CASE PRESENTED BY: Vasco Videira Dias, PsyD, and Sofia Brissos, MD
Neuropsychological assessments of euthymic patients with bipolar disorder suggest that executive function deficits, which include impaired attentional set-shifting, planning, verbal fluency, and response inhibition1,2 persist during remission.3 Despite the beneficial effects of mood stabilizers and atypical antipsychotics on cognition, some patients with bipolar disorder will not return to normative standards of cognitive functioning, with long-term cognitive dysfunction contributing to impairment in social and occupational functioning. Other treatments therefore need to be considered.
The potential utility of cognitive-enhancing agents such as galantamine, a nicotinic and cholinergic agonist, for cognitive dysfunction in bipolar disorder has been examined, but only retrospectively.4 This report describes a case of a positive response to galantamine in a bipolar patient who was prospectively evaluated over the course of 40 weeks using psychiatric and neuropsychological tests.
The patient is a 59-year-old female patient with a 40- year history of bipolar I disorder. She finished 12 years of school and then worked as an air assistant, retiring at age 50. She continued working at home, cooking meals for restaurants. She was evaluated after her most recent hospital admission, which followed a suicide attempt during a depressive episode. The patient described periods of excessive buying, disinhibition, and total insomnia when she would work for several days in a row with almost no sleep. The patient also reported experiencing periods of major depression, with psychomotor slowness and isolation. She has a history of being hospitalized three times, all due to depressive symptomatology. The patient also has a history of frequently being noncompliant with medication and having hypomanic states precipitated by not using medications as prescribed. The patient reported no comorbid drug or alcohol abuse and has never-smoked. Her father was a "temperamental" man, and her mother died of Alzheimer's disease at age 75.
At the baseline evaluation, the patient complained of depressive symptoms, insomnia, memory difficulties, episodes of disorientation, and difficulty completing activities of daily living. The clinical impression was of cognitive difficulties that were out of proportion to the patient's depressive state. There were no neurological abnormalities and investigations for reversible causes of dementia were negative. The electrocardiogram was normal. A non-contrast computed tomography scan of the head revealed mild temporal and occipital atrophy.
The patient reported that she had had adverse reactions to divalproex (alopecia), lithium carbonate (excessive tremor), and selective serotonin reuptake inhibitors (gastric ulcer). She was currently taking mirtazapine 30 mg/day, gabapentin 1,200 mg/day, and lorazepam 2.5 mg/day, and had been compliant with this regimen for approximately 1 year. Lamotrigine 200 mg/day had also recently been added to the treatment regimen. Galantamine was initiated at 4 mg b.i.d. for 2 weeks, increased to 8 mg b.i.d. for the next 5 weeks, and then increased to a final dose of 12 mg b.i.d. (24 mg/day).
The patient's mood was assessed using the Hamilton Rating Scale for Depression (Ham-D)5 and the Young Mania Rating Scale (YMRS).6 The neuropsychological battery consisted of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (subtests: Information, Similarities, and Comprehension), Wechsler Memory Scale (WMS) (subtests: Digit Span and Mental Tracking), Edinburgh Handedness Inventory, Symbol Digit Modalities Test (SDMT), Towers of Hanoi (ToH), Controlled Oral Word Association (COWA), Trail Making Test (TMT A+B), and the Stroop Test Color (STC, Stroop congruent) and the Stroop Text Color-Word (STCW, Stroop incongruent).7 The patient was retested at 5, 20, and 40 weeks after the initiation of galantamine treatment, with all tests repeated at each sitting and under similar circumstances. No new side effects were noted after beginning galantamine treatment.
Improvements became clinically evident 4 to 5 weeks after the patient began galantamine. The patient reported an improvement in mood and in her ability to read; she no longer got lost and was working as before. At baseline, the patient showed the greatest deficits on the tests of verbal executive function (TMT, COWA, and Stroop) and had scores within the normal range on the information and comprehension WAIS sub-tests and on the SDMT and Towers of Hanoi. Two years have elapsed since the patient began galantamine treatment. Galantamine has been continued, because the patient felt that her level of functioning decreased when she once stopped the medication for approximately 3 weeks, and that it improved again after the medication was reintroduced.
Table 1 illustrates the test results at baseline and after 5, 20 and 40 weeks of augmentation treatment with galantamine. Also presented are reference values (mean scores) for the patient's age group and educational status and the impact factor, calculated as the percentage change from baseline to week 40.
Cholinesterase inhibitors may have depressogenic and antimanic properties. Donepezil was found efficacious and safe in the treatment of bipolar disorder in a small open-label pilot study.8 However, the patient had begun lamotrigine shortly before galantamine, which might also have contributed to the improvement in mood.
The pattern of cognitive impairment seen in our patient is similar to that previously described in bipolar patients with cognitive deficits.1,2 The cognitive improvements became evident independent of mood state, which suggests that an improvement in mood is not the only explanation for the observed changes in neuropsychological performance. The most marked improvements observed after galantamine was introduced involved processing speed, divided and sustained attention, response inhibition, and mental control. There was also an improvement in remote memory and verbal abstract reasoning, even though values for these items were within normal limits at baseline. However, the improvement in some tests may have been indirectly caused by an improvement in processing speed rather than being due to an intrinsic improvement of the function measured by the test. The discrete variations found between week 20 and week 40 in some tests might also be due to environmental factors, such as interpersonal and legal problems the patient experienced.
Cholinergic mechanisms have been implicated in the regulation of attention, memory, and processing speed.9 Although the mechanism underlying motor speed enhancement is unknown, the observed benefits may reflect the role of nicotinic receptors in the regulation of basal ganglia function. Alternatively, nicotinic receptors, known to regulate monoaminergic transmitter release and acetylcholinesterase inhibitors, may exert their beneficial effect on motor speed through these mechanisms.10
The neuropsychological battery we used was more likely to detect subtle changes in performance than the more general cognitive measures used in the population of individuals with dementia. Preliminary evidence suggests that the tests we used are differentially sensitive to damage within the human prefrontal cortex.11 The greater improvements seen in tests of verbal function compared with non-verbal tests suggest that galantamine may cause an increased activation of the left dorsolateral prefrontal cortex. The improvement seen in the Stroop Test suggests a meaningful improvement in lateral prefrontal lobe functioning.12
We cannot exclude the hypothesis that this patient could have both disorders (bipolar disorder and Alzheimer's disease), since the patient's mother suffered from Alzheimer's, and that galantamine could have been exclusively treating a recent-onset dementia rather than symptoms associated with the bipolar disorder. However, this seems unlikely. Moreover, the deficit pattern doesn't seem to be attributable to an Alzheimer's-type dementia, since the patient showed an improvement in memory and general executive functions (planning, various attention subtypes, verbal fluency, and information processing speed) that we have not usually seen in patients with Alzheimer's disease after treatment with galantamine or other cholinesterase inhibitors.
The marked improvement in our patient's performance on neuropsychological tests was not likely to be entirely attributable to a practice effect, since these tests are not particularly prone to practice effects.7 Nevertheless, batteries developed for repeated testing, such as the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS),13 which has also been used in characterizing cognitive deficits in bipolar patients,14 would probably be more appropriate for measuring cognitive change in such patients. Conclusions that can be drawn based on the findings presented here are limited since the results are based on only one case and neither patient nor examiners were blind to the treatment being used.
In summary, this patient had cognitive dysfunction, affecting memory, attention, language fluency, executive function, mental tracking, and information processing speed, that did not appear to be accounted for exclusively by depressive symptomatology but was rather probably due to the bipolar disorder disease process and/or evolution. This cognitive dysfunction improved with galantamine, especially at high doses. Galantamine was well tolerated and there appears to be a suggestion of efficacy, specifically for selected cognitive functions unrelated to active mood episodes. Additional work with a larger sample is required to establish this finding with an adequate degree of certainty. Ultimately, such studies may increase our understanding of the contribution of the cholinergic system to the pathophysiology of bipolar disorder.
COMMENTARY by Jack M. Gorman, MD
In recent years, there has been a dramatic shift in the schizophrenia research community from focusing primarily on positive symptoms to giving increased attention to cognitive symptoms. It is widely believed, based on solid experimental data, that cognitive symptoms are likely to be the core enduring symptoms of the disorder. Less attention has been devoted to the possibility that cognitive symptoms are also important in bipolar disorder. The case presented by Drs. Dias and Brissos usefully reminds us that neurocognitive deficits may be an important factor in bipolar disorder as well. Cognitive deficits have been identified in early stages of bipolar disorder, including among adolescents15-17 and new onset patients.18 The latter study, although it involved a relatively small number of patients, established that cognitive deficits can be present during the euthymic stage of the illness, suggesting that such deficits may indeed be a trait rather than a state problem. Very few studies have investigated whether treatment with the cholinesterase inhibitors that are currently in clinical use can improve cognition in patients with bipolar disorder. However, a very small study done almost 30 years ago did show that physostigmine improved IQ scores in patients with bipolar disorder.19 Although one small open-label pilot study showed that donepezil, a cholinesterase inhibitor frequently used in Alzheimer's disease, was effective in patients with treatment-resistant bipolar disorder,8 a placebo-controlled trial failed to find any benefit for donepezil.20 Thus, whether cholinesterase inhibitors work for bipolar disorder in general, or for cognitive deficits in bipolar disorder specifically, remains very much an open question.
A number of interesting issues in this case deserve comment. First, we must wonder how much of the medication, including galantamine, the patient actually took as she is described as "usually non-compliant with medication." In that same vein, her report of no comorbid drug or alcohol abuse may or may not be the case, and it would therefore be helpful if data from a blood or urine drug screen were available. The history states that the patient had "cognitive difficulties out of proportion to the depressive state." More detail on this would be useful. The concept of "pseudo-dementia" is familiar to clinicians and suggests that cognitive difficulties can be quite severe in patients with depression. On the other hand, this patient's depression is characterized by a baseline score of only 19 on the Ham-D, indicating mild to moderate illness. She would not, for example, qualify for most clinical research trials of antidepressant treatments. Hence, with this relatively low level of depression, it may well be the case that her cognitive problems were disproportionate to her mood symptoms. Nevertheless, one possibility is that this patient had cognitive problems as part of her depression that improved with remission of the mood disorder.21,22 She had apparently only been on lamotrigine, at a relatively modest dose, for a short time when she was first evaluated. Lamotrigine has been shown to be effective for depression in patients with bipolar disorder (and most likely for patients with unipolar depression as well). It is unlikely that gabapentin did much to help this patient since this drug has failed to show benefit over placebo in several trials when used either as monotherapy or combined with mood stabilizers in the treatment of bipolar disorder. Hence, it may be that more time on lamotrigine resulted in a lessening of depression and concomitant improvement in cognitive status.
On the other hand, it is not out of the question that the patient has early Alzheimer's disease. She has a family history of Alzheimer's disease, although we do not know at what age her mother first developed symptoms. The finding of "mild temporal and occipital atrophy" is not entirely reassuring. When looking at a CAT scan and its interpretation by a neuroradiologist, a neurologist I know once quipped that the older the radiologist, the more mild the atrophy seems on neuroimaging. The characterization "mild" is always in the eye of the beholder. Alzheimer's disease usually begins with involvement of the enterorhinal cortex, so the location of the atrophy in this patient is anatomically consistent with a diagnosis of early Alzheimer's disease. Obtaining genotyping looking for the ApoE4 allele, although never diagnostic, might be informative. If this allele was found and given the family history of Alzheimer's disease, the patient would then be in a position to consider the range of interventions that some believe may reduce the risk or delay the onset of Alzheimer's, which include exercise, lowering blood pressure and lipids, weight loss, cessation of cigarette smoking (although in this case the patient did not smoke), increased reading, and use of nonsteroidal anti-inflammatory drugs (NSAIDs) and antioxidants.
Another question to be raised is just how much galantamine actually helped. In patients with Alzheimer's disease, cholinesterase inhibitors and memantine slow progression of cognitive decline but do not restore lost function. If galantamine did in fact improve the patient's cognitive functioning, this would suggest it works differently in patients with bipolar disorder than in those with Alzheimer's disease. Looking at Table 1, however, it is not clear how much change in test scores occurred. Some scores, like the SDMT and the information and comprehension sub-tests of the WAIS-R, were normal at baseline. Other scores, such as those on the Towers of Hanoi, COWA, and the congruent (errors) and incongruent (sec) sections of the Stroop, showed very little change between baseline and the assessment at 40 weeks. Improvement was seen in the TMT A, TMT B and comprehension sub-test of the WAIS-R, but these could all be attributed to the improvement in depression.
The data in this case could thus be interpreted in any one of four possible ways:
1. Galantamine improved cognitive deficits that are a trait component of bipolar illness.
2. The patient had cognitive deficits secondary to depression and these improved in concert with remission from depression.
3. The patient has early Alzheimer's disease.
4. The evidence for baseline cognitive impairment and for its response to galantamine is equivocal.
The first conclusion is obviously the most intriguing and provocative and, by suggesting it, Drs. Dias and Brissos have raised an issue that clearly deserves more research attention.
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