Peter H Silverstone, MB, BS, MD, MRCPsych, FRCPC4
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Objective: To determine there are consistent neurobiological differences between patients with bipolar I disorder (BD I) and those with bipolar II disorder (BD II).
Method: We reviewed the literature in areas where the most consistent neurobiological findings have been reported for bipolar disorder, specifically, neuroimaging and brain metabolism. The imaging studies reviewed, examined structure, using magnetic resonance imaging (MRI), and function, using functional MRI, positron emission tomography, and single photon emission computed tomography. We used magnetic resonance spectroscopy to examine brain chemistry. We reviewed those metabolic studies that examined cell calcium, 3-methoxy-4-hydroxyphenylglycol, and protein kinase C.
Results: Some genetic studies suggest that there may be differences between BD II and BD I patients. However, our review of the imaging and metabolic studies identified few studies directly comparing these 2 groups. In those studies, there were few differences, if any, and these were not consistent.
Conclusion: While genetic data suggest there may be differences between BD II patients and BD I patients, the neurobiological findings to date do not provide support. However, this may be owing to the small number of studies directly comparing the 2 groups and also to the fact that those carried out have not been adequately powered to detect possible small true differences. This is an important issue because, if there are no neurobiological differences, it would be anticipated that similar treatments would be similarly effective in both groups. Given the importance of understanding whether there are neurochemical differences between these groups, further research in this area is clearly needed.
(Can J Psychiatry 2004;49:794–801)
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Clinical Implications
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This review suggest that there are no clear-cut differences between bipolar I disorder (BD I) and bipolar II disorder (BD II).
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These disorders may not be easy to clinically distinguish.
Neuroimaging will not help with diagnoses
Limitations
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The literature in this area is limited, with few direct comparator studies between BD I and
BD II.
Most studies reviewed are of small numbers of patients with mixed diagnostic groups.
The effects of medications on any detected changes have not been clarified.
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Key Words: bipolar disorder subtypes, imaging, genetics, metabolism, calcium
Résumé : Les observations neurobiologiques du trouble bipolaire de type
II comparées aux observations du trouble bipolaire de type I
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Bipolar disorder (BD) is characterized by disturbances in mood, cognition, perception, and behaviour (1). Currently, the pathophysiological events underlying these changes are not understood. Bipolar I disorder (BD I) is characterized by a cyclic succession of manic or mixed states with episodes of depression. Dunner and associates further extended the concept of bipolarity to include bipolar II disorder (BD II), which is characterized by an unstable course of alternating depression and hypomania (2). Studies have shown that BD II is more frequent than BD I (3).
Although the neurobiology of BD has yet to be fully elucidated, data from family, twin, and adoption studies indicate a genetic component or a genetically transmitted vulnerability (4). While the lifetime prevalence of BD I is approximately 1% among the general population, familial studies have pointed to a prevalence 10 to 20 times greater among first-degree relatives of bipolar probands (5), with concordance rates as high as 60% reported in monozygotic twins (6). Moreover, families of bipolar probands also have a higher prevalence for other mood disorders and symptoms (7), possibly indicative of a shared genetic basis among diagnostically distinct affective phenotypes. It is unlikely that this genetic vulnerability is due to any single major locus and may involve a more complex, polygenic mode of transmission. Nonetheless, studies examining linkage of BD to specific gene loci have been mixed and inconclusive in their findings (8).
Genetic studies have compared both BD II and BD I patients and suggest that there may be differences between these patient groups. Thus relatives of BD II probands are more likely to suffer from BD II or major depressive disorder (MDD) than they are from BD I (7,9), and in some families, it appears that BD II occurs repeatedly in the absence of BD I (7,11).
If there are genetic differences between the 2 groups, it is possible that there may be underlying neurobiological differences between these 2 subtypes. Thus the current review examines recent studies to determine whether there is neurobiological evidence supporting the suggestion that BD II differs from BD I. This review examines the in vivo neuroimaging findings for BD, including findings from the neuroimaging literature, as well as evidence regarding possible metabolic differences.
Neuroimaging Findings
In vivo neuroimaging modalities include magnetic resonance imaging (MRI), which measures the structure of all brain regions, and magnetic resonance spectroscopy (MRS), which measures the chemical composition of specific brain regions. In addition, 3 techniques allow measurement of the functioning of specific brain regions: positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional MRI (fMRI).
Structural MRI
Structural MRI studies have compared findings within BD patient groups and among BD patients, MDD patients, and healthy control subjects. Reduced prefrontal, frontal, temporal, and limbic volumes have been reported in some recent studies comparing BD patients with healthy control subjects (12,15). It is uncertain whether there are differences between BD and MDD patients (16), though a recent review suggested that abnormalities in ventral and medial prefrontal regions, as well as in the amygdale, might be relatively specific to BD patients (17). Studies comparing regions of the prefrontal, frontal, and temporal cortices, as well as areas of the limbic system and basal ganglia, in both asymptomatic and symptomatic BD I and BD II patients have generally not found structural differences between these 2 BD subtypes (14), irrespective of treatment with lithium (18). Thus there appears little consistent support from studies to date that there are structural differences between the 2 bipolar subtypes.
Functional studies involve measuring indirect changes, which to some extent reflect regional brain activity. These changes are in cerebral blood flow (CBF) and glucose metabolism (measured by PET and SPECT) or in deoxyhemoglobin, usually measured by changes in blood oxygen level–dependent (BOLD) signal changes (measured by fMRI). An important limitation of these studies is that the significant differences in sample size, subject selection, imaging protocol, and image analysis can all limit analysis (19) and interpretative meaning, and only a few directly compare BD I with BD II patients.
Cerebral Blood Flow
Studies examining CBF in BD suggest there may be some differences in CBF during different symptom states. In manic and (or) hypomanic BD patients, compared with healthy control subjects, studies generally found increased CBF in the temporal and limbic regions and reduced CBF in the frontal and prefrontal regions (20,21). Reduced CBF has been reported in most studies examining BD II patients with depression, compared with healthy control subjects, including reduced CBF in temporal, frontal, and limbic regions (22–24). In studies to date, both BD I patients and BD II patients appear to have similar changes in CBF, though there have been no studies directly comparing these groups.
Glucose Metabolism
Most studies to date have found reduced glucose metabolism in many regions in both asymptomatic and symptomatic BD I, BD II, and MDD patients, compared with healthy control subjects. However, this was increased in the limbic system of BD II patients and the prefrontal cortex of BD I patients with mania (25,23). Studies comparing glucose metabolism between BD I and BD II patients have found some differences. Relative to BD II patients, limbic glucose metabolism has been reported to be increased in BD I patients (25), while prefrontal glucose metabolism has been reported to be higher in both manic BD I patients and in patients with depression (25,26). Thus it is possible there are some differences between these groups in glucose metabolism.
Functional MRI
One of the best methods for determining changes in regional brain activation is fMRI, which relies on the delivery of oxygen to actively metabolizing tissue. It has been shown that regional CBF and regional cerebral blood volume (CBV) increase significantly in response to neuronal activation, whereas oxygen consumption does not increase to the same extent. The net result is an overall decrease in the regional deoxyhemoglobin content of the tissue. It is this change in the deoxyhemoglobin concentration in a localized region that allows fMRI techniques to determine changes in brain activation, since it affects the magnetic field and alters the T2 relaxation times. Oxyhemoglobin has an indirect effect in that the influx of increased oxyhemoglobin causes the reduced deoxyhemoglobin concentration; however, it is the change in relative deoxyhemoglobin that affects relaxation times. Less deoxyhemoglobin brings about less signal decay, leading to brighter signal intensity in areas during activation.
It is important to note that the fMRI literature has several problems that taken together make it hard to compare results between studies. This means that the evidence should be considered preliminary or supportive, but not definitive. Almost all studies to date have examined only small numbers of patients, varying in size from 2 to 26 BD patients, with most having between 8 and 14 in each group. Further, the studies vary considerably in the cognitive challenge techniques they use. For this reason, they are difficult to compare, since changing the tasks can significantly alter the findings. While one study may find increased amygdala activation, another may find decreased amygdala activation in response to a different task. These may not necessarily be contradictory findings; both may suggest task-specific alterations in amygdala activation. Different patient groups have been examined, with variable mixes of BD I and BD II patients presenting with differing levels of illness severity, duration, and treatments. Finally, different studies have used different descriptions for the affected areas, with some groups using large area descriptions (such as, “temporal cortex”), while others are more specific regarding the region of interest.
With these limitations, there have been several fMRI studies of BPD patients. While most of the published studies have compared BD I and BD II patients with healthy control subjects, few have directly compared BPD I and BPD II patients. Therefore, any indications of possible differences must be indirect.
Relative to healthy control subjects, studies of regions in the frontal lobes and basal ganglia have consistently reported increased activation in BD I patients with depression (27,28), BD II patients with depression (29,30), and euthymic BD patients (27,31). Increased activation has also been reported in temporal and limbic regions among BD II patients with depression (30), and increased activation in regions of the limbic system and basal ganglia have been reported in BD II patients with hypomania (32). Results in the frontal lobes of BD I patients with mania have been less consistent (33,28). Moreover, prefrontal activation in BD I patients with mania and depression does not appear to differ from that observed in healthy control subjects (33). Thus the evidence supports that, among BD patients, there are likely to be changes in functioning in regions of the frontal and temporal lobes, as well as in the limbic system. There is no evidence of differences between BD I and BD II patients in terms of changes seen in fMRI studies.
Magnetic Resonance Spectroscopy
If differences exist among BD I and BD II patients, it is possible that these could reflect underlying neurochemical differences. Several neurometabolites, including myoinositol, the phosphomonoesters (PME), N-acetylasparate (NAA), and choline, among others, can be detected, identified, and subsequently quantified, using MRS techniques. However, there have been few comparison studies examining possible differences in brain neurometabolite concentrations between BD I and BD II patients.
Myoinositol and Phosphomonoesters
The most widely examined neurochemical hypothesis for BD has been the inositol-depletion hypothesis, which is based on findings that lithium affects the phosphoinositol second messenger system (that is, the PI cycle), in that it decreases myoinositol concentrations in rat brains via inhibition of inositol monophosphatase and inositolpolyphosphate 1-phosphatase (34). Because of this inhibition of the PI cycle by lithium, Berridge and colleagues proposed that lithium decreases myoinositol concentrations (35), which is purported to be the basis for lithium’s mechanism of therapeutic action. This attenuates the usual neuronal responses to receptor activation, since there is less myoinositol with which to produce inositol trisphosphate (IP3). Because there is less IP3 generated, the rise in internal calcium concentrations that would otherwise have occurred is prevented, attenuating cellular responses (35).
Overall, in BD patients with depression, there are abnormalities in brain myoinositol and phosphomonoesters (PME) concentrations in the frontal lobe (36,37), with less support for changes in other regions (36,38). Most studies in euthymic BD patients find no differences in myoinositol concentrations between patients and healthy control subjects (39,40); PME concentrations tend to be reduced (41,42), although the influence of medication is difficult to quantify.
The evidence to date suggests that changes in myoinositol concentration and PI-cycle activity may occur in specific brain regions in BD patients. It could be predicted that if the genetic loading of BD I patients is greater (7,11) and there are differential responses to lithium between the 2 groups (43), then differences in PI-cycle activity could be seen. Unfortunately, there have been no direct comparisons, and present evidence does not allow even an indirect comparison.
N-acetylaspartate
N-acetylaspartate (NAA) is found predominantly in neurons and axons. It is purported to be involved in synthetic processes within these structures and may provide a marker of neuronal integrity (44). In psychiatric disorders, decreased NAA has been proposed to reflect neuronal degeneration (45). It is the most readily MRS-detectable neurometabolite, and as such, it comprises the largest peak, besides water, that is visible in standard magnetic resonance spectra.
While some studies have reported reduced prefrontal and frontal lobe concentrations in asymptomatic and symptomatic BD I and BD II patients (46,47), others have failed to find differences from healthy control subjects (48,40). Only one study has directly compared BD I with BD II patients and found no differences between the 2 subtypes in basal ganglia NAA concentration (49).
Choline
Choline is an important component of cell membranes and is a precursor of acetylcholine. As a result, choline has been implicated in the pathophysiology of mood disorders through several possible mechanisms (50,51).
Compared with healthy control subjects, studies of BD patients have been mixed. There do not appear to be differences in prefrontal (46), temporal (36,52), and limbic (48,53) regions, although effects of medication cannot be ruled out. Some studies have found decreased frontal lobe choline concentrations (36), though not consistently so (54). There may be increased choline concentrations in the basal ganglia of symptomatic BD I and BD II patients (49), with normal levels in euthymic BD patients (55).
Among the studies that have investigated differences in choline concentration between BD subtypes, 3 failed to find differences in regions of the frontal (47) and temporal (52) lobes, as well as the basal ganglia (49), while one study did note greater choline concentration in the basal ganglia of euthymic BD II patients, relative to euthymic BD I patients (56). Overall, the results do not suggest consistent differences in choline concentrations either between healthy control subjects and BD patients or between BD I and BD II patients.
Metabolic Findings
If differences in neurobiology occur between the bipolar subtypes, then it is likely that there would be detectable metabolic differences between them. Three of the most relevant are cell calcium, the primary metabolite of noradrenaline (that is, 3-methoxy-4-hydroxyphenylglycol), and protein kinase C (PKC).
Cellular Calcium
Basal Levels
Intracellular calcium plays a key role in many vital cellular processes, and changes in its concentration are intimately involved in neurotransmitter synthesis and release, acting via intracellular proteins. It is not surprising, then, that altered cellular calcium homeostasis has been implicated in psychiatric disorders (57). It is possible to measure changes in cell calcium concentrations via indicators such as Fura-2 fluorescence, which shift their absorbance wavelengths upon binding to calcium. Several studies have used this technique to measure cellular calcium concentrations in blood cells from BD patients, and several have found abnormally elevated basal levels of intracellular calcium in blood cells from both BD I and BD II patients. Elevated basal calcium levels were found in platelets and lymphoblasts from BD patients in both manic and depressed states (58), as well as in euthymic BD patients treated with lithium (59). Altered basal calcium levels have been reported to normalize following lithium treatment in both BD I and BD II patients (60). Further, studies have consistently reported higher basal calcium levels in BD patients, compared with those in MDD patients (61,62). Conversely, there are several reports of normal cellular calcium levels in BD patients with mania, with depression, and treated with lithium (59,61,63). Thus there have been no consistent findings regarding possible changes in cell calcium in BD patients. There have also been no studies specifically comparing basal values of cell calcium between BD I and BD II patients.
Agonist-Stimulated Levels
More consistently reported is an enhanced calcium response to agonist stimulation in BD. An enhanced calcium response following serotonin administration has been found in platelets from both unmedicated BD patients with mania (64) and BD patients with depression (65). Interestingly, in platelets of euthymic BD patients taking lithium, studies consistently find a normal calcium response to serotonin (65). Thus it is possible that this enhanced response may either normalize with euthymia or with lithium treatment. In those studies that have examined the agonist-stimulated calcium response, it has been consistently reported to be similar between BD I and BD II patients (66,67), with changes in both subtypes being more pronounced than in those reported in MDD patients. Thus there seem to be consistent findings of an increased agonist- stimulated cell calcium response in BD patients and evidence that this differs from findings in MDD patients. However, there are no suggestions that this response differs between BD I and BD II patients.
3-Methoxy-4-hydroxyphenylglycol
In the human brain, the chief metabolite of noradrenaline is considered to be 3-methoxy-4-hydroxyphenylglycol (MHPG) (68). Levels of MHPG in peripheral body fluids (including urine, plasma, and CSF) are believed to be related to levels in the brain (68). Studies that have attempted to determine the activity of the noradrenergic system in patients with depression have largely focused on cumulative measurements of MHPG in urine (69). It is important to note that the relation between peripheral MHPG levels and the functioning of central noradrenergic systems is not well characterized. However, several studies have used these techniques to measure MHPG concentrations in the urine, plasma, and CSF of BD patients and healthy control subjects.
In one of the earliest studies of MHPG in BD patients, Deleon-Jones and associates reported that BD patients with depression secrete less urinary MHPG then do euthymic and manic BD patients (70). In line with this early finding, reduced MHPG levels have been reported in treated (71) and untreated (72) BD patients with depression, relative to MDD patients, and have also been found in untreated BD I patients with depression, compared with BD II patients with depression (73). However, since the patient groups were not the same, this latter finding may indicate differences between mood states rather than between bipolar subtypes. BD I and BD II patients with depression who responded to lithium treatment were found to have higher urinary MPHG levels than were those who did not respond to lithium treatment (73). Conversely, among untreated symptomatic BD I and BD II patients, urinary MHPG concentrations did not differ from healthy control subjects (74,75). This lack of difference has also been reported in studies examining plasma MHPG concentrations (76). In comparisons of plasma MHPG concentrations, there were no differences between BD I and BD II patients (76,77). Findings from CSF measurements of MHPG in euthymic patients found no differences from healthy control subjects in both BD I and BD II patients (77). One postmortem study reported no differences in brain MHPG levels among BD patients and healthy control subjects (78). Thus, overall, the evidence does not consistently support changes in MHPG concentrations in BD and does not support suggestions of any differences between BD I and BD II patients.
Protein Kinase C
PKC is a major intracellular mediator of signals occurring following binding of agonists (such as serotonin and noradrenaline) to their receptors. It is therefore closely involved in regulating both pre- and postsynaptic aspects of neurotransmission. Postmortem studies of brain tissue from BD patients have suggested increased levels of PKC activity (79), though the cause of these changes is uncertain, owing to the confounding effects of medication. In contrast, normal levels of PKC were found in the brains of medicated and unmedicated MDD patients (80). While few in number, postmortem studies to date suggest that PKC may be dysfunctional in BD patients and that the cause and direction of this change is likely different from that of other psychiatric disorders (81). It is unclear from these studies whether changes in PKC activity are a trait of the disorder or an effect of medication; however, these preliminary findings do suggest a potential role for PKC in the neurobiology of BPD.
These postmortem results are supported by findings from platelet studies. In platelets from BD patients with mania, the ratio of active PKC was elevated but appeared to normalize following lithium treatment (82). Another study found that, in euthymic BD patients taking lithium, PKC levels were lowered, compared with healthy control subjects (83). In contrast, unmedicated MDD patients had a higher level of platelet PKC, compared with healthy control subjects (84). Differences in PKC activity have also been reported between BD and MDD patients (85).
Taken together, there is evidence that there may be abnormalities in PKC functioning in BD, patients that may differ from functioning in MDD patients. However, there have been no studies directly comparing BD I and BD II subtypes, so it is not possible to determine whether these differ.
Conclusion
The genetic data suggest possible differences between BD II patients and BD I patients, though the findings are not completely consistent. In contrast, findings from all the neurobiological areas examined in the studies do not support this distinction. Nonetheless, it is also clear that, despite the large number of neurobiological studies of BD patients, there have been relatively few comparing BD II with BD I patients. This suggests 1 of the following 3 possibilities: first, there are no consistent genetic differences between BD II and BD I and therefore no consistent neurobiological differences to detect; second, if there are consistent neurobiological differences between these 2 BD subtypes, they are not being measured by current techniques; and third, there are not enough studies that specifically examine any possible differences, and in addition, the studies that have been carried out comparing the 2 subtypes have been relatively small and may not have been adequately powered to detect small differences between the 2 groups. Of these 3 possibilities, we believe the latter is most likely. Well-powered studies designed to specifically examine this possibility are required. Increased knowledge regarding the possibility of underlying neurobiological differences between BD II and BD I is important to our understanding of these conditions. Any consistent differences detected will influence treatment, outcomes, and etiology for these conditions. On the other hand, if, as appears from the literature available, there are no consistent neurobiological differences, it can be assumed that similar treatments, etiology, and outcome may be expected for these conditions. Thus more research is required to allow more accurate determination of these very important issues.
Funding and Support
This work was supported in part by peer-reviewed grants from the Canadian Institutes of Health Research (CIHR) and the Alberta Heritage Foundation for Medical Research (AHFMR).
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Author(s)
Manuscript received and accepted October 2004.
1 PhD candidate, Department of Psychiatry, University of Alberta, Edmonton, Alberta
2 MSc candidate, Department of Psychiatry, University of Alberta, Edmonton, Alberta
3 Medical Student, Department of Dentistry and Medicine, University of Alberta, Edmonton, Alberta.
4 Professor, Department of Psychiatry and Department of Neuroscience, University of Alberta, Edmonton, Alberta.
Address for correspondence: Dr PH Silverstone, Department of Psychiatry and Department of Neuroscience, University of Alberta, 1E1.07 Mackenzie Center, 8440 112 Street, Edmonton, AB T6G 2B7
e-mail: peter.silverstone@ualberta.ca
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