Letters to the Editors
functionality (although this is not uniform across all brain regions).10 Ketamine exerts its effects by blocking NMDA receptors and stimulating >-amino-3hydroxy-5-methylisoxazole-4-propionic acid receptors.11,12 It is possible that those individuals with geriatric depression do not have sufficient NMDA receptors present for effective binding by ketamine or that the NMDA receptors that are present have functionally changed. Moreover, age-related sensitivity to anesthetic agents has been reported13 possibly because of age-related changes in NMDA receptors. Ketamine’s use as an anesthetic is well established.14 Such age-related sensitivity may result in a heightened response to ketamine and produce more intense adverse effects than described in younger patients. In our case series, patients were administered ketamine at 0.5 mg/kg of ideal body weight as described in the literature, and it was evident that they experienced subjectively severe dissociative states. They reported being ‘‘in another world,’’ ‘‘floating,’’ and being ‘‘outside my body.’’ Patient A terminated the treatment, and patient C reported being frightened by his experience. Further investigation into this age-related anesthesia sensitivity may help to establish appropriate dosage guidelines for administration in geriatric patients with TRD, as well as reduce potential adverse effects. It is known that late-life and late-onset depression differs from that of early-onset depression in many ways.15,16 The lack of well-designed clinical trials of novel treatments of late-life depression makes it difficult to define who would actually benefit from novel, fast-acting antidepressants like such as ketamine. The likelihood of comorbid medical illness makes treatment of depression more complex, and comorbid anxiety disorders in the elderly can increase treatment resistance,17 further complicating the treatment of this group. It is possible that in 2 of our patients (A and B), their depression and lack of response were the result of a subcortical dementia or a frontotemporal variant dementia, respectively. Revisiting diagnoses that may better account for the lack of treatment response to ketamine in geriatric TRD patients is necessary. Moreover, the aging process in general, as well as the age-related brain sensitivity to anesthetic drugs, makes it more difficult to determine the dose of ketamine that should be used. The patients described in this case series were refractory to multiple treatment modalities as are, we believe, all of the patients described in other ketamine reports.2Y7,9 Given this current state of knowledge, it would be unwise at this time to extrapolate the results seen here to more typical or initial presentations of late-life depression.
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We would argue that more comprehensive studies of ketamine in older adults with TRD are needed to determine whether this treatment is worthwhile in this population. Our experience suggests that if geriatric patients are being considered for ketamine therapy, then they should be given an initial dose of ketamine that is less than 0.5 mg/kg of ideal body weight, with the hope of avoiding difficult adverse effects such as dissociation. Once psychologic safety is established, the dosage could be gradually increased to assess for potential benefit. AUTHOR DISCLOSURE INFORMATION Dr Dale has received speaker’s fees from AstraZeneca. There is no source of funding for this project. The remaining authors declare no conflicts of interest. Sarah M. Szymkowicz, MS Department of Clinical and Health Psychology University of Florida Gainesville, FL
Nora Finnegan, BSN Behavioral Health Services, Lutheran Hospital Cleveland Clinic Foundation Cleveland, OH
Roman M. Dale, MD Behavioral Health Services, Lutheran Hospital Cleveland Clinic Foundation Cleveland, OH [email protected]
REFERENCES 1. Ciraulo DA, Evans JA, Qui WQ, et al. Antidepressant treatment of geriatric depression. In: Ciraulo DA, Shader RI, eds. Pharmacotherapy of Depression. 2nd Edition. New York, NY: Humana Press; 2011:125Y183. 2. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351Y354. 3. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856Y864.
6. aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67:139Y145. 7. Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects
Volume 34, Number 2, April 2014
of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74:250Y256. 8. Murrough JW. Ketamine as a novel antidepressant: from synapse to behavior. Clin Pharmacol Ther. 2012;91:303Y309. 9. Szymkowicz SM, Finnegan N, Dale RM. A 12-month naturalistic observation of three patients receiving repeat intravenous ketamine infusions for their treatment-resistant depression. J Affect Disord. 2013;147:416Y420. 10. Magnusson KR, Brim BL, Das SR. Selective vulnerabilities of N-methyl-D-aspartate (NMDA) receptors during brain aging. Front Aging Neurosci. 2010;2:1Y15. 11. Maeng S, Zarate CA Jr, Du J, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63:349Y352. 12. Koike H, Iijima M, Chaki S. Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res. 2011;224:107Y111. 13. Magnusson KR, Scanga C, Wagner AE, et al. Changes in anesthetic sensitivity and glutamate receptors in the aging canine brain. J Gerontol A Biol Sci Med Sci. 2000;55:B448YB454. 14. Green SM, Li J. Ketamine in adults: what emergency physicians need to know about patient selection and emergence reactions. Acad Emerg Med. 2000;7:278Y281. 15. Sachs-Ericsson N, Corsentino E, Moxley J, et al. A longitudinal study of differences in late- and early-onset geriatric depression: depressive symptoms and psychosocial, cognitive, and neurological functioning. Aging Ment Health. 2013;17:1Y11. 16. Dillon C, Allegri RF, Serrano CM, et al. Late- versus early-onset geriatric depression in a memory research center. Neuropsychiatr Dis Treat. 2009;5:517Y526. 17. Lenze EJ. Comorbidity of depression and anxiety in the elderly. Curr Psychiatry Rep. 2003;5:62Y67.
The Syndrome of Delirious Depression Conception and Case Description
4. Messer MM, Haller IV. Maintenance ketamine treatment produces long-term recovery from depression. Primary Psychiatry. 2010;17:48Y50. 5. Messer M, Haller IV, Larson P, et al. The use of a series of ketamine infusions in two patients with treatment-resistant depression. J Neuropsychiatry Clin Neurosci. 2010;22:442Y444.
&
To the Editors: lthough delirious mania, the cooccurrence of equally prominent maniac and delirious syndromes, is well recognized in the psychiatric literature,1,2 an analogous conceptualization of delirious depression is lacking. Here, we report the case of a patient presenting with a
A
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology
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Volume 34, Number 2, April 2014
combination of clear-cut delirious and depressive syndromes without an underlying identifiable cause, refractory to pharmacotherapy but responsive to electroconvulsive therapy (ECT). On the grounds of a phenomenological and treatment-related analogy to delirious mania, we suggest a classification as delirious depression.
CASE The 63-year-old woman had been experiencing recurrent major depressive episodes for 12 years without signs of bipolarity, delirium, or catatonia. Her mother had been experiencing severe depression and had committed suicide at the age of 73. She was smoking approximately 15 cigarettes per day and did not consume alcohol. Before admission to our ward, the patient had been treated in a different psychiatric clinic with a diagnosis of major depressive episode with psychotic symptoms for nearly 12 months. Polypharmacotherapy up to that point had included numerous antidepressant and antipsychotic medications using a variety of mechanisms of action and augmentation with lithium. The patient presented with a severe depressive syndrome featuring depressed mood, strong perceptions of thoracoabdominal pain lacking a somatic correlate, sleep disturbances, and the mood-congruent delusional idea of imminent death due to cancer. Moreover, she displayed catatonic features such as nonpurposeful motor excitement, verbigerations, mutism, and impulsiveness. Habitual repetition of compulsive, unusually heavy, and inappropriate smoking behavior and disinhibited eating were consistent with frontal disinhibition within the frame of a delirious state as was severely disorganized behavior such as eating coffee beans with a spoon. Cognitive performance, including memory, concentration, and spatiotemporal orientation, was heavily disturbed most of the time, although some lucid moments did occur. We tapered all psychotropic medication in a stepwise manner; only lorazepam was given for severe agitation, leading to just minimal and short-term amelioration thereof. Initially, the patient presented with a Hamilton Depression Rating Scale (HDRS;3) score of 42, a Delirium Rating Scale-Revised-98 (DRS-R-98;4) score of 23, and a MiniYMental State Examination5 score of 17, indicating a severe depressive episode and concomitant delirious state with major cognitive deficits. In the course of the first weeks after admission, the HDRS score was 41, and the DRS-R-98 score rose to 30 (Fig. 1). In face of the delirious syndrome and noticeable signs of frontal disinhibition and weight loss of * 2014 Lippincott Williams & Wilkins
approximately 20 kg during the last year, extensive diagnostic measures were performed (including analysis of autoantibodies, tumor-degenerative markers, and neurodegenerative markers; porphyria diagnostics; cranial magnetic resonance imaging; cerebrospinal fluid diagnostics; repeated electroencephalogram; brain positron emission tomography scan; abdominal magnetic resonance imaging; abdominal and thoracic computed tomography scan; and cerebral angiography). No somatic correlate for the symptoms presented, particularly no further evidence for cerebral infection, limbic encephalitis, dementia, paraneoplastic syndrome, or malignancy, was found. In summary, the patient presented with a picture of severe depression with psychotic symptoms and a distinctive delirious state, lacking a somatic, toxicological, or pharmacologic etiology. Clinical features were in part also reminiscent of a catatonia syndrome. Her state was treatment resistant to high-dose risperidone (up to 8 mg/d) and lorazepam (up to 8 mg/d; body weight, 59 kg; body mass index, 23 kg/m2). Given the equal prominence of depressive and delirious syndromes, we conceptualized our patient’s state as one of the delirious depressions in analogy to the well-known syndrome of delirious mania. Extending this analogy to treatment recommendations,6,7 we initiated ECT, which we had been hesitant to start earlier because of the unknown origin of the delirious state. A fast and sustainable effect on psychopathology was achieved with the administration of 11 sessions of unilateral ECT 3 times per week. Moreover, cognitive functioning moderately improved (Fig. 1). The patient remitted fully from depression and delirium and was discharged 3 weeks after the last ECT session, with a pharmacotherapy consisting of venlafaxine, lithium, risperidone, and agomelatine. After 8 months of clinical stability and adherence to pharmacotherapy,
Letters to the Editors
the patient was readmitted to our clinic with the same symptom constellation. On the grounds of the previous full ECT response, we rapidly initiated this treatment modality and observed remission of the depressive and delirious syndromes after 13 sessions of unilateral ECT. Cognitive functioning improved in a protracted manner, and memory in particular remained somewhat deficient at discharge.
DISCUSSION We present the case of a patient with depressive and delirious syndromes as well as catatonic features existing in tandem. Although the overlap syndrome of depression and delirium has been previously investigated with respect to health outcomes such as institutionalization, functional impairment, and death,8Y10 the literature lacks a nosologic characterization of this complex clinical condition in analogy to that of delirious mania.11 In the case presented here, we suggest to consider the simultaneous cooccurrence of depressive and delirious syndromes fulfilling the diagnostic criteria of a depressive episode and delirium, respectively, indeed as delirious depression. Consistent with this analogy, we initiated ECT, which led to fast symptom remission. Fink and Taylor12 suggested delirious mania to be part of the catatonia spectrum. Our patient also displayed a range of additional catatonia and responded well to ECT when lorazepam was not effective, which further supports a nosologic proximity of delirious mania and its analog of delirious depression. One may wonder whether the symptom constellation under discussion may not be adequately captured by currently existing diagnoses or syndromes. The presentation of complex symptoms makes melancholia13 a viable and important candidate for differential diagnosis, particularly because this concept subsumes mood,
FIGURE 1. Development over the clinical course of the depressive, delirious, and cognitive symptoms measured by the HDRS, the DRS-R-98, and the MiniYMental State Examination. www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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psychomotor, and cognitive impairment. However, the full-fledged prominent delirious symptoms, notably the fluctuating course, disturbed orientation, and qualitatively altered consciousness, would be left unaccounted for. Next, full-blown delirious features also differ from catatonia within a depressive state because of the impressive fluctuation of symptoms such as orientation, cognition, and consciousness. One may want to argue that the delirium merely coincided with a manifest depressive episode, which would entail independent occurrence of both syndromes. However, this is unlikely because the same conjunction of symptoms reappeared in a second episode. Furthermore, common treatments of delirious states, such as lorazepam or risperidone, were not at all effective. Instead, the patient recovered after administration of ECT, which has proven highly effective for delirious mania14,15 and for distinct delirious states.11 In light of the preliminary character of our conceptualization, catatonic depression and depressive syndrome accompanying a delirious state of unidentified origin are certainly important differential diagnoses to consider. In the end, drawing a neat dividing line between depression and organic affective disorders with delirium may not adequately reflect the underlying pathophysiology because there are converging pathomechanisms for depressive and delirious syndromes as well as catatonic symptoms (eg, Mo¨hler,16 Northoff et al,17 and Sanders18). In sum, we suggest considering the severe clinical picture of joint delirious and depressive syndromes with optional catatonic features as delirious depression, particularly in the absence of a somatic or toxicological cause. Our experience recommends fast decision making in favor of ECT when there is no rapid response to pharmacologic interventions, particularly lorazepam. Our proposal is grounded in a pragmatic approach that has proven useful for the diagnostic and therapeutic conceptualization of a variety of clinical states presenting with catatonic features. We are aware of the preliminary character of our suggestion, which requires further independent confirmation. Regardless of future refinements, we hope our proposal will turn out to be beneficial in helping to decide upon an effective therapeutic course of cases of treatment-resistant depressive states with unusual clinical presentations. AUTHOR DISCLOSURE INFORMATION Drs Carolin Hoyer, Laura Kranaster, and Sarah Biedermann contributed equally to this study.
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The authors declare no conflicts of interest. Carolin Hoyer, MD, MPhil Department of Psychiatry and Psychotherapy Central Institute of Mental Health Medical Faculty Mannheim Heidelberg University Mannheim, Germany [email protected]
Laura Kranaster, MD Sarah Biedermann, MD Antje Lewien, MD Suna Su Aksay, MD Andreas Meyer-Lindenberg, MD Alexander Sartorius, MD Department of Psychiatry and Psychotherapy Central Institute of Mental Health Medical Faculty Mannheim Heidelberg University Mannheim, Germany
REFERENCES 1. Fink M. Treating neuroleptic malignant syndrome as catatonia. J Clin Psychopharmacol. 2001;21:121Y122. 2. Karmacharya R, England ML, Ongu¨r D. Delirious mania: clinical features and treatment response. J Affect Disord. 2008;109:312Y316. 3. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56Y62.
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10. Turco R, Torpilliesi T, Bellelli G, et al. The overlap syndrome of depression and delirium in elderly patients: a comment. J Am Geriatr Soc. 2010;58:995Y997. 11. Fink M. Delirious mania. Bipolar Disord. 1999;1:54Y60. 12. Fink M, Taylor MA. The many varieties of catatonia. Eur Arch Psychiatry Clin Neurosci. 2001;251(suppl 1):I8YI13. 13. Fink M, Bolwig TG, Parker G, et al. Melancholia: restoration in psychiatric classification recommended. Acta Psychiatr Scand. 2007;115:89Y92. 14. Danivas V, Behere RV, Varambally S, et al. Electroconvulsive therapy in the treatment of delirious mania: a report of 2 patients. J ECT. 2010;26:278Y279. 15. Nicolato R, Costa-Val A, Souza A, et al. Delirious mania associated with bipolar disease in a Brazilian patient: response to ECT and olanzapine. J Neuropsychiatry Clin Neurosci. 2009;21:477. 16. Mo¨hler H. The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology. 2012;62:42Y53. 17. Northoff G, Steinke R, Czcervenka C, et al. Decreased density of GABA-A receptors in the left sensorimotor cortex in akinetic catatonia: investigation of in vivo benzodiazepine receptor binding. J Neurol Neurosurg Psychiatry. 1999;67:445Y450.
4. Trzepacz PT, Mittal D, Torres R, et al. Validation of the Delirium Rating Scale-revised-98: comparison with the delirium rating scale and the cognitive test for delirium. J Neuropsychiatry Clin Neurosci. 2001;13:229Y242.
18. Sanders RD. Hypothesis for the pathophysiology of delirium: role of baseline brain network connectivity and changes in inhibitory tone. Med Hypotheses. 2011;77: 140Y143.
5. Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental state’’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189Y198.
Inhaled Thyrotropin-Releasing Hormone for Treatment of Neuropsychiatric Disorders
6. American Psychiatric Association. The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training, and Privileging: A Task Force Report of the American Psychiatric Association. 2nd ed. Washington, DC: American Psychiatric Association; 2001. 7. Grunze H, Kasper S, Goodwin G, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders, Part II: Treatment of Mania. World J Biol Psychiatry. 2003;4:5Y13. 8. Givens JL, Jones RN, Inouye SK. The overlap syndrome of depression and delirium in older hospitalized patients. J Am Geriatr Soc. 2009;57:1347Y1353. 9. Givens JL, Sanft TB, Marcantonio ER. Functional recovery after hip fracture: the combined effects of depressive symptoms, cognitive impairment, and delirium. J Am Geriatr Soc. 2008;56:1075Y1079.
To the Editors: hyrotropin-releasing hormone (TRH) displays multiple central nervous systemYmediated actions that have therapeutic potential in treating a wide range of neuropsychiatric disorders. Investigations of central nervous system functions and clinical use of TRH are hindered, however, because of its rapid degradation by circulating peptidases.1 To circumvent this problem, Veronesi et al2 have developed an intranasal nanoparticle drug delivery system. Thyrotropin-releasing hormone could be introduced into the nasal cavity, where the olfactory neurons can collect particles directly. The TRH incorporated into biodegradable nanoparticles would dissolve at a controlled rate designed to deliver appropriate doses of the drug to the brain over time. Another approach would be to deliver TRH powder by inhalation. This is
T
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
functionality (although this is not uniform across all brain regions).10 Ketamine exerts its effects by blocking NMDA receptors and stimulating >-amino-3hydroxy-5-methylisoxazole-4-propionic acid receptors.11,12 It is possible that those individuals with geriatric depression do not have sufficient NMDA receptors present for effective binding by ketamine or that the NMDA receptors that are present have functionally changed. Moreover, age-related sensitivity to anesthetic agents has been reported13 possibly because of age-related changes in NMDA receptors. Ketamine’s use as an anesthetic is well established.14 Such age-related sensitivity may result in a heightened response to ketamine and produce more intense adverse effects than described in younger patients. In our case series, patients were administered ketamine at 0.5 mg/kg of ideal body weight as described in the literature, and it was evident that they experienced subjectively severe dissociative states. They reported being ‘‘in another world,’’ ‘‘floating,’’ and being ‘‘outside my body.’’ Patient A terminated the treatment, and patient C reported being frightened by his experience. Further investigation into this age-related anesthesia sensitivity may help to establish appropriate dosage guidelines for administration in geriatric patients with TRD, as well as reduce potential adverse effects. It is known that late-life and late-onset depression differs from that of early-onset depression in many ways.15,16 The lack of well-designed clinical trials of novel treatments of late-life depression makes it difficult to define who would actually benefit from novel, fast-acting antidepressants like such as ketamine. The likelihood of comorbid medical illness makes treatment of depression more complex, and comorbid anxiety disorders in the elderly can increase treatment resistance,17 further complicating the treatment of this group. It is possible that in 2 of our patients (A and B), their depression and lack of response were the result of a subcortical dementia or a frontotemporal variant dementia, respectively. Revisiting diagnoses that may better account for the lack of treatment response to ketamine in geriatric TRD patients is necessary. Moreover, the aging process in general, as well as the age-related brain sensitivity to anesthetic drugs, makes it more difficult to determine the dose of ketamine that should be used. The patients described in this case series were refractory to multiple treatment modalities as are, we believe, all of the patients described in other ketamine reports.2Y7,9 Given this current state of knowledge, it would be unwise at this time to extrapolate the results seen here to more typical or initial presentations of late-life depression.
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We would argue that more comprehensive studies of ketamine in older adults with TRD are needed to determine whether this treatment is worthwhile in this population. Our experience suggests that if geriatric patients are being considered for ketamine therapy, then they should be given an initial dose of ketamine that is less than 0.5 mg/kg of ideal body weight, with the hope of avoiding difficult adverse effects such as dissociation. Once psychologic safety is established, the dosage could be gradually increased to assess for potential benefit. AUTHOR DISCLOSURE INFORMATION Dr Dale has received speaker’s fees from AstraZeneca. There is no source of funding for this project. The remaining authors declare no conflicts of interest. Sarah M. Szymkowicz, MS Department of Clinical and Health Psychology University of Florida Gainesville, FL
Nora Finnegan, BSN Behavioral Health Services, Lutheran Hospital Cleveland Clinic Foundation Cleveland, OH
Roman M. Dale, MD Behavioral Health Services, Lutheran Hospital Cleveland Clinic Foundation Cleveland, OH [email protected]
REFERENCES 1. Ciraulo DA, Evans JA, Qui WQ, et al. Antidepressant treatment of geriatric depression. In: Ciraulo DA, Shader RI, eds. Pharmacotherapy of Depression. 2nd Edition. New York, NY: Humana Press; 2011:125Y183. 2. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351Y354. 3. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856Y864.
6. aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67:139Y145. 7. Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects
Volume 34, Number 2, April 2014
of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74:250Y256. 8. Murrough JW. Ketamine as a novel antidepressant: from synapse to behavior. Clin Pharmacol Ther. 2012;91:303Y309. 9. Szymkowicz SM, Finnegan N, Dale RM. A 12-month naturalistic observation of three patients receiving repeat intravenous ketamine infusions for their treatment-resistant depression. J Affect Disord. 2013;147:416Y420. 10. Magnusson KR, Brim BL, Das SR. Selective vulnerabilities of N-methyl-D-aspartate (NMDA) receptors during brain aging. Front Aging Neurosci. 2010;2:1Y15. 11. Maeng S, Zarate CA Jr, Du J, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63:349Y352. 12. Koike H, Iijima M, Chaki S. Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res. 2011;224:107Y111. 13. Magnusson KR, Scanga C, Wagner AE, et al. Changes in anesthetic sensitivity and glutamate receptors in the aging canine brain. J Gerontol A Biol Sci Med Sci. 2000;55:B448YB454. 14. Green SM, Li J. Ketamine in adults: what emergency physicians need to know about patient selection and emergence reactions. Acad Emerg Med. 2000;7:278Y281. 15. Sachs-Ericsson N, Corsentino E, Moxley J, et al. A longitudinal study of differences in late- and early-onset geriatric depression: depressive symptoms and psychosocial, cognitive, and neurological functioning. Aging Ment Health. 2013;17:1Y11. 16. Dillon C, Allegri RF, Serrano CM, et al. Late- versus early-onset geriatric depression in a memory research center. Neuropsychiatr Dis Treat. 2009;5:517Y526. 17. Lenze EJ. Comorbidity of depression and anxiety in the elderly. Curr Psychiatry Rep. 2003;5:62Y67.
The Syndrome of Delirious Depression Conception and Case Description
4. Messer MM, Haller IV. Maintenance ketamine treatment produces long-term recovery from depression. Primary Psychiatry. 2010;17:48Y50. 5. Messer M, Haller IV, Larson P, et al. The use of a series of ketamine infusions in two patients with treatment-resistant depression. J Neuropsychiatry Clin Neurosci. 2010;22:442Y444.
&
To the Editors: lthough delirious mania, the cooccurrence of equally prominent maniac and delirious syndromes, is well recognized in the psychiatric literature,1,2 an analogous conceptualization of delirious depression is lacking. Here, we report the case of a patient presenting with a
A
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology
&
Volume 34, Number 2, April 2014
combination of clear-cut delirious and depressive syndromes without an underlying identifiable cause, refractory to pharmacotherapy but responsive to electroconvulsive therapy (ECT). On the grounds of a phenomenological and treatment-related analogy to delirious mania, we suggest a classification as delirious depression.
CASE The 63-year-old woman had been experiencing recurrent major depressive episodes for 12 years without signs of bipolarity, delirium, or catatonia. Her mother had been experiencing severe depression and had committed suicide at the age of 73. She was smoking approximately 15 cigarettes per day and did not consume alcohol. Before admission to our ward, the patient had been treated in a different psychiatric clinic with a diagnosis of major depressive episode with psychotic symptoms for nearly 12 months. Polypharmacotherapy up to that point had included numerous antidepressant and antipsychotic medications using a variety of mechanisms of action and augmentation with lithium. The patient presented with a severe depressive syndrome featuring depressed mood, strong perceptions of thoracoabdominal pain lacking a somatic correlate, sleep disturbances, and the mood-congruent delusional idea of imminent death due to cancer. Moreover, she displayed catatonic features such as nonpurposeful motor excitement, verbigerations, mutism, and impulsiveness. Habitual repetition of compulsive, unusually heavy, and inappropriate smoking behavior and disinhibited eating were consistent with frontal disinhibition within the frame of a delirious state as was severely disorganized behavior such as eating coffee beans with a spoon. Cognitive performance, including memory, concentration, and spatiotemporal orientation, was heavily disturbed most of the time, although some lucid moments did occur. We tapered all psychotropic medication in a stepwise manner; only lorazepam was given for severe agitation, leading to just minimal and short-term amelioration thereof. Initially, the patient presented with a Hamilton Depression Rating Scale (HDRS;3) score of 42, a Delirium Rating Scale-Revised-98 (DRS-R-98;4) score of 23, and a MiniYMental State Examination5 score of 17, indicating a severe depressive episode and concomitant delirious state with major cognitive deficits. In the course of the first weeks after admission, the HDRS score was 41, and the DRS-R-98 score rose to 30 (Fig. 1). In face of the delirious syndrome and noticeable signs of frontal disinhibition and weight loss of * 2014 Lippincott Williams & Wilkins
approximately 20 kg during the last year, extensive diagnostic measures were performed (including analysis of autoantibodies, tumor-degenerative markers, and neurodegenerative markers; porphyria diagnostics; cranial magnetic resonance imaging; cerebrospinal fluid diagnostics; repeated electroencephalogram; brain positron emission tomography scan; abdominal magnetic resonance imaging; abdominal and thoracic computed tomography scan; and cerebral angiography). No somatic correlate for the symptoms presented, particularly no further evidence for cerebral infection, limbic encephalitis, dementia, paraneoplastic syndrome, or malignancy, was found. In summary, the patient presented with a picture of severe depression with psychotic symptoms and a distinctive delirious state, lacking a somatic, toxicological, or pharmacologic etiology. Clinical features were in part also reminiscent of a catatonia syndrome. Her state was treatment resistant to high-dose risperidone (up to 8 mg/d) and lorazepam (up to 8 mg/d; body weight, 59 kg; body mass index, 23 kg/m2). Given the equal prominence of depressive and delirious syndromes, we conceptualized our patient’s state as one of the delirious depressions in analogy to the well-known syndrome of delirious mania. Extending this analogy to treatment recommendations,6,7 we initiated ECT, which we had been hesitant to start earlier because of the unknown origin of the delirious state. A fast and sustainable effect on psychopathology was achieved with the administration of 11 sessions of unilateral ECT 3 times per week. Moreover, cognitive functioning moderately improved (Fig. 1). The patient remitted fully from depression and delirium and was discharged 3 weeks after the last ECT session, with a pharmacotherapy consisting of venlafaxine, lithium, risperidone, and agomelatine. After 8 months of clinical stability and adherence to pharmacotherapy,
Letters to the Editors
the patient was readmitted to our clinic with the same symptom constellation. On the grounds of the previous full ECT response, we rapidly initiated this treatment modality and observed remission of the depressive and delirious syndromes after 13 sessions of unilateral ECT. Cognitive functioning improved in a protracted manner, and memory in particular remained somewhat deficient at discharge.
DISCUSSION We present the case of a patient with depressive and delirious syndromes as well as catatonic features existing in tandem. Although the overlap syndrome of depression and delirium has been previously investigated with respect to health outcomes such as institutionalization, functional impairment, and death,8Y10 the literature lacks a nosologic characterization of this complex clinical condition in analogy to that of delirious mania.11 In the case presented here, we suggest to consider the simultaneous cooccurrence of depressive and delirious syndromes fulfilling the diagnostic criteria of a depressive episode and delirium, respectively, indeed as delirious depression. Consistent with this analogy, we initiated ECT, which led to fast symptom remission. Fink and Taylor12 suggested delirious mania to be part of the catatonia spectrum. Our patient also displayed a range of additional catatonia and responded well to ECT when lorazepam was not effective, which further supports a nosologic proximity of delirious mania and its analog of delirious depression. One may wonder whether the symptom constellation under discussion may not be adequately captured by currently existing diagnoses or syndromes. The presentation of complex symptoms makes melancholia13 a viable and important candidate for differential diagnosis, particularly because this concept subsumes mood,
FIGURE 1. Development over the clinical course of the depressive, delirious, and cognitive symptoms measured by the HDRS, the DRS-R-98, and the MiniYMental State Examination. www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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psychomotor, and cognitive impairment. However, the full-fledged prominent delirious symptoms, notably the fluctuating course, disturbed orientation, and qualitatively altered consciousness, would be left unaccounted for. Next, full-blown delirious features also differ from catatonia within a depressive state because of the impressive fluctuation of symptoms such as orientation, cognition, and consciousness. One may want to argue that the delirium merely coincided with a manifest depressive episode, which would entail independent occurrence of both syndromes. However, this is unlikely because the same conjunction of symptoms reappeared in a second episode. Furthermore, common treatments of delirious states, such as lorazepam or risperidone, were not at all effective. Instead, the patient recovered after administration of ECT, which has proven highly effective for delirious mania14,15 and for distinct delirious states.11 In light of the preliminary character of our conceptualization, catatonic depression and depressive syndrome accompanying a delirious state of unidentified origin are certainly important differential diagnoses to consider. In the end, drawing a neat dividing line between depression and organic affective disorders with delirium may not adequately reflect the underlying pathophysiology because there are converging pathomechanisms for depressive and delirious syndromes as well as catatonic symptoms (eg, Mo¨hler,16 Northoff et al,17 and Sanders18). In sum, we suggest considering the severe clinical picture of joint delirious and depressive syndromes with optional catatonic features as delirious depression, particularly in the absence of a somatic or toxicological cause. Our experience recommends fast decision making in favor of ECT when there is no rapid response to pharmacologic interventions, particularly lorazepam. Our proposal is grounded in a pragmatic approach that has proven useful for the diagnostic and therapeutic conceptualization of a variety of clinical states presenting with catatonic features. We are aware of the preliminary character of our suggestion, which requires further independent confirmation. Regardless of future refinements, we hope our proposal will turn out to be beneficial in helping to decide upon an effective therapeutic course of cases of treatment-resistant depressive states with unusual clinical presentations. AUTHOR DISCLOSURE INFORMATION Drs Carolin Hoyer, Laura Kranaster, and Sarah Biedermann contributed equally to this study.
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The authors declare no conflicts of interest. Carolin Hoyer, MD, MPhil Department of Psychiatry and Psychotherapy Central Institute of Mental Health Medical Faculty Mannheim Heidelberg University Mannheim, Germany [email protected]
Laura Kranaster, MD Sarah Biedermann, MD Antje Lewien, MD Suna Su Aksay, MD Andreas Meyer-Lindenberg, MD Alexander Sartorius, MD Department of Psychiatry and Psychotherapy Central Institute of Mental Health Medical Faculty Mannheim Heidelberg University Mannheim, Germany
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10. Turco R, Torpilliesi T, Bellelli G, et al. The overlap syndrome of depression and delirium in elderly patients: a comment. J Am Geriatr Soc. 2010;58:995Y997. 11. Fink M. Delirious mania. Bipolar Disord. 1999;1:54Y60. 12. Fink M, Taylor MA. The many varieties of catatonia. Eur Arch Psychiatry Clin Neurosci. 2001;251(suppl 1):I8YI13. 13. Fink M, Bolwig TG, Parker G, et al. Melancholia: restoration in psychiatric classification recommended. Acta Psychiatr Scand. 2007;115:89Y92. 14. Danivas V, Behere RV, Varambally S, et al. Electroconvulsive therapy in the treatment of delirious mania: a report of 2 patients. J ECT. 2010;26:278Y279. 15. Nicolato R, Costa-Val A, Souza A, et al. Delirious mania associated with bipolar disease in a Brazilian patient: response to ECT and olanzapine. J Neuropsychiatry Clin Neurosci. 2009;21:477. 16. Mo¨hler H. The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology. 2012;62:42Y53. 17. Northoff G, Steinke R, Czcervenka C, et al. Decreased density of GABA-A receptors in the left sensorimotor cortex in akinetic catatonia: investigation of in vivo benzodiazepine receptor binding. J Neurol Neurosurg Psychiatry. 1999;67:445Y450.
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Inhaled Thyrotropin-Releasing Hormone for Treatment of Neuropsychiatric Disorders
6. American Psychiatric Association. The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training, and Privileging: A Task Force Report of the American Psychiatric Association. 2nd ed. Washington, DC: American Psychiatric Association; 2001. 7. Grunze H, Kasper S, Goodwin G, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders, Part II: Treatment of Mania. World J Biol Psychiatry. 2003;4:5Y13. 8. Givens JL, Jones RN, Inouye SK. The overlap syndrome of depression and delirium in older hospitalized patients. J Am Geriatr Soc. 2009;57:1347Y1353. 9. Givens JL, Sanft TB, Marcantonio ER. Functional recovery after hip fracture: the combined effects of depressive symptoms, cognitive impairment, and delirium. J Am Geriatr Soc. 2008;56:1075Y1079.
To the Editors: hyrotropin-releasing hormone (TRH) displays multiple central nervous systemYmediated actions that have therapeutic potential in treating a wide range of neuropsychiatric disorders. Investigations of central nervous system functions and clinical use of TRH are hindered, however, because of its rapid degradation by circulating peptidases.1 To circumvent this problem, Veronesi et al2 have developed an intranasal nanoparticle drug delivery system. Thyrotropin-releasing hormone could be introduced into the nasal cavity, where the olfactory neurons can collect particles directly. The TRH incorporated into biodegradable nanoparticles would dissolve at a controlled rate designed to deliver appropriate doses of the drug to the brain over time. Another approach would be to deliver TRH powder by inhalation. This is
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