LETTERS
To the Editor: Huntington’s disease (HD) is a neurodegenerative disorder characterized by abnormal choreatic movements, subcortical dementia, and psychiatric symptoms. Psychiatric disorders encountered in HD include major depressive disorder, anxiety disorders, or isolated symptoms such as apathy or irritability in 33%276% of patients. Psychotic disorders affect 3%211% of patients.1 Although psychiatric symptomatology often precedes motor symptoms,2 there is a dearth of data regarding psychiatric care in HD.3 The case reported here refers to a patient suffering from HD, major depressive disorder, and psychotic symptomatology. This patient displayed a very poor tolerance to clozapine treatment and differential results with electroconvulsivotherapy (ECT) with remission of major depressive disorder symptoms and a slight improvement in motor symptoms, but there was no effect on psychotic symptoms.
23 for the normal allele and 41 for the HD allele, thus confirming the diagnosis of HD. When the patient was admitted, clozapine was introduced and was titrated up to 350 mg per day in association with mirtazapine. At a dosage of clozapine of 350 mg daily, the patient experienced acute mental confusion, circadian rhythm reversal, restlessness, and a worsening of dysarthria and abnormal movements. All side effects disappeared after the clozapine was stopped (Naranjo score58). An ECT course was implemented, with 18 ECT sessions. At the 12th session, Mr. E’s symptoms were markedly improved, with complete disappearance of major depressive disorder symptoms and suicidal ideation. However, he was still having delusional ideas (Table 1). A continuation course and a maintenance course were decided: the frequency of sessions was progressively decreased to one session every 6 weeks. The patient was maintained with mirtazapine (30 mg per day). At 1 year later, no depressive relapse was observed but delusional symptoms remained unchanged (Table 1).
Case Report
Discussion
Mr. E, a 60-year-old patient with HD, was brought to the emergency department for marked anxiety, depressed mood, major sleep disturbance, and marked weight loss. He planned to commit suicide by defenestration. He claimed to be under the surveillance of a spy network that used earpieces and hacked his electronic devices. Interestingly, the patient was partially convinced by his ideas. Motor symptoms consisted of choreatic movements of the head and extremities and moderate dysarthria. Initial neuropsychiatric assessment is shown in Table 1. The Mini-Mental State Examination z-score was calculated using norms provided by Crum et al.4 Results on CT scan showed a moderate degree of generalized cerebral atrophy. At age 40 years, the patient developed major depressive disorder associated with persecutory delusional symptoms. The duration of the episode led to the diagnosis of late-onset schizoaffective disorder. During 20 years of care, the disease showed a particular refractoriness to all psychopharmacologic strategies implemented (antidepressants, neuroleptics, atypical antipsychotics, and mood stabilizers). No family history of psychosis or neurologic disorders has been reported. At age 59 years, the patient displayed abnormal writhing movements suggestive of HD, which prompted evaluation for this condition. Genetic testing found a CAG repeat size of
This patient’s presentation is remarkable for the long latency between symptom onset and identification of the underlying cause of the symptoms. The diagnosis of HD may explain, at least in part, the marked refractoriness of the patient’s psychotic and depressive symptoms to pharmacologic treatments. Although psychiatric symptoms are known to be prodromal symptoms of HD,5 the very long latency between severe psychiatric symptoms and the onset of motor symptoms observed in this patient is uncommon. Nonetheless, the onset of symptoms suggestive of schizoaffective disorder at age 40 years should have prompted, in retrospect, evaluation for a neurologic cause of the patient’s psychiatric symptoms. Perhaps most noteworthy is the differential response of the patient’s psychotic and depressive symptoms to ECT. Other case reports describing major depressive disorder treatment in patients with HD showed positive results with mirtazapine and fluoxetine contrary to tricyclic antidepressants. Atypical antipsychotic drugs, such as risperidone and clozapine,6 showed good results for treating psychotic dimension. In this case, clozapine induced a worsening of motor symptoms with no efficacy on psychotic symptoms, which is contradictory to the data available in the literature. There are 14 reports of patients with HD with affective symptoms treated by ECT7 in the literature. ECT was effective
Differential Response to ECT of Psychotic and Affective Symptoms in Huntington’s Disease: A Case Report
J Neuropsychiatry Clin Neurosci 28:1, Winter 2016
neuro.psychiatryonline.org
e3
LETTERS
cannot be extended to the regions involved in affective symptoms,12 in which a hypoPatient Assessment dopaminergic state—as well as a depletion in serotonin and norepinephrine—is observed. Maximal After 12 Scale Score Admission ECT Sessions After 1 Year This may explain the differential response observed here, with potentially less severe Psychiatric assessment MADRS 60 47 7 — GABAergic neuronal degeneration in the reBPRS-E 168 88 38 — gions involved in affective symptoms, such as CGI 7 6 5 — the long-range projections from the raphe HD assessment nuclei. This leads to the hypothesis that the (using the UHDRS) degenerative process may progress at variMotor symptoms 124 47 37 57 ous speeds according to the structures, or that Behavioral abnormalities 88 54 26 — slightly different degenerative processes are Functional assessment 50 41 36 42 Independence scale 100 45 60 55 at work according to the affected structures. Total functional capacity 5 2 3 4 These hypotheses are, however, speculative Cognitive assessment because the imaging data from the patient show (using the MMSE) only a generalized cerebral atrophy. LargeRaw score 30 24 — — scale neuroimaging studies are needed to b 0 –2.35 — — z score identify the structural and functional neua BPRS-E, expanded version of the Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; roanatomic abnormalities in HD according to HD, Huntington’s disease; MADRS, Montgomery-Åsberg Depression Rating Scale; MMSE, Minithe various psychiatric symptoms observed. Mental State Examination; UHDRS, Unified Huntington’s Disease Rating Scale. b The MMSE z-score was calculated using the norms provided by Crum et al.4 For this patient This case report is the first to describe (aged 60 years and with an education level of 12 years), the mean MMSE score is 2861.7. a refractory psychotic symptomatology to clozapine and ECT in a patient with HD. The differences with other case reports may be explained by the and well tolerated in 13 of 14 cases. As for psychotic disorpossible existence of subtypes of HD. Moreover, this case ders, the five cases reported in the literature8 show positive underscores the importance of psychiatrists to take into acresults of ECT. The available studies often lack standardized assessment of psychopathologic improvement. Here, valicount the possibility of a primary organic disorder in latedated psychiatric scales (Montgomery-Åsberg Depression onset and atypical disorders. Rating Scale, Brief Psychiatric Rating Scale–Expanded, and REFERENCES Clinical Global Impressions Scale) were used to assess re1. van Duijn E, Kingma EM, van der Mast RC: Psychopathology in sponse to ECT. The Unified Huntington’s Disease Rating verified Huntington’s disease gene carriers. J Neuropsychiatry Clin Scale,9 which was developed as a clinical rating scale to asNeurosci 2007; 19:441–448 sess four domains of clinical performance and capacity in 2. Amann B, Sterr A, Thoma H, et al: Psychopathological changes HD: motor function, cognitive function, behavioral abnorpreceding motor symptoms in Huntington’s disease: a report on four cases. World J Biol Psychiatry 2000;1:55–58. malities, and functional capacity, was also used. To our 3. Bonelli RM, Hofmann P: A systematic review of the treatment studies knowledge, this case is the first to show a psychotic resisin Huntington’s disease since 1990. Expert Opin Pharmacother 2007; tance to ECT in patients with HD. As for motor symptoms, 8:141–153 these data provide clues for the safety of the procedure for 4. Crum RM, Anthony JC, Bassett SS, et al: Population-based norms nonpsychiatric features. for the Mini-Mental State Examination by age and educational level. JAMA 1993; 269:2386–2391 HD motor symptoms are linked to a massive loss of striatal 5. Di Maio L, Squitieri F, Napolitano G, et al: Onset symptoms in 510 GABAergic medium spiny neurons. One current hypothesis patients with Huntington’s disease. J Med Genet 1993; 30:289–292 consists of the involvement of excitotoxic neuronal death 6. Sajatovic M, Verbanac P, Ramirez LF, et al: Clozapine treatment of 10 mediated by altered glutamatergic neurotransmission. Morepsychiatric symptoms resistant to neuroleptic treatment in patients over, striatal medium spiny neurons expressing dopamine with Huntington’s chorea. Neurology 1991; 41:156 7. Beale MD, Kellner CH, Gurecki P, et al: ECT for the treatment receptors are known to be mainly affected in the early stage of Huntington’s disease: a case study. Convuls Ther 1997; 13:108–112 of HD.11 Altered dopamine signaling may then play a key role 8. Nakano T, Ono S, Yamaguchi J, et al: Modified electroconvulsive in the pathogenesis of HD. In this case, the patient displayed therapy for the treatment of refractory schizophrenia-like psychosis psychotic and affective symptoms at the prodromal stage associated with Huntington’s disease. J Neurol 2013; 260:312–314 of HD. One may speculate that mesocorticolimbic dopami9. Huntington Study Group: Unified Huntington’s Disease Rating Scale: reliability and consistency. Mov Disord 1996; 11:136–142 nergic projection may be implicated in these early symp10. Estrada Sánchez AM, Mejía-Toiber J, Massieu L: Excitotoxic neuronal toms. The hyperdopaminergic state in mesolimbic regions death and the pathogenesis of Huntington’s disease. Arch Med Res known to be involved in delusional disorders may lead to the 2008; 39:265–276 loss of long-range GABAergic projections from the ventral 11. van Oostrom JC, Dekker M, Willemsen AT, et al: Changes in tegmental area, making these structures unresponsive to anstriatal dopamine D2 receptor binding in pre-clinical Huntington’s disease. Eur J Neurol 2009; 16:226–231 tipsychotic treatment and ECT. However, such a mechanism TABLE 1. Neuropsychiatric Assessment of HD at Admission, After 12 ECT Sessions, and After 1 Year of Carea
e4
neuro.psychiatryonline.org
J Neuropsychiatry Clin Neurosci 28:1, Winter 2016
LETTERS
12. Koutsouleris N, Meisenzahl EM, Borgwardt S, et al: Individualized differential diagnosis of schizophrenia and mood disorders using neuroanatomical biomarkers. Brain 2015; 138: 2059–2073 Anne-Cécile Petit, Ph.D. Franz Hozer, M.D. Katia Youssov, M.D. Pierre Lavaud, M.D. Patrick Hardy, M.D., Ph.D. Fayçal Mouaffak, M.D., Ph.D.
J Neuropsychiatry Clin Neurosci 28:1, Winter 2016
Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Univ. Paris Sud XI, INSERM U1178, Département de Psychiatrie, Le-Kremlin Bicêtre, France (A-CP, FH, PL, PH, FM); and Centre de référence Maladie de Huntington, Hôpital Henri Mondor, Créteil, France (KY). Send correspondence to Dr. Petit; e-mail: [email protected] The authors report no financial relationships with commercial interests. Received April 11, 2015; revisions received June 7, 2015; accepted June 20, 2015. J Neuropsychiatry Clin Neurosci 2016; 28:e3–e5; doi: 10.1176/appi.neuropsych. 15040084
neuro.psychiatryonline.org
e5
To the Editor: Huntington’s disease (HD) is a neurodegenerative disorder characterized by abnormal choreatic movements, subcortical dementia, and psychiatric symptoms. Psychiatric disorders encountered in HD include major depressive disorder, anxiety disorders, or isolated symptoms such as apathy or irritability in 33%276% of patients. Psychotic disorders affect 3%211% of patients.1 Although psychiatric symptomatology often precedes motor symptoms,2 there is a dearth of data regarding psychiatric care in HD.3 The case reported here refers to a patient suffering from HD, major depressive disorder, and psychotic symptomatology. This patient displayed a very poor tolerance to clozapine treatment and differential results with electroconvulsivotherapy (ECT) with remission of major depressive disorder symptoms and a slight improvement in motor symptoms, but there was no effect on psychotic symptoms.
23 for the normal allele and 41 for the HD allele, thus confirming the diagnosis of HD. When the patient was admitted, clozapine was introduced and was titrated up to 350 mg per day in association with mirtazapine. At a dosage of clozapine of 350 mg daily, the patient experienced acute mental confusion, circadian rhythm reversal, restlessness, and a worsening of dysarthria and abnormal movements. All side effects disappeared after the clozapine was stopped (Naranjo score58). An ECT course was implemented, with 18 ECT sessions. At the 12th session, Mr. E’s symptoms were markedly improved, with complete disappearance of major depressive disorder symptoms and suicidal ideation. However, he was still having delusional ideas (Table 1). A continuation course and a maintenance course were decided: the frequency of sessions was progressively decreased to one session every 6 weeks. The patient was maintained with mirtazapine (30 mg per day). At 1 year later, no depressive relapse was observed but delusional symptoms remained unchanged (Table 1).
Case Report
Discussion
Mr. E, a 60-year-old patient with HD, was brought to the emergency department for marked anxiety, depressed mood, major sleep disturbance, and marked weight loss. He planned to commit suicide by defenestration. He claimed to be under the surveillance of a spy network that used earpieces and hacked his electronic devices. Interestingly, the patient was partially convinced by his ideas. Motor symptoms consisted of choreatic movements of the head and extremities and moderate dysarthria. Initial neuropsychiatric assessment is shown in Table 1. The Mini-Mental State Examination z-score was calculated using norms provided by Crum et al.4 Results on CT scan showed a moderate degree of generalized cerebral atrophy. At age 40 years, the patient developed major depressive disorder associated with persecutory delusional symptoms. The duration of the episode led to the diagnosis of late-onset schizoaffective disorder. During 20 years of care, the disease showed a particular refractoriness to all psychopharmacologic strategies implemented (antidepressants, neuroleptics, atypical antipsychotics, and mood stabilizers). No family history of psychosis or neurologic disorders has been reported. At age 59 years, the patient displayed abnormal writhing movements suggestive of HD, which prompted evaluation for this condition. Genetic testing found a CAG repeat size of
This patient’s presentation is remarkable for the long latency between symptom onset and identification of the underlying cause of the symptoms. The diagnosis of HD may explain, at least in part, the marked refractoriness of the patient’s psychotic and depressive symptoms to pharmacologic treatments. Although psychiatric symptoms are known to be prodromal symptoms of HD,5 the very long latency between severe psychiatric symptoms and the onset of motor symptoms observed in this patient is uncommon. Nonetheless, the onset of symptoms suggestive of schizoaffective disorder at age 40 years should have prompted, in retrospect, evaluation for a neurologic cause of the patient’s psychiatric symptoms. Perhaps most noteworthy is the differential response of the patient’s psychotic and depressive symptoms to ECT. Other case reports describing major depressive disorder treatment in patients with HD showed positive results with mirtazapine and fluoxetine contrary to tricyclic antidepressants. Atypical antipsychotic drugs, such as risperidone and clozapine,6 showed good results for treating psychotic dimension. In this case, clozapine induced a worsening of motor symptoms with no efficacy on psychotic symptoms, which is contradictory to the data available in the literature. There are 14 reports of patients with HD with affective symptoms treated by ECT7 in the literature. ECT was effective
Differential Response to ECT of Psychotic and Affective Symptoms in Huntington’s Disease: A Case Report
J Neuropsychiatry Clin Neurosci 28:1, Winter 2016
neuro.psychiatryonline.org
e3
LETTERS
cannot be extended to the regions involved in affective symptoms,12 in which a hypoPatient Assessment dopaminergic state—as well as a depletion in serotonin and norepinephrine—is observed. Maximal After 12 Scale Score Admission ECT Sessions After 1 Year This may explain the differential response observed here, with potentially less severe Psychiatric assessment MADRS 60 47 7 — GABAergic neuronal degeneration in the reBPRS-E 168 88 38 — gions involved in affective symptoms, such as CGI 7 6 5 — the long-range projections from the raphe HD assessment nuclei. This leads to the hypothesis that the (using the UHDRS) degenerative process may progress at variMotor symptoms 124 47 37 57 ous speeds according to the structures, or that Behavioral abnormalities 88 54 26 — slightly different degenerative processes are Functional assessment 50 41 36 42 Independence scale 100 45 60 55 at work according to the affected structures. Total functional capacity 5 2 3 4 These hypotheses are, however, speculative Cognitive assessment because the imaging data from the patient show (using the MMSE) only a generalized cerebral atrophy. LargeRaw score 30 24 — — scale neuroimaging studies are needed to b 0 –2.35 — — z score identify the structural and functional neua BPRS-E, expanded version of the Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; roanatomic abnormalities in HD according to HD, Huntington’s disease; MADRS, Montgomery-Åsberg Depression Rating Scale; MMSE, Minithe various psychiatric symptoms observed. Mental State Examination; UHDRS, Unified Huntington’s Disease Rating Scale. b The MMSE z-score was calculated using the norms provided by Crum et al.4 For this patient This case report is the first to describe (aged 60 years and with an education level of 12 years), the mean MMSE score is 2861.7. a refractory psychotic symptomatology to clozapine and ECT in a patient with HD. The differences with other case reports may be explained by the and well tolerated in 13 of 14 cases. As for psychotic disorpossible existence of subtypes of HD. Moreover, this case ders, the five cases reported in the literature8 show positive underscores the importance of psychiatrists to take into acresults of ECT. The available studies often lack standardized assessment of psychopathologic improvement. Here, valicount the possibility of a primary organic disorder in latedated psychiatric scales (Montgomery-Åsberg Depression onset and atypical disorders. Rating Scale, Brief Psychiatric Rating Scale–Expanded, and REFERENCES Clinical Global Impressions Scale) were used to assess re1. van Duijn E, Kingma EM, van der Mast RC: Psychopathology in sponse to ECT. The Unified Huntington’s Disease Rating verified Huntington’s disease gene carriers. J Neuropsychiatry Clin Scale,9 which was developed as a clinical rating scale to asNeurosci 2007; 19:441–448 sess four domains of clinical performance and capacity in 2. Amann B, Sterr A, Thoma H, et al: Psychopathological changes HD: motor function, cognitive function, behavioral abnorpreceding motor symptoms in Huntington’s disease: a report on four cases. World J Biol Psychiatry 2000;1:55–58. malities, and functional capacity, was also used. To our 3. Bonelli RM, Hofmann P: A systematic review of the treatment studies knowledge, this case is the first to show a psychotic resisin Huntington’s disease since 1990. Expert Opin Pharmacother 2007; tance to ECT in patients with HD. As for motor symptoms, 8:141–153 these data provide clues for the safety of the procedure for 4. Crum RM, Anthony JC, Bassett SS, et al: Population-based norms nonpsychiatric features. for the Mini-Mental State Examination by age and educational level. JAMA 1993; 269:2386–2391 HD motor symptoms are linked to a massive loss of striatal 5. Di Maio L, Squitieri F, Napolitano G, et al: Onset symptoms in 510 GABAergic medium spiny neurons. One current hypothesis patients with Huntington’s disease. J Med Genet 1993; 30:289–292 consists of the involvement of excitotoxic neuronal death 6. Sajatovic M, Verbanac P, Ramirez LF, et al: Clozapine treatment of 10 mediated by altered glutamatergic neurotransmission. Morepsychiatric symptoms resistant to neuroleptic treatment in patients over, striatal medium spiny neurons expressing dopamine with Huntington’s chorea. Neurology 1991; 41:156 7. Beale MD, Kellner CH, Gurecki P, et al: ECT for the treatment receptors are known to be mainly affected in the early stage of Huntington’s disease: a case study. Convuls Ther 1997; 13:108–112 of HD.11 Altered dopamine signaling may then play a key role 8. Nakano T, Ono S, Yamaguchi J, et al: Modified electroconvulsive in the pathogenesis of HD. In this case, the patient displayed therapy for the treatment of refractory schizophrenia-like psychosis psychotic and affective symptoms at the prodromal stage associated with Huntington’s disease. J Neurol 2013; 260:312–314 of HD. One may speculate that mesocorticolimbic dopami9. Huntington Study Group: Unified Huntington’s Disease Rating Scale: reliability and consistency. Mov Disord 1996; 11:136–142 nergic projection may be implicated in these early symp10. Estrada Sánchez AM, Mejía-Toiber J, Massieu L: Excitotoxic neuronal toms. The hyperdopaminergic state in mesolimbic regions death and the pathogenesis of Huntington’s disease. Arch Med Res known to be involved in delusional disorders may lead to the 2008; 39:265–276 loss of long-range GABAergic projections from the ventral 11. van Oostrom JC, Dekker M, Willemsen AT, et al: Changes in tegmental area, making these structures unresponsive to anstriatal dopamine D2 receptor binding in pre-clinical Huntington’s disease. Eur J Neurol 2009; 16:226–231 tipsychotic treatment and ECT. However, such a mechanism TABLE 1. Neuropsychiatric Assessment of HD at Admission, After 12 ECT Sessions, and After 1 Year of Carea
e4
neuro.psychiatryonline.org
J Neuropsychiatry Clin Neurosci 28:1, Winter 2016
LETTERS
12. Koutsouleris N, Meisenzahl EM, Borgwardt S, et al: Individualized differential diagnosis of schizophrenia and mood disorders using neuroanatomical biomarkers. Brain 2015; 138: 2059–2073 Anne-Cécile Petit, Ph.D. Franz Hozer, M.D. Katia Youssov, M.D. Pierre Lavaud, M.D. Patrick Hardy, M.D., Ph.D. Fayçal Mouaffak, M.D., Ph.D.
J Neuropsychiatry Clin Neurosci 28:1, Winter 2016
Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Univ. Paris Sud XI, INSERM U1178, Département de Psychiatrie, Le-Kremlin Bicêtre, France (A-CP, FH, PL, PH, FM); and Centre de référence Maladie de Huntington, Hôpital Henri Mondor, Créteil, France (KY). Send correspondence to Dr. Petit; e-mail: [email protected] The authors report no financial relationships with commercial interests. Received April 11, 2015; revisions received June 7, 2015; accepted June 20, 2015. J Neuropsychiatry Clin Neurosci 2016; 28:e3–e5; doi: 10.1176/appi.neuropsych. 15040084
neuro.psychiatryonline.org
e5
