Chromosome 6
In an older study of an Amish pedigree, Ginns et al. 1996 reported suggestive linkage signals at marker D6S7. Another report of findings related to chromosome 6 comes from Dick et al. 2003 , who conducted genome-wide linkage analyses on 1,152 individuals mostly Caucasian from 250 families in the multisite NIMH Genetics Initiative bipolar survey. Bipolar I disorder and SABP diagnostic criteria were derived from DSM-III-R, and bipolar II and recurrent major depression UPR were diagnosed following...
Physiological Studies
Before direct brain imaging studies were available, bipolar depression was studied using electroencephalograms, evoked potentials, and neu-ropsychological tests. As summarized in Table 2-3, these experiments have produced interesting leads that are consistent with subtle abnormalities in arousal, lateralization, and susceptibility to impulsivity in TABLE 2-2. Specificity of transmitter-related data in bipolar disorder Response to orthostasis, bipolar gt unipolar Distribution of receptors in...
Chromosome 9
The Segurado et al. 2003 study described above produced weak findings for a region on chromosome 9p-q being linked to bipolar disorder. In weighted analyses, this region attained nominal statistical significance under a very narrow disease phenotype. Lithium and valproate may produce some of their effects by action on NMDAR subunit 1 thus, genes that code for the subunits of the NM-DAR may be regarded as candidate genes for bipolar disorder. The NMDAR 1 subunit is coded by a gene on chromosome...
Chromosome 8
In an effort to identify regions of linkage across multiple data sets, Segurado et al. 2003 applied meta-analytic techniques to 18 bipolar genome scans, including some unpublished studies. The authors used a ranking of binned areas within each genome scan to permit a nonpara-metric meta-analysis for a more detailed description of the methods of this study, see Levinson et al. 2003 . Studies were analyzed by using very narrow bipolar I and SABP , narrow adding bipolar II , and broad adding UPR...
Course of Illness
Differences also exist between bipolar and unipolar depression in the course of those conditions Table 1-2 . Kraepelin 1921 viewed the course of illness as the key diagnostic validator that differentiated illnesses. In the case of bipolar disorder, its earlier age at onset differentiates it from unipolar depression, which has a later age at onset range, with a median in the late 20s to early 30s. Follow-up studies of depressed patients with an age at onset below 25 or 30 indicate that such...
Chromosome X
With a 1 1 equal gender distribution, it is counterintuitive to suggest that susceptibility for bipolar illness inheritance may be X-linked. However, there appears to an association whereby disease inherited from the father may be more severe, suggesting a possible contributing effect on the X chromosome. Analyses of the NIMH Genetics Initiative pedigrees waves 1 and 2 153 families support linkage to the X chromosome on Xp22.1, with a heterogeneity LOD of 2.3 Mclnnis et al. 1999 . More...
The Bipolar Spectrum
The above discussion of ways to differentiate bipolar from unipolar depression is also relevant to the general concept of a bipolar spectrum. The notion of a bipolar spectrum begins from the fact that many patients do not meet classical definitions of unipolar depression or bipolar disorder type I or II. As shown in Figure 1-1, many patients appear to demonstrate features of bipolarity such as the depressive phenomenology or the illness course mentioned above, and yet the inability to diagnose...
Overdiagnosis
Despite the evidence that bipolar misdiagnosis has not decreased in the past decade, some clinicians and researchers express concern about possible overdiagnosis of bipolar disorder. This concern is especially voiced in relation to discussion of broadening the definition of the bipolar spectrum. Differential diagnosis of depression Secondary Clear psychosocial stress, clear medical illness FIGURE 1-3. How the polarity-based approach to bipolar disorder in DSM-IV-TR can lead to misdiagnosis....
Studies of Neurotransmitter Function
Neurotransmitter function in bipolar and nonbipolar depressions has been investigated using transmitter metabolite levels in body fluids, receptors on peripheral cells, and receptor function using agonist or neuroendocrine challenge techniques. The studies were guided by a series of simple and heuristically useful hypotheses, summarized in Table 2-1. Despite supporting data for each hypothesis, each also had contradictory findings. At a fairly early stage, it was possible to reject hypotheses...
Chromosome 11
Chromosome 11 has been of interest to investigators since the first indication of linkage in an Old Order Amish kindred. Recent association and linkage studies continue to suggest that chromosome 11 may play a role in bipolar disorder. As part of the National Institute of Mental Health NIMH Genetics Initiative on bipolar disorder, Zandi and colleagues 2003 scanned chromosomes 2, 11, 13, 14, and X in 56 families of 354 individuals. Microsatellite markers were used, and multipoint parametric and...
Chromosome 22
Several groups have reported suggestive to significant linkage to chromosome 22 in bipolar samples, including the NIMH Genetics Initiative samples, the NIMH neurogenetics pedigrees, and Kelsoe et al. 2001 . In Badner and Gershon's 2002 meta-analysis of published whole-genome scans of bipolar disorder and schizophrenia, there was strong evidence for 22q harboring a common susceptibility locus for both disorders. Potash et al. 2003 also reported evidence of linkage in families with psychotic mood...
Phenomenology
At a superficial level, the phenomenology of bipolar depression can be described as twofold past mania or hypomania and current depression. The diagnosis of past manic or hypomanic episodes is where the standard DSM-IV-TR-based approach to bipolar depression begins and ends. This is a necessary but insufficient approach to diagnosing bipolar depression. While the presence of past manic or hypomanic episodes in the depressed patients meets the diagnostic criteria for bipolar depression, the...
The Validators Of Diagnosis
The classic validators of psychiatric diagnoses were first discussed by Eli Robins and Samuel Guze in 1970 in reference to schizophrenia. They identified five validators signs and symptoms, delimitation from other disorders, the follow-up study outcome , family history, and laboratory tests. The basic rationale for having multiple validators for a psychiatric diagnosis is the absence of a gold standard. Whereas in medicine clinicians often argue over a potential diagnosis only to have the...
Clinical Specificity
The basic depressive syndrome consists of the inhibition of goal-directed and reward-related activity, experienced as anhedonia and anxious pessimism. Biological models for depression have focused largely on the effects of uncontrollable stressors. These models have moderate pharmacological validity but lack evidence of specificity for bipolar disorder Machado-Vieira et al. 2004 Nestler et al. 2002 . The core depressive or melancholic syndrome appears essentially identical in unipolar and...
Depressive Phenomenology
The current symptoms of bipolar depression have been thought by many to be similar to those seen in unipolar depression. Yet it appears that there are differences between unipolar and bipolar in the phenom-enological presentation of depression. These likely differences are highlighted in Table 1-1. Atypical depressive symptoms seem to be more common in bipolar than in unipolar depression Agosti and Stewart, 2001 Benazzi 1999, 2001a Ghaemi et al. 2002 Mitchell et al. 2001 . In the National...
DIGFAST A Mnemonic for Mania
DIGFAST is a mnemonic aid for the following concepts Distractibility An inability to maintain one's concentration, as opposed to the decreased concentration of depression, where one is unable to initiate concentration. In mania, this leads to the initiation of multiple tasks, none of which are finished. Insomnia A decreased need for sleep, as opposed to the decreased sleep of depressive insomnia. The patient sleeps less, but has intact or increased energy the next day. Alternatively, there is...