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Bipolar disorder is characterized by periods of mania and ⁄ or
hypomania, generally interspersed between episodes of depression. The latter
is its predominant mood state conferring the bulk of its associated burden
and risk of suicide and yet diagnostic distinction is still based on the presence
of mania. Like major depression, bipolar disorder is a common psychiatric illness
that has been estimated in previous studies to have a lifetime prevalence of
less than 1%, but recent studies indicate a lifetime prevalence closer to 6.4%
(using criteria that include subsyndromal manic or hypomanic symptoms. However,
it is often undetected with a third of patients waiting more than a decade
after the onset of the illness before seeking help, and even then almost 70%
are repeatedly misdiagnosed. The delay in detection and diagnosis occurs most
commonly because of a misdiagnosis of unipolar depression. This is consistent
with the fact that most patients with
Increasingly, bipolar disorder is viewed as a spectrum that comprises a variety of overlapping syndromes. Patients with bipolar disorder that initially present with depressive episodes and are consequently incorrectly diagnosed as having unipolar disorder are often called “converters”. These patients tend to have a more volatile illness than unipolar patients, with only brief periods of being well. Furthermore, they are more likely to have a history of temperamental instability, a younger age of onset, an unstable interpersonal and occupational history and to have suffered postnatal episode. Thus a patient presenting with these clinical features should signal the possibility of bipolarity. Additional features that are thought to indicate bipolar depression include a family history of bipolar disorder, a premorbid hyperthymic personality, the occurrence of atypical depressive features, psychotic episodes, antidepressant-induced mania ⁄ hypomania, antidepressant wear-off and a lack of response to three or more antidepressant treatment trials. In practice, mixed states form a large subgroup of patients within bipolar disorder. However, despite the potential clinical significance of mixed features in cohorts with predominantly depressive presentations, there is little prevalence data for this subgroup. Like bipolar disorder, mixed states form a spectrum that extends from depressive features within mania to manic features within depression, with admixtures in between. The Diagnostic and Statistical Manual of Disorders, 4th edition (DSMIV), defines mixed states as the concurrent presence of a full manic and depressive syndrome, most likely the least common subtype. Indeed the most common manifestation of mixed states is the presence of a few features of one pole of the illness during the polar opposite phase further highlighting the restrictive nature of DSM-IV criteria.
The emergence of manic features in a dominantly depressive presentation is difficult to diagnose. Here there is an overlap with the concept of agitated depression. Patients with depressive mixed states tend to have low scores on mania rating scales and the hyperactivity they experience tends not to be goal-directed. Clinically meaningful signs and symptoms, such as changes in energy, neurovegetative symptoms and distorted cognitions tend to characterize the manic or hypomanic component of such mixed presentations. Conventional depression rating scales make no attempt to detect and measure these symptoms. Clinically the phenomenological separation of unipolar and bipolar depression should be underpinned by differences across other domains. The neuropsychological profiles for instance overlap considerably with patients in both groups demonstrating memory and executive functioning impairment. However, patients with bipolar depression have impaired sustained attention and poor immediate and delayed verbal recall, greater than that found in unipolar depressed patients. Similarly, preliminary functional neuroimaging studies are differentiating patterns of activation in unipolar and bipolar-depressed patients and across the phases of bipolar disorder. However, most of the findings are as yet tentative and await replication.
Depression rating scales
Firstly, these scales do not evaluate all aspects of depression
and unfortunately some of the aspects omitted are particularly relevant to
the assessment of bipolar disorder. For example the MADRS does not assess worthlessness,
motor retardation or loss of pleasure ⁄ interest. The utility of these
scales in the assessment of bipolar depression is hence diminished, especially
as the construct of depression itself is not that of a homogeneous entity.
Depression is clearly heterogeneous and multifaceted and the factors brought
together to measure and evaluate depression vary from scale
Another limitation is that atypical depressive symptoms such as hyperphagia and hypersomnia are not included in the 17- item HAM-D or the MADRS. These symptoms are disproportionately common in bipolar disorder, and the HAM-D only provides unidirectional measures of sleep and appetite, and is excessively weighted with regard to the former. The pertinence of these symptoms to the diagnosis of atypical depression is in itself a topic of some discussion however, such omissions clearly have implications for delineating depressive subtypes and capturing depressive symptomatology across phenotypes. In patients with bipolar disorder mixed states are relatively common with up to a third meeting criteria for a mixed episode and almost half having a lifetime history of mixed episodes. Of particular interest in the latter study is the finding that HAM-D rating failed to discriminate, both on individual items and total score, patients with a mixed episode from those with depression alone. None of the unipolar rating scales have any items that identify mixed state constructs, despite the frequency with which they occur and their clinical significance. The lack of a recognized instrument that measures depressive mixed episodes may add to their misidentification. Constructs including irritability, lability, increased speech and motor drive and agitation are typical of mixed states and merit concurrent assessment. Clearly, the HAM-D is not a “one size fits all” instrument and its use as such raises serious concerns as regards its symptom sensitivity and phenotype specificity. Items such as hypochondriasis and insight have been criticized in their ability to gauge depression severity and are not symptoms commonly described in bipolar cohorts. Furthermore, the value of rating weight loss in hospitalized patients has been questioned as hospital staff routinely strive to prevent weight loss. Indeed it is weight gain that is more frequently present in atypical depression and is more frequent in bipolar than unipolar individuals. Such contextual elements are also important in the rating of items such as sexual interest, which patients tend to underrate when away from their partners. Despite the introduction of structured guidelines, interrater reliability in the HAM-D has been found to be problematic with raters at different facilities being trained using separate guidelines and versions. Items such as those involving subjective evaluation are inherently difficult to interpret even for trained observers and the scoring of items is somewhat idiosyncratic. For instance, depressed mood rates a maximum of 4 compared to 6 points for sleep disturbance.
Naturally, the robustness of the MADRS in rating overall depression and in particular change in total score is achieved at the expense of specificity for symptoms and its brevity that makes it so easy to administer sacrifices comprehensiveness. In common with the HAM-D the validity of some MADRS items has been questioned, namely sleep disturbance, reduced appetite and suicidal ideation. The MADRS also lacks discriminant validity to the extent that total scores equating to a diagnosis of Major Depression have been described when rating patients with bulimia nervosa. Recently it has been suggested that because the MADRS was developed to be maximally sensitive to change in treatment following the administration of older antidepressants (amytryptiline, clomipramine, mianserin and maprotiline) it cannot be assumed to be as sensitive to changes that occur in response to the newer classes of antidepressants. Clearly this has significant implications for its use in pharmaceutical research especially as there is little consensus with respect to a normative cut-off score for defining remission. Similar problems exist with the HAM-D resulting in different cut-off points being suggested for different disorders including stroke, Parkinson’s Disease and Alzheimer’s Disease. This further compounds the problem of interrater reliability. It seems that Hamilton’s instructions indicating that the scale was devised solely for the assessment of primary depressive illness have been largely forgotten. As awareness of differences between unipolar and bipolar depression increases it highlights the necessity of being aware of the limitations of commonly used assessment tools.
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