of comorbidities: the two groups differed significantly only for comorbidity with Generalized Anxiety Disorder that was higher in the group with anxious distress. McIntyre et al., (2016) in a sample of 830 patients with MDD found that anxious distress specifier was associated with Posttraumatic stress disorder, Social phobia and Generalized Anxiety Disorder. This study show also a correlation of the specifier with alcohol abuse while our results indicate no differences in substance abuse except for cocaine that was more used in patients without anxious distress.
About symptomatology at baseline the group with anxious distress show higher scores of YMRS, HDRS and CGI-s compared to the group without the specifier. This is in line with studies that show greater severity of depression and greater functional disability, lower quality of life and more suicidality in patients with anxious distress (McIntyre et al., 2016; Gaspersz et al., 2017). However in our study there were not significant differences between the two groups in scores of GAF and in lifetime suicidality.
Our results show that the most used therapies in patients with anxious distress were SSRI but also antipsychotics. Shim et al., (2016) in a study on 177
37
patients with a depressive disorder indicate that in depressive episodes with anxious distress there was a higher use of antipsychotics. In fact monotherapy with antidepressants may increase agitation and recent trends show an increase in the use of second generation antipsychotics (such as quetiapine and aripiprazole) as adjunctive treatment or on monotherapy for bipolar or unipolar depressed patients unresponsive to mood stabilizers, to improve symptoms of depression with high levels of anxiety. Moreover Gaspersz et al., (2017) in a study show that the specifier significantly predicted antidepressant side effects and poor treatment outcome.
Response after twelve weeks indicates the presence of more anxiety and higher YMRS score in the group with anxious distress. Partly this is in line with studies that show higher levels of somatic, cognitive and behavioral anxiety (McIntyre et al., 2016) with more time to achieve remission (Gaspersz et al., 2017). Moreover these studies show also a lower compliance while in our group there was a higher adherence to therapies in the group with anxious distress.
In our study the two groups did not differ significantly in rates of response after twelve weeks. Gaspersz et al., (2017) instead show a median time of remission 50% longer in the presence of anxious distress than without anxious distress (six vs four months).
38
Considering symptomatology progression from baseline to twelve weeks there was a significant reduction of HDRS score in the two groups while there was a significant reduction of YMRS score only in the group without anxious distress. YMRS score was not significantly reduced in the group with anxious distress, with an increase after eight weeks.
Also treatment response may suggest a relationship between the presence of anxious distress specifier and bipolar spectrum confirmed by the comparison of the three groups in which there was a significant increase of YMRS score from baseline to endpoint in the group with anxious distress.
These data are only partially explained by the greater use of antidepressants, in particular SSRIs and association of two antidepressants in this group with anxious distress while antiepileptics and atypical antipsychotics were most commonly utilized in the group where the specifier was associated with mixed features. In fact a treatment response suggesting a relationship with bipolar spectrum was present even if patients with anxious distress were separated by patients with DSM-5 mixed features and also with mixed attenuated features.
Until now studies have not investigated the relationship between anxious distress specifier and bipolar spectrum while studies on the other specifiers suggest that mixed depressive features, even in their subthreshold form, may be associated with significantly hallmarks of bipolarity (Zaninotto et al., 2014). In fact the presence of mixed features in MDD is considered a risk
39
factor for bipolar disorder and a bridge between bipolar and major depressive disorders because characteristics of individuals with this condition and the clinical trajectory of the illness are more closer to bipolar patients (Liu et al., 2014; Suppes et al., 2017; Swann 2017). Studies indicate also the idea that MDD and BD exist on a continuum, a spectrum from pure unipolar depression to threshold levels of mania (Cassano et al 2004; Stahl et al., 2017).
Moreover also comorbidity with anxiety disorders has been studied as a risk factor for bipolar disorder, with a risk of transition from unipolar to bipolar depression (Faedda et al., 2014).
Some authors showed the importance to consider non overlapping symptoms as agitation, anxiety, irritability and insomnia for diagnosis of mixed features for therapeutic implications (McIntyre et al 2016).
Symptoms such as psychomotor agitation and distractibility are considered important symptoms of mixed features and bipolar spectrum (Malhi et al., 2014). Furthermore Uher et al., (2014) indicate that psychomotor agitation has been deleted by mixed features in DSM-5 and added to anxious distress specifier in the fourth grade (“severe”), with more misdiagnosis.
In “The Primacy of mania” Koukopoulos conceptualized mixed states with “hypomanic equivalents” in depressive episodes. They were racing or
crowded thoughts, heightened anxiety, aggressive impulses, psychomotor agitation and sleep disturbances. He considered that nervous excitement was
40
related to states as mania, hypomania, hypomanic equivalents and anxiety (Koukopoulos et al.,2009, Faedda et al., 2015).
Benazzi et al. (2004) and Sani et al. (2014) validated the Koukopoulos’s criteria and Koukopoulos’s definition of mixed depression as a mixed state associated with variables (such as bipolar family history), that typically distinguished bipolar disorders from unipolar major depressive disorders.
Other studies (Takeshima et al., 2015) have showed that the prevalence of Benazzi’mixed depression was higher (33.6%) compared to DSM-5 (3.2%) and was higher in patients with BP than in MDD and could better discriminate BP from MDD.
In our sample only six (2.5%) patients had a diagnosis of mixed features acconding to DSM-5 while 117 (48.5%) patients had a diagnosis of mixed attenuated depression.
Our results show a significant correlation between anxious distress specifier and bipolar spectrum.
In the spectrum approach bipolar spectrum involve core symptoms but also atypical and subclinical symptoms and signs, temperaments, personality traits, prodromes, sequelae of previous disorders, vulnerability factors for the development of a not yet fully expressed disorder (Cassano et al., 1999; Frank E 1998).
41
Depression in bipolar spectrum is associated to early age at onset, family history for BD or suicide, hyperthymic or cyclothymic temperament, post-partum depression, seasonality, high rate of recurrences, severity of depressive episodes, higher comorbidities (substance abuse), subsyndromal hypomanic symptoms, worse response to antidepressants or antidepressant-induced hypomania (Cassano et al., 2011; Stahl et al.,2017).
Our study shows that the specifier is significantly correlated to characteristics of bipolar spectrum such as history of bipolar disorder, mixed attenuated features, seasonal pattern, hypomanic episodes, typical symptoms of bipolar II disorder.
Also the response to antidepressant treatment may correlate with bipolar spectrum.
Some studies show also the importance of a broadly defined excitement to better understand the pathophysiology of mood disorders and to establish more effective treatments. Anxiety in fact may be considered an excitatory process susceptible to activation by antidepressants. Moreover anxiety is central in mixed depressive episodes and it is inherent to the psychic agitation itself. Thus anxiety conditions can be more safely treated with antiexcitatory (such as anxiolytics, antipsychotics or antiepileptic agents), than with antidepressant agents that can worse the symptomatology (Koukopoulos et al., 2009; Sani et al., 2014).
42
In conclusion in this study according to our hypothesis the specifier is associated with a different outcome than in patients without the specifier, with more severity of illness and a greater symptomatology. Moreover the clinical outcome of the specifier and its response to treatments may indicate its correlation with bipolar spectrum. This correlation was still present if anxious distress was separated by mixed features (also attenuated mixed features).
Several limitations in the present study should be considered.
The most important limitation is the size of the sample, it was in fact a small sample. Addictionally the follow-up was in a short period of time (twelve weeks).
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7.Tables and figures
Table 1 : Demographic and clinical features in patients with and without “anxious distress” Patients with anxious distress (N=142) Patients without anxious distress (N=99) p Female (%) 76.8 71.7 0.376 Age (mean±SD) 48.8±13.0 46.3±14.4 0.161 Marital status (%) Married 66.9 51.5 (a>b) (b>a) 0.032 Single 23.9 39.4 Separated/widowed 9.2 9.1
Years of education (mean±SD) 13.3±4.3 13.5±3.8 0.701
Work (%) Employed 48.6 48.5 0.777 Student/housewife/ pens 37.3 34.3 Unemployed 14.1 17.2 Diagnosis (%) BD-I 12.7 13.1 (a>b) (b>a) 0.015 BD-II 43 26.3 Recurrent MDD 26.1 44.4 Single episode MDD 18.3 16.2
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Table 2: Clinical features
Patients with anxious distress (N=142) Patients without anxious distress (N=99) p Melancholic features (%) 7 30.3 0 Psychotic features (%) 8.5 4.0 0.176 Peri-partum onset (%) 3.5 2.0 0.495 Seasonal pattern (%) 28.2 12.1 0.003 Atypical features (%) 7.0 6.1 0.763 Mixed features DSM-5 (%) 3.5 1.0 0.218 Mixed attenuated Koukopoulos
(%) 64.8 25.3 <0.001 DSM-5 Severity of index episode
(mean±SD) 3.1(0.69) 3.0(0.65) 0.168 Duration index episode weeks
(median±SD) 32.2(73.6) 42(91.9) 0.999 Lifetime delusions (%) absent 76.1 84.8 0.057 In depression 10.6 2 In mania 4.2 6.1 In mixed states 5.6 2 In all phases 3.5 5.1
45 Table 3: Comorbidity Patients with anxious distress (N=142) Patients without anxious distress (N=99) p Comorbidity (%) Absent 51.4 46.5 0.442 1 36.6 44.4 >1 12 9.1
Obsessive compulsive disorder (%) 14.1 19.2 0.29
Panic Disorder (%) 26.1 27.3 0.833
Social Anxiety Disorder (%) 4.9 6.1 0.702
Generalized Anxiety Disorder (%) 7 0 0.007
Eating disorders (%) 15.5 10.1 0.225 Somatoform disorders (%) 2.8 2 0.696 Alcohol abuse (%) 16.9 16.2 0.879 Substance abuse (%) 14.1 18.2 0.391 Cannabis (%) 6.3 11.1 0.186 Cocaine (%) 2.8 9.1 0.034 Heroin (%) 0 0 Na BDZ (%) 7 3 0.175
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Table 4: Temperament and family history
Patients with anxious distress (N=142) Patients without anxious distress (N=99) p Dysthymic temperament (mean±SD) 20.9±6.7 19.9±6.8 0.247 Cyclothymic temperament (mean±SD) 17.7±7.7 18±6.7 0.579 Hyperthymic temperament (mean±SD) 19.8±6.5 19.2±6.9 0.597 Irritable temperament (mean±SD) 14.6±5.9 14.7±6.4 0.950
Anxious temperament (mean±SD) 16.1±6.0 15.8±6.1 0.665
Family history (%) Absent 26.1 14.1 (b>a) (a>b) 0.004 Depression 28.9 45.5 Bipolar 35.2 22.2 Anxiety 9.2 15.2 Psychosis 0.7 3
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Table 5: Previous course
Patients with anxious distress (N=142) Patients without anxious distress (N=99) p
Age of onset (mean±SD) 33.1±13.5 31.6±12.3 0.298
Polarity onset (%) Depression 76.6 68.7 0.26 hypo/mania 7 11.1 Mixed mania 0 2.1 Mixed depression 16.2 20.2
Length of illness (mean±SD) 15.6±13.3 15.0±11.8 0.978 N previous depressive episodes
(mean±SD) 3.22±4.9 3.2±4.0 0.408
N previous manic episodes
(mean±SD) 0.21±1.1 0.35±1.4 0.167
N previous hypomanic episodes
(mean±SD) 2.1±3.6 1.1±2.5 0.017
N previous manic episodes with
mixed features (mean±SD) 0.29±2.53 0.05±0.26 0.248 N previous depressive episodes with
mixed features (mean±SD) 1.1±2.3 1.4±4.4 0.494
N total previous episodes
(mean±SD) 6.6±8.5 5.9±7.2 0.726
Suicide attempts (%) 17.6 16.2 0.769
Hospitalizations (%) 26.8 21.2 0.324
48
Figure 1: Symptomatology at baseline
0 2 4 6 8 10 12 14 16 18 20 HDRS YMRS 20 2.2 18.6 P=0.005 1.3 anxiety non anxiety p=0.004
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Figure 2: Symptomatology at baseline
0 10 20 30 40 50 60 CGI-s GAF 4.8 51.3 p=0.021 4,6 52.2 anxiety no anxiety
50 Table 6: Treatment Patients with anxious distress (N=142) Patients without anxious distress (N=99) p Antidepressants (%) 83.7 78.8 0.334 SSRI (%) 57 38.4 0.004 TCA (%) 24.6 37.4 0.034 Association of two antidepressants (%) 23.9 18.2 0.285 Lithium (%) 26.8 19.2 0.174
Median serum level of lithium
(mean±SD) 0.54(0.21) 0.47(0.16) 0.108
Valproic acid (%) 33.1 28.3 0.427
Carbamazepine (%) 11.3 14.1 0.506
SGA (%) 38.7 26.3 0.044
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Table 7. Prospective course: outcome at week 12
Patients with anxious distress (N=142) Patients without anxious distress (N=99) p Drop out (%) 38.7 43.4 0.465 Compliance (%) 100 89.3 0.002 Suicide attempts (%) 0 0 Na Hospitalizations (%) 2.3 0 0.253 Switch induced (%) 4.6 0 0.104 Anxiety (%) 17.4 5.4 0.034 Remission 51.7 53.6 0.829 Response 50% 49.4 58.9 0.266 Remission CGIs ≤2 46.0 57.1 0.192 Remission CGIi ≤2 80.5 91.1 0.086
52
Figure 3: Symptomatology at week 12
0 1 2 3 4 5 6 7 8 9 HDRS YMRS 8.5 1.6 7.9 0.4 anxiety no anxiety p=0.006
53
Figure 4: Symptomatology at week 12
0 10 20 30 40 50 60 70 CGI-s CGI-i GAF 2.7 1.7 68.4 2.6 1.3 63.5 anxiety no anxiety
54
Figure 5
CHANGES FROM BASELINE TO 12 WEEKS ESTIMATED USING A MIXED EFFECTS MODEL: HDRS
NO ANXIETY GROUP: estimated change -10.77 (SE 0.748),p<0.001
ANXIETY GROUP: estimated change -11.71 (SE 0.694), p<0.001
55
Figure 6
CHANGES FROM BASELINE TO 12 WEEKS ESTIMATED USING A MIXED EFFECTS MODEL: YMRS
NO ANXIETY GROUP: estimated change - 0.797 (SE 0.224), p<0.001
ANXIETY GROUP: estimated change -0.57 (SE 0.304), p=0.059(NS)
56
Figure 7
CHANGES FROM BASELINE TO 12 WEEKS ESTIMATED USING A MIXED EFFECTS MODEL: YMRS
NOT MIXED: estimated change -0.19 (SE 0.176),p=0.276(NS)
ONLY ANXIETY: estimated change +1.17 (SE 0.540), p<0.05
MIXED: estimated change -1.77 (SE 0.315),p<0.001
57
Figure 8
CHANGES FROM BASELINE TO 12 WEEKS ESTIMATED USING A MIXED EFFECTS MODEL: HDRS
NOT MIXED: estimated change -10.37 (SE 0.846),p<0.001
ONLY ANXIETY: estimated change -12.57 (SE 1.125), p<0.001
MIXED: estimated change -11.37 (SE 0.773),p<0.001
58
Table 8: Treatment in patients without mixed features (DSM-5 and koukopoulos’s criteria) and anxious distress; with only anxious distress; with mixed features (DSM-5 and Koukopoulos’s criteria) and anxious distress.
Without mixed features/ anxious distress (N=74) Anxious distress (N=50) Mixed features (DSM-5 and AK) and anxious distress (N=117) p Antidepressants (%) 86.5 93.9 73.5 0.004 (a,b>c) SSRI (%) 40.5 68.0 47.0 0.009 (b>a,c) TCA (%) 41.9 30.0 22.2 0.015 (a>c) Other antidepressants (%) 23.0 26.0 14.5 0.153 Two antidepressants association
(%)
23.0 34.0 15.4 0.026 (b>c) Lithium (%) 20.3 24.0 25.26 0.695 Median serum level of lithium
(mean±SD) 0.4 (0.20-0.85) 0.6 (0.30-0.90) 0.47-0.15-0.90 0.056 Antiepileptics (%) 33.8 40.0 60.7 0.001 (c>a,b) SGA (%) 20.3 26.0 45.3 0.001 (c>a,b) FGA (%) 0 6.0 2.6 0.109
59
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