Lifetime rhythmicity and mania as correlates of suicidal ideation and attempts in mood disorders

BACKGROUND: The aim of this study is to establish to what degree variation in lifetime experience of rhythmicity and manic-hypomanic features correlates with suicidality in individuals with mood disorders and other major psychiatric diagnoses and in a comparison group of controls. METHOD: Suicidal ideation and attempts were investigated in a clinical sample, including 77 patients with schizophrenia, 60 with borderline personality disorder, 61 with bipolar disorder, 88 with unipolar depression, and 57 with panic disorder, and in a comparison group of 102 controls. Using information derived from the diagnostic interview and a self-report assessment of mood spectrum symptoms, subjects were assigned to 3 categories according to the maximum level of suicidality achieved in the lifetime (none, ideation/plans, and suicide attempts). The association of categorical and continuous variables with suicidality levels was investigated using multinomial logistic regression models. RESULTS: Suicidal ideation and plans were more common in unipolar depression (50%) and bipolar disorder (42.4%) than in borderline personality disorder (30%), whereas the reverse was true for suicidal attempts. In each of the study groups, the number and the type of mood spectrum items endorsed, including depressive and manic-hypomanic items and rhythmicity and vegetative symptoms, were associated with increased levels of suicidality. CONCLUSIONS: Our results suggest that the assessment of lifetime rhythmicity and manic-hypomanic features may be clinically useful to identify potential suicide attempters in high-risk groups.     

Agitated "unipolar" major depression: prevalence, phenomenology, and outcome

OBJECTIVE: This study aimed to explore how prevalent agitated "unipolar" major depression is, whether it belongs to the bipolar spectrum, and whether it differs from nonagitated "unipolar" major depression with respect to course and outcome. METHOD: The study was conducted from January 1, 1978, to December 31, 1996. From 361 patients with major depressive disorder, the authors selected those fulfilling Research Diagnostic Criteria for agitated depression. These 94 patients were compared to 94 randomly recruited patients with nonagitated major depressive disorder regarding demographic and historical features, the clinical characteristics of the index episode, the percentage of time spent in an affective episode during a prospective observation period, and the 5-year outcome. Patients with agitated major depressive disorder who had at least 2 manic/hypomanic symptoms in their index episode were compared to the other patients with agitated major depressive disorder with respect to the same variables. RESULTS: Patients with agitated major depressive disorder were more likely to receive antipsychotics during their index episode and spent a higher proportion of time in an affective episode during the observation period compared with patients with nonagitated major depressive disorder. The presence of at least 2 manic/hypomanic symptoms in the index episode was associated with a higher rate of family history of bipolar I disorder, a higher score for suicidal thoughts during the episode, a longer duration of the episode, and a higher affective morbidity during the observation period. CONCLUSION: The diagnosis of agitated major depressive disorder is not uncommon and has significant therapeutic and prognostic implications. The subgroup of patients with at least 2 manic/hypomanic symptoms may suffer from a mixed state and/or belong to the bipolar spectrum.     

Cognitive styles in hypomanic episodes of bipolar I disorder

Lex C, Hautzinger M, Meyer TD. Cognitive styles in hypomanic episodes of bipolar I disorder.
Bipolar Disord 2011: 13: 355–364. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Cognitive vulnerability‐stress theories have recently been extended to bipolar disorder by suggesting that an activation of negative cognition might lead to depressive mood episodes and an activation of positive cognition might lead to manic mood episodes. Alternatively, the manic defense hypothesis claims that hypomanic and manic states are not the opposite of depression but rather contain similar underlying negative cognitions. The objective of this study was to further evaluate these theories by examining the cognitive patterns in bipolar I hypomania. Methods: We compared 15 hypomanic bipolar I disorder patients, 26 remitted bipolar I disorder patients, and 21 healthy individuals in a cross‐sectional study. All participants completed the Dysfunctional Attitude Scale, the Attributional Style Questionnaire, the Emotional Stroop Task, and the Emotional Auditory Verbal Learning Test. Results: Hypomanic bipolar disorder individuals showed cognitions associated with depressive states as well as cognitions associated with manic states. The results for the remitted bipolar disorder patients paralleled those for the control group. Conclusion: Dysfunctional cognition in bipolar disorder seems to relate to state rather than to trait. Hypomania includes depression‐related as well as mania‐related cognitions and can therefore not be considered as the mere opposite of depression.     

Parental expressed emotion and suicidal ideation in adolescents with bipolar disorder

Family environmental variables are risk factors for recurrent courses of mood disorder in adolescents. The present study examined the association between parental expressed emotion (EE)—critical, hostile and/or emotionally overinvolved attitudes toward a concurrently ill offspring—and suicidal ideation in adolescents with bipolar disorder. The sample consisted of 95 adolescents with a bipolar I or II diagnosis who had experienced a mood episode in the prior 3 months. Participants (mean age=15.54 years, S.D.=1.4) were interviewed and completed questionnaires regarding current and past suicidal ideation prior to their participation in a treatment trial. Parents completed five-minute speech samples from which levels of EE were assessed. High EE attitudes in parents were associated with current suicidal ideation in adolescents. This relationship was independent of the effects of age, gender, current depressive or manic symptoms, comorbid diagnoses, bipolar I/II subtypes, family adaptability, and family cohesion. These results underscore the importance of addressing the emotional reactivity of caregivers in treating adolescents with bipolar disorder who have suicidal ideation.     

Mood patterns and classification in bipolar disorder

PURPOSE OF REVIEW: The aim of this review is to highlight recent studies that have questioned the current split of mood disorders into the categories of bipolar and depressive disorders. RECENT FINDINGS: A continuity between bipolar disorders (mainly bipolar II disorder) and major depressive disorder was supported by several lines of evidence: depressive mixed states (mixed depression) and dysphoric (mixed) hypomania (opposite polarity symptoms in the same episode do not support the splitting between mania/hypomania and depression); family history, major depressive disorder is the most common mood disorder in relatives of bipolar probands; lack of points of rarity between the depressive syndromes of bipolar II disorder and major depressive disorder; bipolar features in major depressive disorder; major depressive disorder shifting to bipolar disorders; history of manic/hypomanic symptoms in major depressive disorder and correlation between lifetime manic/hypomanic symptoms and depressive symptoms in major depressive disorder; factors of hypomania inside major depressive disorder; recurrent course of major depressive disorder; depression more common than mania and hypomania in bipolar disorders; trait mood lability in major depressive disorder. SUMMARY: This review of the recent findings on the relationship between bipolar disorders (especially bipolar II disorder) and depressive disorders seems to support a continuity among mood disorders, and runs against the current classification of mood disorders dividing them into independent categories. Further research is needed in the area, in part because of its possible treatment impact.     

Retrospective analysis of psychomotor agitation, hypomanic symptoms, and suicidal ideation in unipolar depression

In bipolar depression, psychomotor agitation is relatively common and often is associated with other noneuphoric hypomanic symptoms and suicidal ideation. Our goal in this retrospective study was to ascertain the co-occurrence of agitation, bipolar features, and suicidal ideation in unipolar disorder. We retrospectively evaluated 314 inpatients with DSM-IV major depressive disorder (MDD) and no other Axis I diagnosis with the National Institutes of Mental Health (NIMH) Life Chart Method and the Operational Criteria for Psychotic Illness (OPCRIT) checklist to ascertain their symptom profiles across all episodes. Univariate and multivariate comparisons were performed between the subgroups with and without psychomotor agitation (OPCRIT item 23> or =1). Agitated depression (AD, a major depressive episode with psychomotor agitation) was present in 19% of the sample. Compared to nonagitated counterparts, patients with AD were older and had lower educational levels and more dysphoria, insomnia, positive thought disorder, and psychotic manifestations. Hypomanic symptoms other than agitation were relatively uncommon (<10%) and more represented in subjects with AD. No significant differences emerged between AD and control groups with respect to most bipolar validators (gender, familiarity, recurrence). Patients with AD had higher levels of suicidal ideation than non-AD controls; however, such a difference was no longer significant after controlling for psychotic features. Excessive self-reproach, early awakening, diurnal changes, poor appetite, and hypomanic symptoms were independently associated with suicidal thoughts in nonpsychotic MDD. Incomplete information on drug treatment, exclusion of patients with Axis I comorbidity, and tertiary care setting were the most important limitations of the study. Although we failed to support the bipolar nature of MDD-AD by common validators, probably because we used a more heterogeneous definition of agitation compared to similar studies, our data confirm the association of agitation with hypomanic symptoms and suicidal thoughts in major depression, and emphasize the complex phenomenology of AD in an inpatient setting.     

Mood episodes and mood disorders: patterns of incidence and conversion in the first three decades of life

Objectives: Significant questions remain regarding both the incidence patterns of mood episodes in adolescents and young adults from the community and the conversion rate from unipolar to bipolar disorders. We addressed these issues by examining data from a prospective longitudinal community study to (i) determine the cumulative incidence of mood episodes and disorders in the first three decades of life; (ii) determine the risk for first onset of depression among individuals with a previous history of hypomanic/manic episodes and vice versa; and (iii) determine the clinical and treatment characteristics of these subjects. Methods: Using the Munich‐Composite International Diagnostic Interview, clinically trained interviewers assessed mood episodes and mental disorders in 3,021 community subjects (aged 14–24 at baseline and 21–34 at third follow‐up). Results: The estimated cumulative incidence at age 33 was 2.9% for manic, 4.0% for hypomanic, 29.4% for major depressive, and 19.0% for minor depressive episodes; overall, 26.0% had unipolar major depression, 4.0% bipolar depression, 1.5% unipolar mania, and 3.6% unipolar hypomania (no major depression). Overall, 0.6% and 1.8% had unipolar mania or hypomania, respectively, without indication for even minor depression. A total of 3.6% of the initial unipolar major depression cases subsequently developed (hypo)mania, with particularly high rates in adolescent onset depression (< 17 years: 9%). A total of 49.6% of the initial unipolar mania cases subsequently developed major depression and 75.6% major or minor depression. While bipolar cases had more adverse clinical and course depression characteristics and higher treatment rates than unipolar depressed cases, bipolar cases did not significantly differ in mania characteristics from unipolar mania cases. Conclusions: Unipolar and bipolar mood disorders are more frequent than previously thought in adolescence and young adulthood, a time period when both the recognition and the intervention rates by the healthcare system are rather low. ‘Conversion’ to bipolar disorder is limited in initial unipolar depression, but common in initial unipolar mania. The remaining unipolar mania cases appear to be significant in terms of clinical and course characteristics and thus require more research attention to replicate these findings.     

Introduction to bipolar disorder and comorbid conditions

Bipolar disorder presents with symptoms that overlap with other, often comorbid, psychiatric disorders, such as borderline personality disorder, substance use disorder, and unipolar depression, and also often co-occurs with medical disorders. Appropriate screening for manic and hypomanic symptoms may lessen the frequency of misdiagnosis of bipolar disorder as unipolar depression, which has serious treatment implications. Further, following the appropriate guidelines for monitoring the physical health of patients with bipolar disorder, especially those treated with mood stabilizers and atypical antipsychotic agents, is important to achieve optimal outcomes.     

Differential item functioning of DSM-IV depressive symptoms in individuals with a history of mania versus those without: an item response theory analysis

Objectives:  Although major depression is characteristic of both bipolar disorder and major depressive disorder, there is disagreement as to whether there are distinct features of depression that differentiate these two conditions. The primary aim of this study was to use methods based in item response theory to evaluate differences in DSM-IV depression symptom endorsement in an epidemiological sample of individuals with a history of mania (i.e., bipolar depression) versus those without (i.e., unipolar depression).
Methods:  Clinical interview data were drawn from a subsample (n = 13,058) of individuals with bipolar or unipolar depression who had participated in the National Epidemiologic Survey on Alcohol and Related Conditions. Using these data, a two-parameter item response model was used to estimate differential item functioning of DSM-IV depressive symptoms between these two groups.
Results:  Differences in severity parameter estimates revealed that suicidal ideation and psychomotor disturbance were more likely to be endorsed across most levels of depression severity in bipolar versus unipolar depression. Differences in discrimination parameter estimates revealed that fatigue was significantly less discriminating in bipolar versus unipolar depression.
Conclusions:  Equating for level of depression symptom severity, study results revealed that suicidal ideation and psychomotor disturbance are endorsed more frequently in bipolar versus unipolar depression. Study data also suggested that fatigue may be endorsed more frequently in unipolar relative to bipolar samples at moderate (versus low or high) levels of depression symptom severity.     

Clinical characteristics of unipolar disorder and bipolar disorder according to the lifetime presence of recurrent panic attacks

Objectives:  The frequent comorbidity of panic and affective disorders has been described in previous studies. However, it is not clear how panic disorder comorbidity in unipolar disorder and bipolar disorder is related to illness course.
Methods:  We compared lifetime clinical characteristics of illness and items of symptomatology in samples of individuals with bipolar I disorder (n = 290) and unipolar disorder (n = 335) according to the lifetime presence of recurrent panic attacks.
Results:  We found significant differences in clinical course of illness characteristics that were shared across the unipolar and bipolar samples according to the lifetime presence of panic attacks. We also found a number of differences according to the presence of panic attacks that may be specific to the diagnostic group.
Conclusions:  Distinguishing patients who have mood disorder diagnoses, especially bipolar I disorder, according to the lifetime presence of panic attacks may not only be of use in clinical practice, but may also be informative for aetiological research, such as molecular genetic studies.     

Bipolar depression in a low-income primary care clinic

OBJECTIVE: This study estimated the proportion of patients attending an urban general medical practice with current major depression and a history of bipolar disorder and compared the history, presentation, and treatment of patients with unipolar and bipolar depression. METHOD: A group of 1,143 patients was assessed with measures of past and current mental health and treatment. Patients were partitioned into bipolar and unipolar groups based on a predefined cutoff on the Mood Disorder Questionnaire. The groups were compared on sociodemographic characteristics, depressive symptoms, comorbid mental disorders, and mental health treatment. RESULTS: Approximately one-quarter of the patients with major depression had lifetime bipolar depression. Patients with unipolar and bipolar depression did not significantly differ on background or health characteristics. Patients with bipolar depression were significantly more likely to report hallucinations, current suicidal ideation, and low self-esteem than patients with unipolar depression but less likely to report disturbed appetite. Patients with bipolar depression were significantly more likely to have an alcohol use disorder and to report inpatient psychiatric care and antipsychotic treatment during the past month than patients with unipolar depression. Nearly one-half of the patients with bipolar depression had taken an antidepressant in the last month, but most were not also being treated with an antipsychotic or mood stabilizer. CONCLUSIONS: Bipolar depression is common in urban general medicine practice. When patients took antidepressants, they seldom received concurrent antimanic medications. Because of the risks of treating bipolar disorder with antidepressant monotherapy, physicians should assess their depressed patients for mania before prescribing antidepressants.     

Depression with racing thoughts

The aim of this study was to explore the clinical and family history correlates of depression with racing thoughts, an understudied phenomenon. Consecutive outpatients with a major depressive episode (MDE, N=336; unipolar subtype, n=130; bipolar-II subtype, n=206) were interviewed with the Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version. Depression with racing thoughts was present in 213 patients (63.3%), a subgroup characterized by significantly more patients with bipolar-II disorder, lower age and lower age of onset, more atypical features, psychomotor agitation, diminished ability to think, suicidal ideation, guilt, leaden paralysis, MDE symptoms, and bipolar-II disorder family history than found in the subgroup without racing thoughts. Logistic regression controlled the diagnosis of bipolar-II disorder (which was associated with most of these variables). Comparisons in the separate bipolar-II and unipolar samples of depression with racing thoughts vs. the variables found significantly different in the total group found that associations with depression with racing thoughts were partly related to bipolar-II and partly related to unipolar diagnoses. Limitations of the study include reliance upon a single interviewer, non-blind cross-sectional assessment and bipolar-II diagnosis based on history. Depression with racing thoughts was very common in depressed outpatients, and was associated with suicidal ideation. Possible differential effects of antidepressants vs. mood stabilizers and antipsychotics are discussed.     

Antidepressant-induced mania in bipolar patients: identification of risk factors

BACKGROUND: Concerns about possible risks of switching to mania associated with antidepressants continue to interfere with the establishment of an optimal treatment paradigm for bipolar depression. METHOD: The response of 44 patients meeting DSM-IV criteria for bipolar disorder to naturalistic treatment was assessed for at least 6 weeks using the Montgomery-Asberg Depression Rating Scale and the Bech-Rafaelson Mania Rating Scale. Patients who experienced a manic or hypomanic switch were compared with those who did not on several variables including age, sex, diagnosis (DSM-IV bipolar I vs. bipolar II), number of previous manic episodes, type of antidepressant therapy used (electroconvulsive therapy vs. antidepressant drugs and, more particularly, selective serotonin reuptake inhibitors [SSRIs]), use and type of mood stabilizers (lithium vs. anticonvulsants), and temperament of the patient, assessed during a normothymic period using the hyperthymia component of the Semi-structured Affective Temperament Interview. RESULTS: Switches to hypomania or mania occurred in 27% of all patients (N = 12) (and in 24% of the subgroup of patients treated with SSRIs [8/33]); 16% (N = 7) experienced manic episodes, and 11% (N = 5) experienced hypomanic episodes. Sex, age, diagnosis (bipolar I vs. bipolar II), and additional treatment did not affect the risk of switching. The incidence of mood switches seemed not to differ between patients receiving an anticonvulsant and those receiving no mood stabilizer. In contrast, mood switches were less frequent in patients receiving lithium (15%, 4/26) than in patients not treated with lithium (44%, 8/18; p = .04). The number of previous manic episodes did not affect the probability of switching, whereas a high score on the hyperthymia component of the Semistructured Affective Temperament Interview was associated with a greater risk of switching (p = .008). CONCLUSION: The frequency of mood switching associated with acute antidepressant therapy may be reduced by lithium treatment. Particular attention should be paid to patients with a hyperthymic temperament, who have a greater risk of mood switches.     

Treatment of seasonal affective disorder: Unipolar versus bipolar differences

Evidence-based treatments for seasonal affective disorder (SAD) include light therapy and pharmacotherapy. We briefly review the diagnosis and treatment of SAD, focusing on clinical and treatment differences between patients with unipolar and bipolar illness. Special considerations for the management of SAD in patients with bipolar disorder are discussed, including the need to monitor for emergence of manic and hypomanic mood switches, to use mood stabilizers in patients with bipolar I disorder, and to be aware of potential interactions between bright light and medications used in treating bipolar disorder. Chronobiological treatments such as bright light therapy may be combined with pharmacotherapy to enhance therapeutic effects, reduce adverse side effects, and optimize treatment in patients with seasonal and nonseasonal bipolar disorder.     

Discriminating primary clinical states in bipolar disorder with a comprehensive symptom scale

Objective: We assessed the spectrum and severity of bipolar symptoms that differentiated bipolar disorder (BD) clinical states, employing the Bipolar Inventory of Symptoms Scale (BISS) which provides a broader item range of traditional depression and mania rating scales. We addressed symptoms differentiating mixed states from depression or mania/hypomania. Method: One hundred and sixteen subjects who met DSM‐IV‐TR criteria for BD and were currently in a depressed, manic/hypomanic, mixed episode, or recovered state were interviewed using the BISS. Results: A subset of manic items differed between mixed episodes and mania/hypomania or depression. Most anxiety items were more severe in mixed subjects. BISS Depression and Manic subscales differentiated episodes from recovered status. The majority of depression and manic symptoms differentiated mood states in the predicted direction. Mixed episodes had overall greater mood severity than manic/hypomanic episodes or depressed episodes. Conclusion: These results indicate that a small subset of symptoms, several of which are absent in DSM‐IV‐TR criteria and traditional rating scales for bipolar studies, aid in distinguishing mixed episodes from depressive or manic/hypomanic episodes. The results also support the utility of a comprehensive BD symptom scale in distinguishing primary clinical states of BD.     

Bipolar depression: phenomenological overview and clinical characteristics

OBJECTIVES: There has been increasing interest in the depressed phase of bipolar disorder (bipolar depression). This paper aims to review the clinical characteristics of bipolar depression, focusing upon its prevalence and phenomenology, related neuropsychological dysfunction, suicidal behaviour, disability and treatment responsiveness. METHODS: Studies on the prevalence of depression in bipolar disorder, the comparative phenomenology of bipolar and unipolar depression, as well as neuropsychology and brain imaging studies, are reviewed. To identify relevant papers, a literature search using MEDLINE and PubMed was undertaken. RESULTS: Depression is the predominant mood disturbance in bipolar disorder, and most frequently presents as subsyndromal, minor or dysthymic depression. Compared with major depressive disorder (unipolar depression), bipolar depression is more likely to manifest with psychosis, melancholic symptoms, psychomotor retardation (in bipolar I disorder) and 'atypical' symptoms. The few neuropsychological studies undertaken indicate greater impairment in bipolar depression. Suicide rates are high in bipolar disorder, with suicidal ideation, suicide attempts and completed suicides all occurring predominantly in the depressed phase of this condition. Furthermore, the depressed phase (even subsyndromal) appears to be the major contributant to the disability related to this condition. CONCLUSIONS: The significance of the depressed phase of bipolar disorder has been markedly underestimated. Bipolar depression accounts for most of the morbidity and mortality due to this illness. Current treatments have significant limitations.     

Hypomanic symptoms predict an increase in narcissistic and histrionic personality disorder features in suicidal young adults

Consistent with the "scar hypothesis", according to which mood depression might impact personality, we examined the effect of unipolar and hypomanic mood disturbances on cluster B (i.e., narcissistic, histrionic, and borderline) personality disorder features. Data from 113 suicidal young adults were utilized, and cross-lagged associations between unipolar and hypomanic mood disturbances and cluster B personality disorder features were examined using manifest-variable structural equation modeling (SEM). Hypomanic symptoms predicted an increase in narcissistic and histrionic personality disorder features over the Time 1-Time 2 period, as well as an increase in narcissistic personality disorder features over the Time 1-Time 3 period. Unipolar depressive symptoms and borderline features were reciprocally and longitudinally associated, albeit at different time periods. The sample distinct features restrict generalization of the findings. An exclusive use of self-report measures might have contributed to shared method variance. Results are consistent with the notion that hypomanic symptoms increase narcissistic personality disorder tendencies.     

Antidepressants and suicidal behavior in bipolar disorder

Patients with bipolar disorder are at very high risk for suicidal ideation, non-fatal suicidal behaviors and suicide and are frequently treated with antidepressants. However, no prospective, randomized, controlled study specifically evaluating an antidepressant on suicidality in bipolar disorder has yet been completed. Indeed, antidepressants have not yet been shown to reduce suicide attempts or suicide in depressive disorders and may increase suicidal behavior in pediatric, and possibly adult, major depressive disorder. Available data on the effects of antidepressants on suicidality in bipolar disorder are mixed. Considerable research indicates that mixed states are associated with suicidality and that antidepressants, especially when administered as monotherapy, are associated with both suicidality and manic conversion. In contrast, growing research suggests that antidepressants administered in combination with mood stabilizers may reduce depressive symptoms in patients with bipolar depression. Further, the only prospective, long-term study evaluating antidepressant treatment and mortality in bipolar disorder, although open-label, found antidepressants and/or antipsychotics in combination with lithium, but not lithium alone, reduced suicide in bipolar and unipolar patients (Angst F, et al. J Affect Disord 2002: 68: 167–181). We conclude that antidepressants may induce suicidality in a subset of persons with depressive (and probably anxious) presentations; that this induction may represent a form of manic conversion, and hence a bipolar phenotype, and that lithium's therapeutic properties may include the ability to prevent antidepressant-induced suicidality.     

Depressive mixed state frequency: age/gender effects

Depressive mixed state (DMX), a major depressive episode (MDE) combined with few manic/hypomanic symptoms, is understudied. Age and gender are important variables in mood disorders. The aim of the present study was to determine whether age and gender had any effect on the frequency of DMX. Consecutive unipolar (n = 144) and bipolar II (n = 218) drug-free MDE out-patients were interviewed with the Structured Clinical Interview for DSM-IV when presenting for MDE treatment. The presence of hypomanic symptoms during the index MDE was assessed systematically. Depressive mixed state was defined as a MDE with three or more concurrent hypomanic symptoms (DMX3), following previous reports. Associations were tested by logistic regression. The results showed that the DMX3 frequency was 43.9% and that it affected more females than males. Frequency decreased with age. The lower frequency with age was related to the lower frequency of bipolar II disorder with age. Bipolar disorder family history of DMX3 patients did not change with age. In conclusion, the frequency of DMX3 was high and related to age. The high frequency of DMX3 supports the clinical usefulness of the definition, as well as observations that antidepressants may worsen its hypomanic symptoms, whereas antipsychotics and mood stabilisers may treat them. A bipolar vulnerability seems to be required for the appearance of DMX3 also in later life.