This study is the first to use a standardized epidemiological case–control design and standardized diagnostic tools (DSM-IV SCID-ANTAS) for studying the association between mood disorders and WD. The results indicated that the lifetime prevalence of DSM-IV bipolar and major depressive disorders is higher in people with WD than in sex- and age-matched controls. The OR was 12.9 for bipolar disorders and 6.7 for major depressive disorders. Notably, there was a difference in prevalence even though (due the random hazard method) the randomized control sample had a particularly high prevalence of bipolar and major depressive disorders than the population from which it was drawn [22
]. For example, MDQ positivity was 3.0% in the database population, but 9.8% in the random control sample. These differences were in part due to the fact that MDQ frequencies are highly influenced by sex, age and, in particular residency, and a high frequency in the control group is likely because of these variables. While the controls had a higher prevalence of MDQ (and BP detected by SCID-ANTAS thus, with another method) than in the population from which it was extracted, cases of WD had higher prevalence of MDQ
and BP-DSMIV at statistically significant level than the controls.
According to the algorithm of DSM-IV MDD diagnosis excludes BP and vice versa, and 11 (47.8%) cases had MDD and 7 (30.4%) had BD. The percentage of cases with depressive disorder is in the same range as previous studies cited in the introduction (30–60% for depression as noted in the review of Akil and Brewer [13
]). In general, the previous case series showed about 60–80% of comorbidity between WD and psychiatric disorders [17
], similar to our data considering that out of 4 cases of Anxiety Disorders, 1 had co-morbidity with MDD and 2 had comorbidity with PD, and only 1 was independent of the mood disorder. Thus, the total psychiatric cases were 19 (82.6%).
The association with bipolar spectrum disorders was confirmed using this more inclusive method, i.e. the MDQ questionnaire, which is capable of including a wider spectrum of bipolar disorders in the “positives” compared to the DSM-IV criteria. The reliability of the diagnosis of Bipolar Disorder using structured tools and the clinical judgment in a clinic is in fact controversial, with some researchers viewing them as reliable [32
] and others considering them as not reliable [20
Our study shows an association between Bipolar Disorder and WD using the strict algorithm of DSM-IV or using the more comprehensive “spectrum” subject detected by MDQ.
Our study showed an association between bipolar disorders and lower quality of life as measured using SF-12. However, the design of the study did not allow us to clarify whether the bipolarity caused the lower quality of life or whether this was a confounding factor due to another factor (as cerebral damage) causing both bipolarity and lower quality of life.
The strong association between bipolar disorders and WD should be interpreted, keeping in mind the modification of the diagnostic criteria and the evolution of the concept of “Bipolar Spectrum Disorders” in the last few decades [35
]. It seems likely that literature reports in the past of “schizophrenia-like psychosis” in WD were due to use of a different definition of schizophrenia compared to current psychiatric diagnostic criteria. In contrast, the association of WD and bipolar disorder may explain the frequent descriptions of “loss of emotional control, hyperactivity, or loss of sexual inhibition, irritability” reported in WD patients [4
]. A high risk of bipolar disorders in WD may also be related to the higher incidence of suicidal behavior, which is present in 4% to 16% of patients with WD across studies [13
Machado and colleagues [16
] suggested that there was a higher association between bipolar disorder and WD than has been reported in the literature. In their case series, which describes the neurological manifestations of 119 patients with WD, the authors observed the psychiatric disorders catatonia, agitation, aggression, delusional thoughts, and mania. The same group, noting that there are few reports in the literature of WD patients with typical bipolar affective disorder [18
], described a patient with WD whose initial manifestation was a manic episode followed by depression. Tremors in the upper limbs appeared one year after the onset of symptoms. The diagnosis of WD was established three years after the first symptoms appeared, based on the neuropsychiatric picture, detection of Kayser-Fleischer rings, and the results of diagnostic tests that indicated chronic liver disease and excess copper. Another case of mania as the first manifestation of WD was described earlier by Kumar Chand et al. [19
] in an 18-year-old boy who presented to a psychiatric clinic with manic syndrome and a high propensity for extrapyramidal symptoms due to a neuroleptic. The author concluded that psychiatrists need to recognize that WD can rarely present as an isolated psychiatric symptom, including mania. Thus, early and severe extrapyramidal symptoms secondary to neuroleptic exposure in an adolescent warrant a detailed evaluation to rule out underlying neuropsychiatric conditions. Our results, which underline the strong association between bipolar disorder and WD, support this idea.
It is interesting to consider these results in light of the pathogenic hypothesis.
Early studies showed that women affected by chronic depression sometimes have copper, zinc, and cesium deficiencies [37
]. Later studies suggest that the presence of depression and other neuropsychiatric symptoms is due to the deposit of copper in the central nervous system [39
]. Eggers et al. [40
] used SPECT to demonstrate a reduction in thalamic-hypothalamic presynaptic dopamine and serotonin transporters due to the accumulation of copper. There was a negative correlation between the density of presynaptic dopamine transporters and the severity of depression as assessed using the Hamilton Rating Scale for Depression.
It was recently hypothesized that trace elements play an important role in the pathogenesis of bipolar disorders by causing neurodegeneration [41
]. Moreover, essential elements like vanadium have been implicated as a causative factor for bipolar mood disorder, while elevated vanadium and molybdenum levels have been reported in serum samples from bipolar mood disorder patients [41
]. This latter study showed, using DSM-IV standard diagnostic criteria and classification into types I, II, and V according to the concept of Young and Klerman, that Na, K, P, Cu, Al, and Mn were elevated significantly in Bipolar I (Mania) (P
0.001). In Bipolar II hypomania, Na, S, Al, and Mn were increased significantly (P
0.02), while in Bipolar II depression, Na, K, Cu, and Al were increased significantly (P
0.001). Finally, in Bipolar V, Na, Mg, P, Cu, and Al were increased significantly (P
0.002) compared to a control group [41
]. A recent study by Gonzales-Estecha and colleagues [21
] found higher serum copper and zinc, blood lead and cadmium, and urine lead, cadmium, and thallium concentrations in patients diagnosed with bipolar disorders compared to a control group.
Increased neuronal oxidative stress (OxS) induces deleterious effects on signal transduction, structural plasticity and cellular resilience, mostly by inducing lipid peroxidation in membranes, proteins and genes [42
]. It has been hypothesized that these pathological processes occur in critical brain circuits that regulate affective functioning, emotions, motoric behavior and pleasure involved in bipolar disorder (BD) [43
The brain is particularly vulnerable to oxidative damage since it contains large amounts of polysaturated fatty acids and possesses low antioxidant capacity [45
]. Several studies have demonstrated altered OxS parameters in the pathophysiology and therapeutics of BD, including changes in the levels of enzymes superoxide dismutase (SOD), catalase (CAT) and thiobarbituric acid reactive substances (TBARS) [46
]. The well-known stabilizing agent Lithium was found to limit the enzyme activity, potentially lowering hydrogen peroxide and hydroxyl radical formation. Similarly, lithium was also shown to reverse increased OxS parameters in BD [43
]. For instance, a decline in lipid peroxidation and an increase in CAT levels were observed in valproate and lithium-treated rats [42
]. Accumulation of copper was shown to increase oxidative stress in bivalve species [49
]. In skeletal muscle of Broilers Under Heat Stress, copper decreases because of dietary Selenium, Vitamin E, and their combination with an increase in antioxidant defense [50
]. In humans accumulation of copper was associated with oxidative stress in allergic asthma patients, and introduction of nutritional supplement therapy accompanies improved oxidative stress, immune response, pulmonary function, and decrease in copper plasma levels [51
]. On the other hands copper levels were elevated in several brain areas in a degenerative disease such as Niemann-Pick C [52
]. Interestingly, Nieman-Pick C disease was specifically indicated to be associated with Bipolar Disorders [53
]. If the results of our study are further confirmed, it will lend significant support to the hypothesis that minerals such as copper play an etiological role in psychiatric disorders, and WD may serve as a pathogenic model for the bipolar disorder.