CASE REPORT
A Case of Abulia, Status/Post Right Middle Cerebral Artery Territory Infarct, Treated Successfully With Olanzapine David R. Spiegel, MD and Aparna Chatterjee, BS Abstract: Abulia refers to a pathological deficit of willpower. Disruption of frontal-subcortical-mesolimbic circuits caused by lesions in certain central nervous system structures has been associated with abulia. Given the neurobiological link between the dopaminergic reward system and the psychological phenomenon of motivation, it has been speculated that modulating dopaminergic neurotransmission will potentially alter the clinical presentation of abulia. We present a case of abulia S/P right middle cerebral artery, treated successfully with olanzapine. Key Words: abulia, anterior cingulate cortex circuit, olanzapine, dopamine (Clin Neuropharm 2014;37: 186–189)
A
bulia, akinetic mutism, and apathy are terms that have been used to describe diminished motivation relating to reduced goal-directed behavior (GDB) and slowness, including facial expression, gestures, and speech output. Several investigators proposed that these clinical states are simply a continuum of severity of reduced behavior, with apathy as the least and akinetic mutism as the most severe1,2 (see Table 1 for a clinical description). We describe a patient who developed abulia status/post (S/P) right middle cerebral artery (MCA) infarct and was treated successfully with olanzapine.
CASE HISTORY Our patient is a 62-year-old black man with a history significant for compensated chronic heart failure (ejection fraction of 60%), coronary artery disease s/p coronary artery bypass graft complicated by methicillin-resistant Staphylococcus aureus infection of the sternotomy site, and type II diabetes mellitus (hemoglobin A1c of 7.3%), who presented to our emergency department with a week history of fever and a productive cough, associated with nonradiating sharp retrosternal chest pain. Computed tomography of the chest demonstrated an ascending aortic aneurysm and abscess posterior to sternum. Treated with vancomycin and zosyn and S/P surgical repair of the aneurysm, our patient was intubated for 2 weeks with an uneventful extubation. On the next day, he became minimally responsive with blood pressure of 122/56 mm Hg, heart rate of 110 bpm, temperature of 99.3 °F, and respiratory rate of 24/min. Complete blood count and complete metabolic profile were unremarkable; however, magnetic resonance imaging (MRI) of the head showed an early right MCA infarct, affecting high frontal and parietal cortex. We were consulted, 5 days after right MCA infarct was diagnosed, because of “altered mental status with a refusal to eat.” On Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA. Address correspondence and reprint requests to David R. Spiegel, MD, Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, 825 Fairfax Avenue, Norfolk, VA 23507; E-mail: [email protected] Conflicts of Interest and Source of Funding: Dr Spiegel is on the Speaker's Bureau for Forest Pharmaceuticals. For the remaining author, none were declared. Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/WNF.0000000000000053
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evaluation, our patient presented with minimal eye contact, blunt affect, and paucity of (spontaneous) speech. He was oriented to person, with a Richmond Agitation Scale Score of 0 (alert and calm), Vigilant A (test of sustained attention) was intact, and an Apathy Evaluation Scale, Clinical Version4 (AES-C) score was 63. In short, he screened negative for delirium based on the Confusion Assessment Method-Intensive Care Unit5 and negative for depression based on the Hospital Anxiety and Depression Scale (scored a 5, which is within the reference range)6 but with severe apathy, that is, abulia, based on his AES-C score (see Table 2 for descriptors of abovementioned screen). Our patient was unable to perform a Mini-Mental State Examination. Electroencephalogram showed diffuse background slowing with theta waves at 7 Hz, consistent with mild encephalopathy. We initiated olanzapine of 2.5 mg intramuscular after dinner, which increased to 2.5 mg intramuscular q1600 and at bedtime after 2 days. At this point, our patient began speaking and moving. Within 6 days of treatment, he was alert and oriented 3 and began engaging in spontaneous conversations and movement. After a total of 8 days of treatment, AES-C score was 10, and olanzapine was tapered/discontinued by discharge 3 days later.
DISCUSSION Frontal-subcortical circuits are effector mechanisms that allow the organism to act on its environment and have been reviewed extensively.9 Dysfunction of subcortical-frontal circuits can effect motivation, attention, and emotional response to novel stimuli and executive function.10 Abulia is a disorder of executive frontal lobe function. It is characterized by severe reduction in spontaneous speech and volitional GDB and limited and delayed responses to environmental stimuli in a conscious and awake person and in the absence of complete muscle paralysis and dementia. It is thought to occur from a disconnection of thought and sensory information from mental or physical action. It is not clear whether abulia is a primary motivational difficulty or a disconnection between intention to act and the ability to act. The person with abulia may show an apparent alertness but displays limited initiation and can be slow to initiate movements or speech after requests.11 The neural basis of volition, vis-à-vis a “willed action system,” consists of the dorsolateral prefrontal cortex, anterior cingulate cortex (ACC), supplementary motor area, thalamus, and basal ganglia, with dopamine (DA) as an important neurotransmitter12 (see Fig. 1 for structural/functional connectivity of ACC circuit). Functional perturbation of the ACC is generally agreed to be responsible for the medial frontal-anterior cingulate syndrome and in generation of diminution of motivation, including abulia.1 Our patient's MRI findings were suggestive of a right MCA distribution infarction, with primarily frontal and parietal cortex ischemia (although our patient consented to submit this manuscript, unfortunately, we were unable to provide the actual MRI imaging because we were unable to locate the patient postdischarge to obtain additional consent). According to the literature, and as in our patient's case, abulia has been found in association with subcortical and unilateral/bilateral diffuse frontal lobe lesions.14
Clinical Neuropharmacology • Volume 37, Number 6, November/December 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Clinical Neuropharmacology • Volume 37, Number 6, November/December 2014
A Case of Abulia Treated With Olanzapine
TABLE 1. Disorders of Diminished Motivation3 Apathy
Abulia
Akinetic Mutism
A. Lack of motivation relative to the patient's previous level 1. Difficulty to initiate Postulated definitions: of functioning or the standards of his/her age and culture and sustain purposeful as indicated either by subjective account or observation movements by others. B. Presence for at least 4 weeks during most of the day of 2. Poverty of -The inability to initiate action in a patient who seems at least 1 symptom belonging to each of the following spontaneous alert. 3 domains: movements -Diminished GDB -Diminished goal-directed cognition 3. Reduced spontaneous -State of immobility due to lack of voluntary movement, speech mutism or the articulation of monosyllables, and a vigilant gaze. -Diminished concomitants of GDB 4. Increased response -Total absence of spontaneous behavior and speech, time to queries occurring in the presence of preserved visual tracking. C. Symptoms cause clinically significant distress or 5. Passivity impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to diminished level of 6. Reduced emotional consciousness or the direct physiological effects responsiveness and of a substance. spontaneity 7. Reduced social interaction 8. Reduced interest in usual pastimes
Diagnostically, poststroke depression has been reported to occur in approximately 25% to 50% of stroke patients.15 Its phenomenological overlap with abulia, namely, affective blunting, loss of interest, and psychomotor retardation, can make differential diagnosis difficult.16 The use of structured scales, such as the hospital anxiety and depression scale and/or AES-C, could be helpful in delineating these 2 syndromes/diagnoses. For instance, our patient's hospital anxiety and depression scale score was low, whereas AES-C was markedly elevated, aiding in the more likely diagnosis of abulia rather than depression. Evidence suggests that patients with abulia may respond to treatment with dopaminergic drugs.11 Atypical antipsychotic drugs, all of which are relatively more potent as serotonin type 2A (5-HT) 2A than DA type 2 (D2) receptor antagonists, may increase cortical DA release. The 5-HT1A agonism has been also suggested to contribute to the ability to increase cortical DA release.17 Olanzapine has been demonstrated to produce increases in DA release in rat medial prefrontal cortex (mPFC). The mPFC and ACC are both contained within the medial walls of the frontal
lobe and, for the sake of this article, are structurally grouped together.18 The ability to increase DA release in the mPFC has been shown to inversely correlate with the ratio of the affinity of atypical antipsychotics for serotonin (5-HT)2A and D2 receptors.17 Olanzapine may increase DA release in the mPFC, in part, via 5-HT1A receptor activation, which is produced by simultaneous blockade of 5-HT2A/D2 receptors; however, olanzapine seems to lack significant direct agonism of 5HT1A receptors.17 However, olanzapine has been reported to induce a dose-dependent increase in mPFC DA output equally in wild-type and 5-HT2A receptor knockout mice, whereas the DA increase was absent in 5-HT1A receptor knockout mice.19 The timeline of the effectiveness of olanzapine in our patient was similar to other reports of previous medical management of abulia. We saw moderate improvement in our patient's condition within 2 days of treatment; however, full resolution of symptoms occurred after completing 8 days of treatment. A review of the literature shows that patients treated with bromocriptine showed initial improvement after 3 to 4 days of treatment and marked
TABLE 2. Characteristics of Rating Scales Used in Case Report4,5,7,8 Test
Description
Scoring
Interpretation
AES-C
Consists of 18 items that provide an index of overt The items are rated on a The score for healthy individuals: GDB, goal-related cognitions, and goal-related 4-point Likert scale from 26 (±6) emotional responses. 1 (not at all characteristic) Cutoffs for apathy ≥ 39-41 to 4 (very characteristic). Confusion Assessment Consists of 4 features of delirium/assessing content These 4 features are scored as If both (1) and (2) in “description Method-Intensive of consciousness: present (or not present). column” are present and either Care Unit (3) or (4) in (1) Acute change or fluctuating course “description column” are present of mental status, (2) inattention, (3) → delirium. altered level of consciousness, and (4) disorganized thinking
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began treatment with olanzapine 5 days after the CVA was demonstrated by MRI. Almost complete resolution of abulia symptoms occurred 8 days subsequent to olanzapine administration. Thus, although we cannot rule out that near-symptom resolution S/P 2 weeks after CVA was not spontaneous, given the abovementioned data concerning the natural history of the lesser severe form of abulia, that is, apathy, we posit that olanzapine use seemed likely in accelerating our patient's outcome.3 We propose future research and larger placebo-controlled trials to address the potential benefit of olanzapine in the treatment of abulia. REFERENCES 1. Yang CP, Huang WS, Shih HT, et al. Diminution of basal ganglia dopaminergic function may play an important role in the generation of akinetic mutism in a patient with anterior cerebral arterial infarct. Clin Neurol Neurosurg 2007;109(7):602–606. 2. Hasatak SM, Gorawara PS, Mishra NK. Abulia: no will, no way. J Assoc Physicians India 2005;53:814–818.
FIGURE 1. Willed action system: ACC circuit.1,13 Each cingulate gyrus has complex reciprocal connections with other limbic structures and frontal cortex and seems to provide an interface between the decision-making process of the frontal lobe and the emotional world of the limbic system. Converging evidence suggests the limbic (or ventral) striatopallidum as an “interface between motivation and action” or as the site of “conversion of motivational processes into behavioral output.” Such conceptions are derived from the observation that the limbic striatopallidum receives afferents from the amygdala and from the hippocampal formation and projects to the rest of the basal ganglia mass, involved in initiating and organizing motor acts.
improvement after 10 to 14 days of treatment.20,21 It has also been shown that patients treated with carbidopa/levodopa demonstrated marked improvements after 7 to 14 days of treatment.22 Most of the adverse effects of dopaminergic drugs are dose dependent and are unlikely to occur as abulic patients usually respond to a small dose of a single dopaminergic drug. Similarly, our patient responded to a low dose of olanzapine and demonstrated no side effects.11 Whereas there is a dearth of evidence for the treatment of abulia, anecdotal reports have shown efficacy for the previously discussed DA agonist. In addition, the similar but less severe syndrome of apathy has also been reported to respond to the psychostimulants and acetylcholinesterase inhibitors, especially when apathy is associated with dementia.23 Our reasons for initiating treatment in our patient with olanzapine was 2-fold: first, olanzapine has been reported to be effective in the more severe form of abulia (ie, akinetic mutism)24 and has demonstrated efficacy in apathy in depressed patients25 and those with schizophrenia.26 Second, and on more of a practical level, our patient was not taking medications orally, and olanzapine could be (and was) administered intramuscularly. One limitation in our case report includes that our patient's improvement in abulia could have been due to natural recovery/ longitudinal course of stroke signs and symptoms. To the best of our knowledge, the longitudinal course of abulia S/P cerebrovascular accident (CVA) has not been reported; however, the extent of apathetic behavior S/P CVA has been reported to remain fairly stable during the first year after stroke—only 7% of poststroke apathy patients have shown any sign of improvement during the ensuing year.27 Toward that end, we were consulted and
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3. Cavanna A, Bertero L, Cavanna S, et al. Persistent akinetic mutism after bilateral paramedian thalamic infarction. J Neuropsychiatry Clin Neurosci 2009;9(3):151–155. 4. Marin RS. A neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 1991;(3):243–254. 5. Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med 2001;29(7): 1370–1379. 6. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67(6):361–370. 7. Yang SR, Hua P, Shang XY, et al. Predictors of early post ischemic stroke apathy and depression: a cross-sectional study. BMC Psychiatry 2013;13(1):164. 8. Hsieh CJ, Chu H, Cheng JJ, et al. Validation of apathy evaluation scale and assessment of severity of apathy in Alzheimer's disease. Psychiatry Clin Neurosci 2012;66(3):227–234. 9. Bonelli RM, Cummings JL. Frontal-subcortical circuitry and behavior. Dialogues Clin Neurosci 2007;9(2):141–151. 10. van Reekum R, Stuss DT, Ostrander L. Apathy: why care? J Neuropsychiatry Clin Neurosci 2005;17:7–19. 11. Bakheit AM, Fletcher K, Brennan A. Successful treatment of severe abulia with co-beneldopa. NeuroRehabilitation 2011;29(4): 347–351. 12. Vijayaraghavan L, Krishnamoorthy ES, Brown RG, et al. Abulia: a delphi survey of British neurologists and psychiatrists. Mov Disord 2002;17(5):1052–1057. 13. Habib M. Athymhormia and disorders of motivation in basal ganglia disease. J Neuropsychiatry Clin Neurosci 2004;16(4):509–524. 14. Yamanaka K, Fukuyama H, Kimura J. Abulia from unilateral capsular genu infarction: report of two cases. J Neurol Sci 1996;143(1–2):181–184. 15. Chemerinski E, Levine SR. Neuropsychiatric disorders following vascular brain injury. Mt Sinai J Med 2006;73(7):1006–1014. 16. Hackett ML, Köhler S, O'Brien JT, et al. Neuropsychiatric outcomes of stroke. Lancet Neurol 2014;13(5):525–534. 17. Ichikawa J, Ishii H, Bonaccorso S, et al. 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 2001;76(5):1521–1531. 18. Etkin A, Egner T, Kalisch R. Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn Sci 2011;15(2):85–93.
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Clinical Neuropharmacology • Volume 37, Number 6, November/December 2014
19. Bortolozzi A, Masana M, Díaz-Mataix L, et al. Dopamine release induced by atypical antipsychotics in prefrontal cortex requires 5-HT(1A) receptors but not 5-HT(2A) receptors. Int J Neuropsychopharmacol 2010;13(10):1299–1314. 20. Barrett K. Treating organic abulia with bromocriptine and lisuride: four case studies. J Neurol Neurosurg Psychiatry 1991;54:718–721. 21. Hastak SM, Gorawara PS, Mishra NK. Abulia: no Will, No way. J Assoc Physicians India 2005;53:814–818.
A Case of Abulia Treated With Olanzapine
24. Spiegel DR, Casella DP, Callender DM, et al. Treatment of akinetic mutism with intramuscular olanzapine: a case series. J Neuropsychiatry Clin Neurosci 2008;20(1):93–95. 25. Marangell LB, Johnson CR, Kertz B, et al. Olanzapine in the treatment of apathy in previously depressed participants maintained with selective serotonin reuptake inhibitors: an open-label, flexible-dose study. J Clin Psychiatry 2002;63(5):391–395.
22. Drubach DA, Zelig G, Perez J, et al. Treatment of abulia with carbidopa/levodopa. Neurorehabil Neural Repair 1995;9:151–155.
26. Tollefson GD, Sanger TM. Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine. Am J Psychiatry 1997;154(4):466–474.
23. Paranthaman R, Baldwin RC. Treatment of psychiatric syndromes due to cerebrovascular disease. Int Rev Psychiatry 2006;18(5):453–470.
27. Mayo NE, Fellows LK, Scott SC, et al. A longitudinal view of apathy and its impact after stroke. Stroke 2009;40(10):3299–3307.
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A Case of Abulia, Status/Post Right Middle Cerebral Artery Territory Infarct, Treated Successfully With Olanzapine David R. Spiegel, MD and Aparna Chatterjee, BS Abstract: Abulia refers to a pathological deficit of willpower. Disruption of frontal-subcortical-mesolimbic circuits caused by lesions in certain central nervous system structures has been associated with abulia. Given the neurobiological link between the dopaminergic reward system and the psychological phenomenon of motivation, it has been speculated that modulating dopaminergic neurotransmission will potentially alter the clinical presentation of abulia. We present a case of abulia S/P right middle cerebral artery, treated successfully with olanzapine. Key Words: abulia, anterior cingulate cortex circuit, olanzapine, dopamine (Clin Neuropharm 2014;37: 186–189)
A
bulia, akinetic mutism, and apathy are terms that have been used to describe diminished motivation relating to reduced goal-directed behavior (GDB) and slowness, including facial expression, gestures, and speech output. Several investigators proposed that these clinical states are simply a continuum of severity of reduced behavior, with apathy as the least and akinetic mutism as the most severe1,2 (see Table 1 for a clinical description). We describe a patient who developed abulia status/post (S/P) right middle cerebral artery (MCA) infarct and was treated successfully with olanzapine.
CASE HISTORY Our patient is a 62-year-old black man with a history significant for compensated chronic heart failure (ejection fraction of 60%), coronary artery disease s/p coronary artery bypass graft complicated by methicillin-resistant Staphylococcus aureus infection of the sternotomy site, and type II diabetes mellitus (hemoglobin A1c of 7.3%), who presented to our emergency department with a week history of fever and a productive cough, associated with nonradiating sharp retrosternal chest pain. Computed tomography of the chest demonstrated an ascending aortic aneurysm and abscess posterior to sternum. Treated with vancomycin and zosyn and S/P surgical repair of the aneurysm, our patient was intubated for 2 weeks with an uneventful extubation. On the next day, he became minimally responsive with blood pressure of 122/56 mm Hg, heart rate of 110 bpm, temperature of 99.3 °F, and respiratory rate of 24/min. Complete blood count and complete metabolic profile were unremarkable; however, magnetic resonance imaging (MRI) of the head showed an early right MCA infarct, affecting high frontal and parietal cortex. We were consulted, 5 days after right MCA infarct was diagnosed, because of “altered mental status with a refusal to eat.” On Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA. Address correspondence and reprint requests to David R. Spiegel, MD, Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, 825 Fairfax Avenue, Norfolk, VA 23507; E-mail: [email protected] Conflicts of Interest and Source of Funding: Dr Spiegel is on the Speaker's Bureau for Forest Pharmaceuticals. For the remaining author, none were declared. Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/WNF.0000000000000053
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evaluation, our patient presented with minimal eye contact, blunt affect, and paucity of (spontaneous) speech. He was oriented to person, with a Richmond Agitation Scale Score of 0 (alert and calm), Vigilant A (test of sustained attention) was intact, and an Apathy Evaluation Scale, Clinical Version4 (AES-C) score was 63. In short, he screened negative for delirium based on the Confusion Assessment Method-Intensive Care Unit5 and negative for depression based on the Hospital Anxiety and Depression Scale (scored a 5, which is within the reference range)6 but with severe apathy, that is, abulia, based on his AES-C score (see Table 2 for descriptors of abovementioned screen). Our patient was unable to perform a Mini-Mental State Examination. Electroencephalogram showed diffuse background slowing with theta waves at 7 Hz, consistent with mild encephalopathy. We initiated olanzapine of 2.5 mg intramuscular after dinner, which increased to 2.5 mg intramuscular q1600 and at bedtime after 2 days. At this point, our patient began speaking and moving. Within 6 days of treatment, he was alert and oriented 3 and began engaging in spontaneous conversations and movement. After a total of 8 days of treatment, AES-C score was 10, and olanzapine was tapered/discontinued by discharge 3 days later.
DISCUSSION Frontal-subcortical circuits are effector mechanisms that allow the organism to act on its environment and have been reviewed extensively.9 Dysfunction of subcortical-frontal circuits can effect motivation, attention, and emotional response to novel stimuli and executive function.10 Abulia is a disorder of executive frontal lobe function. It is characterized by severe reduction in spontaneous speech and volitional GDB and limited and delayed responses to environmental stimuli in a conscious and awake person and in the absence of complete muscle paralysis and dementia. It is thought to occur from a disconnection of thought and sensory information from mental or physical action. It is not clear whether abulia is a primary motivational difficulty or a disconnection between intention to act and the ability to act. The person with abulia may show an apparent alertness but displays limited initiation and can be slow to initiate movements or speech after requests.11 The neural basis of volition, vis-à-vis a “willed action system,” consists of the dorsolateral prefrontal cortex, anterior cingulate cortex (ACC), supplementary motor area, thalamus, and basal ganglia, with dopamine (DA) as an important neurotransmitter12 (see Fig. 1 for structural/functional connectivity of ACC circuit). Functional perturbation of the ACC is generally agreed to be responsible for the medial frontal-anterior cingulate syndrome and in generation of diminution of motivation, including abulia.1 Our patient's MRI findings were suggestive of a right MCA distribution infarction, with primarily frontal and parietal cortex ischemia (although our patient consented to submit this manuscript, unfortunately, we were unable to provide the actual MRI imaging because we were unable to locate the patient postdischarge to obtain additional consent). According to the literature, and as in our patient's case, abulia has been found in association with subcortical and unilateral/bilateral diffuse frontal lobe lesions.14
Clinical Neuropharmacology • Volume 37, Number 6, November/December 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Clinical Neuropharmacology • Volume 37, Number 6, November/December 2014
A Case of Abulia Treated With Olanzapine
TABLE 1. Disorders of Diminished Motivation3 Apathy
Abulia
Akinetic Mutism
A. Lack of motivation relative to the patient's previous level 1. Difficulty to initiate Postulated definitions: of functioning or the standards of his/her age and culture and sustain purposeful as indicated either by subjective account or observation movements by others. B. Presence for at least 4 weeks during most of the day of 2. Poverty of -The inability to initiate action in a patient who seems at least 1 symptom belonging to each of the following spontaneous alert. 3 domains: movements -Diminished GDB -Diminished goal-directed cognition 3. Reduced spontaneous -State of immobility due to lack of voluntary movement, speech mutism or the articulation of monosyllables, and a vigilant gaze. -Diminished concomitants of GDB 4. Increased response -Total absence of spontaneous behavior and speech, time to queries occurring in the presence of preserved visual tracking. C. Symptoms cause clinically significant distress or 5. Passivity impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to diminished level of 6. Reduced emotional consciousness or the direct physiological effects responsiveness and of a substance. spontaneity 7. Reduced social interaction 8. Reduced interest in usual pastimes
Diagnostically, poststroke depression has been reported to occur in approximately 25% to 50% of stroke patients.15 Its phenomenological overlap with abulia, namely, affective blunting, loss of interest, and psychomotor retardation, can make differential diagnosis difficult.16 The use of structured scales, such as the hospital anxiety and depression scale and/or AES-C, could be helpful in delineating these 2 syndromes/diagnoses. For instance, our patient's hospital anxiety and depression scale score was low, whereas AES-C was markedly elevated, aiding in the more likely diagnosis of abulia rather than depression. Evidence suggests that patients with abulia may respond to treatment with dopaminergic drugs.11 Atypical antipsychotic drugs, all of which are relatively more potent as serotonin type 2A (5-HT) 2A than DA type 2 (D2) receptor antagonists, may increase cortical DA release. The 5-HT1A agonism has been also suggested to contribute to the ability to increase cortical DA release.17 Olanzapine has been demonstrated to produce increases in DA release in rat medial prefrontal cortex (mPFC). The mPFC and ACC are both contained within the medial walls of the frontal
lobe and, for the sake of this article, are structurally grouped together.18 The ability to increase DA release in the mPFC has been shown to inversely correlate with the ratio of the affinity of atypical antipsychotics for serotonin (5-HT)2A and D2 receptors.17 Olanzapine may increase DA release in the mPFC, in part, via 5-HT1A receptor activation, which is produced by simultaneous blockade of 5-HT2A/D2 receptors; however, olanzapine seems to lack significant direct agonism of 5HT1A receptors.17 However, olanzapine has been reported to induce a dose-dependent increase in mPFC DA output equally in wild-type and 5-HT2A receptor knockout mice, whereas the DA increase was absent in 5-HT1A receptor knockout mice.19 The timeline of the effectiveness of olanzapine in our patient was similar to other reports of previous medical management of abulia. We saw moderate improvement in our patient's condition within 2 days of treatment; however, full resolution of symptoms occurred after completing 8 days of treatment. A review of the literature shows that patients treated with bromocriptine showed initial improvement after 3 to 4 days of treatment and marked
TABLE 2. Characteristics of Rating Scales Used in Case Report4,5,7,8 Test
Description
Scoring
Interpretation
AES-C
Consists of 18 items that provide an index of overt The items are rated on a The score for healthy individuals: GDB, goal-related cognitions, and goal-related 4-point Likert scale from 26 (±6) emotional responses. 1 (not at all characteristic) Cutoffs for apathy ≥ 39-41 to 4 (very characteristic). Confusion Assessment Consists of 4 features of delirium/assessing content These 4 features are scored as If both (1) and (2) in “description Method-Intensive of consciousness: present (or not present). column” are present and either Care Unit (3) or (4) in (1) Acute change or fluctuating course “description column” are present of mental status, (2) inattention, (3) → delirium. altered level of consciousness, and (4) disorganized thinking
© 2014 Lippincott Williams & Wilkins
www.clinicalneuropharm.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
187
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Clinical Neuropharmacology • Volume 37, Number 6, November/December 2014
began treatment with olanzapine 5 days after the CVA was demonstrated by MRI. Almost complete resolution of abulia symptoms occurred 8 days subsequent to olanzapine administration. Thus, although we cannot rule out that near-symptom resolution S/P 2 weeks after CVA was not spontaneous, given the abovementioned data concerning the natural history of the lesser severe form of abulia, that is, apathy, we posit that olanzapine use seemed likely in accelerating our patient's outcome.3 We propose future research and larger placebo-controlled trials to address the potential benefit of olanzapine in the treatment of abulia. REFERENCES 1. Yang CP, Huang WS, Shih HT, et al. Diminution of basal ganglia dopaminergic function may play an important role in the generation of akinetic mutism in a patient with anterior cerebral arterial infarct. Clin Neurol Neurosurg 2007;109(7):602–606. 2. Hasatak SM, Gorawara PS, Mishra NK. Abulia: no will, no way. J Assoc Physicians India 2005;53:814–818.
FIGURE 1. Willed action system: ACC circuit.1,13 Each cingulate gyrus has complex reciprocal connections with other limbic structures and frontal cortex and seems to provide an interface between the decision-making process of the frontal lobe and the emotional world of the limbic system. Converging evidence suggests the limbic (or ventral) striatopallidum as an “interface between motivation and action” or as the site of “conversion of motivational processes into behavioral output.” Such conceptions are derived from the observation that the limbic striatopallidum receives afferents from the amygdala and from the hippocampal formation and projects to the rest of the basal ganglia mass, involved in initiating and organizing motor acts.
improvement after 10 to 14 days of treatment.20,21 It has also been shown that patients treated with carbidopa/levodopa demonstrated marked improvements after 7 to 14 days of treatment.22 Most of the adverse effects of dopaminergic drugs are dose dependent and are unlikely to occur as abulic patients usually respond to a small dose of a single dopaminergic drug. Similarly, our patient responded to a low dose of olanzapine and demonstrated no side effects.11 Whereas there is a dearth of evidence for the treatment of abulia, anecdotal reports have shown efficacy for the previously discussed DA agonist. In addition, the similar but less severe syndrome of apathy has also been reported to respond to the psychostimulants and acetylcholinesterase inhibitors, especially when apathy is associated with dementia.23 Our reasons for initiating treatment in our patient with olanzapine was 2-fold: first, olanzapine has been reported to be effective in the more severe form of abulia (ie, akinetic mutism)24 and has demonstrated efficacy in apathy in depressed patients25 and those with schizophrenia.26 Second, and on more of a practical level, our patient was not taking medications orally, and olanzapine could be (and was) administered intramuscularly. One limitation in our case report includes that our patient's improvement in abulia could have been due to natural recovery/ longitudinal course of stroke signs and symptoms. To the best of our knowledge, the longitudinal course of abulia S/P cerebrovascular accident (CVA) has not been reported; however, the extent of apathetic behavior S/P CVA has been reported to remain fairly stable during the first year after stroke—only 7% of poststroke apathy patients have shown any sign of improvement during the ensuing year.27 Toward that end, we were consulted and
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3. Cavanna A, Bertero L, Cavanna S, et al. Persistent akinetic mutism after bilateral paramedian thalamic infarction. J Neuropsychiatry Clin Neurosci 2009;9(3):151–155. 4. Marin RS. A neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 1991;(3):243–254. 5. Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med 2001;29(7): 1370–1379. 6. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67(6):361–370. 7. Yang SR, Hua P, Shang XY, et al. Predictors of early post ischemic stroke apathy and depression: a cross-sectional study. BMC Psychiatry 2013;13(1):164. 8. Hsieh CJ, Chu H, Cheng JJ, et al. Validation of apathy evaluation scale and assessment of severity of apathy in Alzheimer's disease. Psychiatry Clin Neurosci 2012;66(3):227–234. 9. Bonelli RM, Cummings JL. Frontal-subcortical circuitry and behavior. Dialogues Clin Neurosci 2007;9(2):141–151. 10. van Reekum R, Stuss DT, Ostrander L. Apathy: why care? J Neuropsychiatry Clin Neurosci 2005;17:7–19. 11. Bakheit AM, Fletcher K, Brennan A. Successful treatment of severe abulia with co-beneldopa. NeuroRehabilitation 2011;29(4): 347–351. 12. Vijayaraghavan L, Krishnamoorthy ES, Brown RG, et al. Abulia: a delphi survey of British neurologists and psychiatrists. Mov Disord 2002;17(5):1052–1057. 13. Habib M. Athymhormia and disorders of motivation in basal ganglia disease. J Neuropsychiatry Clin Neurosci 2004;16(4):509–524. 14. Yamanaka K, Fukuyama H, Kimura J. Abulia from unilateral capsular genu infarction: report of two cases. J Neurol Sci 1996;143(1–2):181–184. 15. Chemerinski E, Levine SR. Neuropsychiatric disorders following vascular brain injury. Mt Sinai J Med 2006;73(7):1006–1014. 16. Hackett ML, Köhler S, O'Brien JT, et al. Neuropsychiatric outcomes of stroke. Lancet Neurol 2014;13(5):525–534. 17. Ichikawa J, Ishii H, Bonaccorso S, et al. 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 2001;76(5):1521–1531. 18. Etkin A, Egner T, Kalisch R. Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn Sci 2011;15(2):85–93.
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19. Bortolozzi A, Masana M, Díaz-Mataix L, et al. Dopamine release induced by atypical antipsychotics in prefrontal cortex requires 5-HT(1A) receptors but not 5-HT(2A) receptors. Int J Neuropsychopharmacol 2010;13(10):1299–1314. 20. Barrett K. Treating organic abulia with bromocriptine and lisuride: four case studies. J Neurol Neurosurg Psychiatry 1991;54:718–721. 21. Hastak SM, Gorawara PS, Mishra NK. Abulia: no Will, No way. J Assoc Physicians India 2005;53:814–818.
A Case of Abulia Treated With Olanzapine
24. Spiegel DR, Casella DP, Callender DM, et al. Treatment of akinetic mutism with intramuscular olanzapine: a case series. J Neuropsychiatry Clin Neurosci 2008;20(1):93–95. 25. Marangell LB, Johnson CR, Kertz B, et al. Olanzapine in the treatment of apathy in previously depressed participants maintained with selective serotonin reuptake inhibitors: an open-label, flexible-dose study. J Clin Psychiatry 2002;63(5):391–395.
22. Drubach DA, Zelig G, Perez J, et al. Treatment of abulia with carbidopa/levodopa. Neurorehabil Neural Repair 1995;9:151–155.
26. Tollefson GD, Sanger TM. Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine. Am J Psychiatry 1997;154(4):466–474.
23. Paranthaman R, Baldwin RC. Treatment of psychiatric syndromes due to cerebrovascular disease. Int Rev Psychiatry 2006;18(5):453–470.
27. Mayo NE, Fellows LK, Scott SC, et al. A longitudinal view of apathy and its impact after stroke. Stroke 2009;40(10):3299–3307.
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