by Ö Asan — between catatonia and schizophrenia which lasts over one hundred years ended picture of catatonia with chronic psychotic disorder in terms of symptoms and

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Psikiyatride Güncel Yakla˜˚mlar -Current Approaches in Psychiatry 201 9; 11(3):257-270 doi: 10.18863/pgy. 507214 Psik iyatride Güncel Yakla˜˚mlar – Current Approaches in Psychiatry Catatonia: Clinical Features and Treatment Katatoni: Klinik Özellikler ve Tedavi Ömer Asan 1 Abstract Catatonia was first introduced by Karl Kahlbaum in 1874 and it is a syndrome characterized by motor, cognitive, affective and autonomic symptoms. As first, it was linked with just schizophrenia for many years but it is currently known that this disorder may occur with many psychiatric disorders and other medical conditions. In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders that published in 2013, the subtypes of schizophrenia have been removed and the relationship between catatonia and schizophrenia which lasts over one hundred years ended. In this paper, we revie wed the literature about catatonia and aimed to look over its history, epidemiology, etiology, clinical features, prognosis and treatment through current knowledge. Keywords : Etiology, malign catatonia, pathogenesis, schizophrenia, treatment Öz Katatoni ilk kez 1874 y˚l˚nda Karl Kalbaum taraf˚ndan tan˚mlanm˚˜, motor, bili˜sel, affektif ve otonomik belirtilerle karakterize bir nöropsikiyatrik sendromdur. ˛lk ba˜ta sadece ˜izofreniyle ili˜kilendirilirken günümüzde birçok psikiyatrik hastal˚k ve t˚bbi durumla birlikte görüldü˝ü bilinmektedir. 2013 y˚l˚nda yay˚nlanan DSM -5 (Diagnostic and Statistical Manual of Mental Disorders: Ruhsal bozukluklar˚n tan˚sal ve say˚msal el kitab˚)™te ˜izofreni™nin alttipleri kald˚r˚lm˚˜ ve yüz y˚l˚ a˜k˚n katatoni -˜izofreni birlikteli˝i sona ermi˜tir. Bu yaz˚da katatoni ile ilgili literatür gözden geçirilmi˜, tarihçesi, epidemiyolojisi, etiyolojisi, klinik belirtileri, prognoz ve tedavisi güncel bilgiler ˚˜˚˝˚nda ele al˚nm˚˜t˚r. Anahtar sözcükler : Etiyoloji, katatoni, mali gn katatoni, patogenez, ˜izofreni, tedavi. 1 Sakarya University Education and Research Hospital , Sakarya , Turkey Ömer Asan , Sakarya University Education and Research Hospital, Sakarya , Turkey Geli˜ tarihi/Sub mission date: 02.01 .2019 | Kabul tarihi/Ac cepted: 30.01.201 9 | Çevrimiçi yay˚n/Online published: 12.0 2.2019

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Asan 258 Psikiyatride Güncel Yakla˜˚mlar – Current Approaches in Psychiatry CATATONIA is a neuropsychiatric syndrome characterized by motor, cognitive, affective and autonomic symptoms. More than 40 symptoms associated with catatonia have been described in the literature; stupor, posturing, negativism and mutism are the most common symptoms among these. Catatonia is an important syndrome, it is po- tentially life -threatening and can dramatically improve with rapid diagnosis an d treat- ment. Although it has been associated with only schizophrenia in the past, today, it is known that this disorder may occur with numerous psychiatric disorder and general medical conditions. In the fifth edition of DSM (Diagnostic and Statistical Ma nual of Mental Disorders) published in 2013, which is one of the most widely used classifica- tion systems worldwide, the association of schizophrenia and catatonia has been ended . Catatonia was reclassified under a separate heading in the chapter of “Schizo phrenia Spectrum and Other Psychotic Disorders” (American Psychiatric Association 2013) . In this review article, the literature on catatonia was reviewed and its history, epidemio- logy, etiology, clinical symptoms, prognosis and treatment were discussed thr ough current information. History Catatonia was first described by Karl Kahlbaum in 1874. In Greek, it means “stretching tight”. The term “catatonia” was described at a time when psychiatrists just began to associate psychiatric disorders with brain disfun ction. In the article of “catatonia or tension insanity” published in 1874, Kahlbaum described catatonia as a degenerative brain disease with motor, cognitive and vegetative symptoms caused by birth trauma, alcoholism, or another brain disease. Kahlbaum st ated that hebephrenia and catatonia were separate diseases, and that catatonia had a better prognosis despite lethal outcomes in some cases. However, as of 1877, numerous cases of chronic catatonia cases with residual symptoms and many cases of hebephrenia with motor symptoms similar to catatonia have been reported (Arndth 1902, Brosius 1877, Aschaffenburg 1898). In the light of these developments, Kraepelin described hebephrenia and catatonia as the sub -groups of the same disease called “dementia praecox” in 1 893. Kraepelin reported that catatonia arising with mood disorders was different from the clinical picture of catatonia with chronic psychotic disorder in terms of symptoms and progno- sis and had a better prognosis . He differentiated melancholic and ma nic catatonia and chronic catatonia. Moreover, Kraepelin (1913) came up against the view of Kahlbaum suggesting that catatonia develops in association with organic causes, and argued that catatonia was a psychogenic disease caused by mental block. In 1911, Bleuler replaced the term of Kraepelin “dementia praecox” with the term “schizophrenia” and described catatonia as a subtype of schizophrenia. Bleuler refused the pathophysiological theories for the etiology of catatonia, indicated that the manifestation was of psychogenic origin and explained it psychoanalytically. According to Bleuler, catatonia is a psychogenic condition characterized by withdrawal under harmful environmental conditions. Geor- ge Kirby separated the degenerative and non -degenerative types of catatonia in 1913 and suggested that it was more related to manic -depressive disorder rather than psycho- tic disorder, and argued that Kahlbaum and Bleuler had drawn the boundaries of schi- zophrenia too broadly. Kleist (1943) and Leonhard (1935) describe d cycloid psychosis characterized by increased and decreased motor activity and reported that this presenta- tion was associated with manic -depressive disorder in the classification of Kraepelin.

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259 Catatonia Psikiyatride Güncel Yakla˜˚mlar – Current Approaches in Psychiatry Antipsychotics that were discovered in the 1950s made a break through in the tre- atment of schizophrenia, other psychotic disorders and mood disorders, but added a new dimension to the controversy regarding catatonia. With the use of antipsychotic drugs, there was a significant decrease in the number of chronic catato nia cases presen- ting with schizophrenia, but this time, motor disorders secondary to drugs started to be observed. In the 1960s, drug -induced dyskinesia, its stereotype and mannerism cases were reported (Uhrband and Arild 1960, Rogers 1985). It has been r eported that neu- roleptic malignant syndrome (NMS), a life -threatening condition, which occurs as a side effect of antipsychotic drugs, is quite similar to catatonia and may even be a type of catatonia (Caroff 1980, Fink 1996). DSM and Catatonia Two commonl y used classification systems in the world are the DSM and the ICD (International Statistical Classification of Diseases and Health Problems) classification systems. Catatonia was classified only as a subtype of schizophrenia until the DSM -4 published in 1 994, despite numerous studies demonstrating that catatonia could be seen with many medical conditions, especially with mood disorders. Especially the studies by Fink and Taylor made a tremendous impact and catatonia was reclassified in three different form s in the DSM -4 as catatonic schizophrenia, catatonia secondary to mania or major depressive disorder and catatonia due to another medical condition (Fink and Taylor 1991). This revision is important in terms of revealing that catatonia is not only associat ed with schizophrenia but also may arise with other disorders. However, some researchers did not find this revision sufficient and argued that catatonia should be addressed as a completely separate heading in the DSM (Peralta et al. 1997, Taylor and Fink 2 003). The fact that catatonia may be seen with metabolic, toxic, neurological and various psychiatric disorders, rapidly improve with the ECT (electroconvulsive treatment) and benzodiazepines unlike schizophrenia, and does not respond well to antipsychoti cs that treat psychosis, and even antipsychotics may result in the emergence of catatonia -like conditions (neuroleptic malignant syndrome) has formed the basis of this view. Articles reporting that diseases such as Klein -Levine syndrome, autoimmune encepha litis, Prader -Willi syndrome and tic disorders, seen in children and adolescents, may be a clinical manifestation of catatonia (Dhossche and Wachtel 2010). In light of all these findings, the subtypes of schizophrenia were removed from the DSM -5 published in 2013, and the relationship between schizophrenia and catatonia, which lasted for more than a hundred years, ended. In the DSM -5, catatonia was rec- lassified under a separate heading in the chapter of “Schizophrenia Spectrum and Other Psychotic Disorders ” and under this heading, catatonia appears in three forms as ficata- tonia associated with another mental disorderfl, ficatatonic disorder due to another medical conditionfl and fiunspecified catatoniafl. Due to these revisions, patients diagno- sed with catatonic schizophrenia in the DSM -4 also receive the diagnoses of “schizoph- renia”, as well as “catatonia associated with another mental disorder” in the DSM -5 Epidemiology The studies to determine the estimated prevelance of catatonia usually include indivi-

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Asan 260 Psikiyatride Güncel Yakla˜˚mlar – Current Approaches in Psychiatry duals wi th acute psychiatric disease. In the studies on catatonia, the prevelance rate ranges from 8% to 40% (Ungvari et al. 2009). The prevalence rate of catatonia has been reported to be about 10% in individuals with psychiatric disease; however, this rate range s from 5% to 20% in studies conducted in different psychiatric clinics (Rosebush et al. 1990, Chalasani et al. 2005). This difference between the results probably de- pends on the type of study and how catatonia was diagnosed (the DSM -5 criteria, diagnostic scales). In clinical practice, there is an impression that catatonia is less com- mon than in the past. It is a known fact that the number of severe chronic catatonia cases with dramatic symptoms such as posturing and waxy flexibility, especially seen in sch izophrenia patients, decreased due to the widespread use of antipsychotics. However, the studies report that the diagnose of catatonia is frequently overlooked and the prevalence is higher than assumed. In a study included 139 acute psychotic patients in t he Netherlands, it was reported that the researchers investigating the prevalence of catatonia determined the diagnosis of catatonia in 18% of the patients, but the team conducting the treatment of the patients diagnosed 2% of the patients with catatonia (van der Heijden et al. 2005). It has been reported that catatonia can be most commonly seen with unipolar dep- ression and bipolar disorder from psychiatric disorders. In a study included 106 patients admitted to the acute geriatric psychiatry unit, it was f ound that the prevalence of cata- tonia was 20.8% according to the DSM -5 diagnostic criteria and it was reported that it was most commonly seen in depression patients (48.6%) (Esteban et al. 2017). Apart from psychiatric disorders, catatonia can also be seen with numerous other medical conditions. In a meta -analysis of 73 studies included 110,559 patients, it was reported that the prevalence of catatonia was 20.6% in patients with another medical condition or neurological disease, 20.1% in bipolar disorder pa tients, 20% in post -partum psycho- sis patients, 11.1% in patients with the diagnosis of autism and 9.8% in schizophrenia patients (Solmi et al. 2017). In a study by Grover et al. investigating the prevalence of catatonia in 205 delirium patients consulted t o the consultation -liaison psychiatry unit, they found catatonia in 12.2% of patients according to the DSM -5 diagnostic criteria and in 30.2% of the patients according to the Bush -Francis Catatonia Rating Scale (BFCRS). Excitation (72.7%), immobility/stupo r (21.4%) and mutism (15.6%) were the most common symptoms in these patients (Denysenko et al. 2015). Pathogenesis and Etiology A psychodynamic view for the pathogenesis of catatonia is that it is a response to severe anxiety (Moskowitz 2004). Anxiety sym ptoms seen simultaneously with or before catatonic symptoms, the reports of the patients thinking that they should remain im- mobile against threats from others, the improving effects of benzodiazepines, which are an anxiolytic, on catatonic symptoms have be en reported as the findings supporting this theory. Today, no catatonia -specific laboratory finding, no genetic or neurobiological pathology has yet been found; however, numerous studies are conducted on this issue. Some neurobiological findings associated with catatonia were identified, but it is not known exactly whether these are the causes of catatonia or arise in the course of catato- nia. In some neurobiological studies, a hypothesis suggesting that catatonia may be the result of a pathology in the path ways connecting the basal ganglia to the cortex and thalamus has been proposed (Mann et al. 2005). In the literature, catatonia cases asso-

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261 Catatonia Psikiyatride Güncel Yakla˜˚mlar – Current Approaches in Psychiatry ciated with a single lesion in some regions (frontal lobe, basal ganglia, cerebellum, pons, corpus callosum) of the ce ntral nervous system (CNS) and due to frontal lobe degenera- tion and anterior cerebral artery aneurysm were reported (Fink and Taylor 2003, Arora and Praharaj 2007). However, there are more case reports and studies arguing the hypothesis that catatonia is a diffuse CNS pathology rather than a single CNS lesion. The post -mortem studies on cases of catatonia due to a medical condition did not reveal any definite CNS finding associated with catatonia (Carroll and Goforth 2004). Whereas, in some neuropathologica l studies conducted on patients with catatonic schizophrenia, it was found that there were some changes in the basal ganglia (nucleus caudatus, nucleus accumbens and globus pallidus) and thalamus (Northoff 2002). Also, functional anomalies of the prefronta l, orbitofrontal and parietal cortex were detected in patients with catatonia in neuroimaging studies (Northoff 2000). It has been reported that there is a link between lateral prefrontal cortex lesions and imitative behavior which may be associated with symptoms such as echolalia and echopraxia (Northoff et al. 1999, van der Heijden et al. 2005). Furthermore, it has been reported that dysfunc- tion of the pathways between the prefrontal cortex and amygdala may be associated with extreme cowardice and timidi ty frequently described by catatonic patients. In neuropsychological tests carried out on catatonic patients, impaired visual -spatial ability indicating the right parietal cortex function has been reported. The hypothesis most emphasized in neurotransmit ter studies is the decreased GABA -A receptor activity. Recently, evidences suggest that NMDA antagonists were effective in the treatment of catatonia obtained, and accordingly, glutamate NMDA receptor hyperactivity has been suggested to also play a role in catatonic symptoms. It has been reported that NMDA hyperactivity inhibits GABA -A function, NMDA antagonists indirectly regulate GABA -A activity in the frontal lobes, but this effect is slower compared to GABA -A receptor agonists (Daniels 2009). The role o f dopamine in catatonia is quite complicated. The dopaminergic pathways along with other neurotransmitters and pathways play an important role in catatonia, malignant catatonia and NMS, but the role of dopamine is still not exactly known. According to Nort hoff, who conducted numerous studies in this field, the basic neurochemical disorder in catatonia is a cortical dysfunction caused by disruption of the GABA -A system in the thalamocortical pathways and subcortical area and subsequent dysregulation of the d opaminergic system (Northoff 2002). In addition, it was reported that catatonia and malignant catatonia may show up due to direct cortical dopamine antagonism (top -down) and NMS may show up as a result of subcortical dopaminergic dysregulation (bottom -up). In another study, it was reported that dopaminergic dysre- gulation in the corticothalamic pathway between the medial orbitofrontal cortex and the lateral hypothalamus may be responsible for autonomic symptoms in malignant catatonia and NMS (Mann et al. 200 5). Although genetic studies has found no catatonia -specific definitive finding to date, it is suggested that periodic catatonia may have a genetic basis. The studies reporting that the genes on the chromosomes 15 (15q15) and 22 (22q13) may be associated w ith periodic catatonia and the results of some family studies support this information (Me- yer et al. 2001, Stöber 2001). About a quarter of catatonia cases have been reported to be associated with other medical conditions (usually neurological) and drugs. Catatonia may occur in cases of

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Asan 262 Psikiyatride Güncel Yakla˜˚mlar – Current Approaches in Psychiatry alcohol and other CNS depressant agents’ intoxication or deprivation, benzodiazepine deprivation and lithium intoxication. The other drugs and agents reported to cause catatonia are corticosteroids, opiates, interferon, qui nolones, levetiracetam, azithromy- cin, disulfiram, methylphenidate, cannabinoids, cocaine, amphetamines, mescaline and phencyclidine (Dubovsky and Dubovsky 2018). Antipsychotics used in the treatment of many psychiatric disorders, especially schizophrenia a nd bipolar disorder, may also lead to catatonia -like syndroms (NMS) and aggravate the existing catatonic disorder. Alt- hough there are publications reporting that second -generation antipsychotics can be used because of being effective in the treatment of co morbid psychosis and mood disor- ders in catatonia, all antipsychotics may exacerbate catatonia and clinicians should be careful while using these agents. The most common etiological factors in catatonia due to a medical condition are infections (encephaliti s, sepsis), electrolyte imbalance (hypo- natremia), autoimmune encephalopathy, paraneoplastic syndromes, neurodegenerative disorders, brain trauma, CNS tumors, vascular and hemorrhagic cerebrovascular events, wilson’s disease and epilepsy (Denysenko et al. 2 018). The most significant characteris- tic of catatonia due to a medical condition is the emergence during the course of co- morbid medical condition and presence of evidence to suggest that catatonia is the direct result of the pathophysiology of another hea lth condition in anamnesis, physical examination or laboratory findings. Although clinical symptoms are similar to catatonia secondary to psychiatric disorders, they may vary depending on the underlying medical condition. An important problem in cases of c atatonia secondary to a medical condition is delirium. According to the DSM -5 diagnostic criteria, symptoms should not arise in the delirium period in order to diagnose comorbid catatonia in another medical condi- tion. It has been reported that this is a di agnostic problem, and that delirium may also coexist in some cases of catatonia with another medical condition. The fact that the fluctuation in consciousness (delirium) is a diagnostic feature in malignant catatonia reveals this contradiction. Although t here is still no consensus on whether neuroleptic malignant syndrome is a subtype of catatonia or a separate disorder, there are numerous publications arguing that there is a catatonic syndrome secondary to neuroleptic use. This view is supported by the fa ct that NMS has similar motor symptoms with catatonia and both conditions are treated with electroconvulsive therapy (ECT) and benzodiazepines (Öncü et al. 1998). Catatonic Symptoms To date, more than 40 symptoms of catatonia have been described in the li terature. In this section, catatonic symptoms are defined based on the DSM -5 diagnostic criteria. According to the DSM -5 criteria, catatonia is diagnosed based on the presence of three or more of the following symptoms: 1. Stupor: Not actively relating to en vironment and/or absence of spontaneous movements and activity. 2. Catalepsy; is the temporary loss of contractions in the muscles. In some refe- rences, it is used to describe the same condition with waxy flexibility. 3. Waxy flexibility; is a plastic -like resist ance similar to waxy flexibility against to change the strange posture of the patient.

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Asan 264 Psikiyatride Güncel Yakla˜˚mlar – Current Approaches in Psychiatry al. 2001). In other words, in a catatonia case, it is not necessary to have one of these subtypes fixedly, and patients may exhibit variation between the symptoms of retarded and excited catatonia. Moreover, retarded and excited catatonia manifestations may evolve in malignant catat onia. Periodic and late -onset catatonia are less mentioned forms in the literature. Retarded Catatonia The retarded form of catatonia is characterized by mutism, slowness of movements, posturing and negativism (Chalasani et al. 2005). Spontaneous speech an d spontaneous motor movements are reduced. Response to sound and painful stimuli is decreased. In severe forms, the patient may stop eating and drinking, and incontinence may be seen. Excited Catatonia It is characterized by increased, purposeless motor ac tivity (hyperkinesia) in the lower and upper limbs, restlessness, stereotype, impulsivity, enthusiasm and ill temper. Deli- rium -like fluctuations in consciousness may be seen in these patients, and the patient may harm himself/herself and his/her environmen t due to increased motor activity (Fink ve Taylor 2001 ). Malignant Catatonia It is a life -threatening picture in which symptoms such as feveri autonomic instability (sudden increase -decrease in blood pressure, tachycardia, tachypnea, sweating), fluctua- tion in consciousness, and rigidity may arise (Trigo et al. 2001, Özkul et al. 2010). It is a very rapidly progressive, fulminant disorder. Laboratory tests may reveal increased levels of leukocytosis and serum creatinine, and low serum iron levels (Northoff et al. 1996). The symptoms of malignant catatonia are quite similar to NMS. The emergence of NMS typically after initiating or increasing the dose of an antipsychotic drug is the most significant distinctive characteristic. Periodical Catatonia In 1908, Ka hlbaum described periodic catatonia as a picture characterized by shifts between stupor and excitation. Today, periodic catatonia is defined as rapid -onset, repetitive, short hypokinetic and hyperkinetic episodes that last for 4 -10 days, which may last for weeks and years (Carroll 2001). Some periodic catatonia cases have been shown to be familial with autosomal dominant inheritance associated with the chromo- some 15q15 (Wijemanne and Jankovic 2015). Late -onset Catatonia In particular, it is extensively inv olved in the Japanese literature (Kocha ve ark. 2014). It is characterized by catatonic symptoms following a prodromal phase in which hypoc- hondriac and depressive symptoms are seen during a stressful life event most commonly in women. In some patients, ini tial anxiety and hypochondriac symptoms may be ac- companied by hallucinations, delusions, and excitatory behaviors. In the following phase, catatonic symptoms such as excitation, retardation, negativism, autonomic insta- bility arise. It has been reported tha t it may be associated with late -onset schizophrenia and bipolar disorder.

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265 Catatonia Psikiyatride Güncel Yakla˜˚mlar – Current Approaches in Psychiatry Treatment and Prognosis The treatment of catatonic patients is mainly based on the treatment of catatonic symp- toms and underlying psychiatric disorders or other medical conditions. The goal of treatment is full remission. Although catatonia may be life -threatening, especially in severe cases, it can dramatically improve with rapid diagnosis and treatment. Today, benzodiazepines and ECT are the most commonly used and most effective m ethods in the treatment of catatonia. Amobarbital has been widely used in the treatment of cata- tonia since the 1930s. In a study included 20 catatonic patients, it was reported that 10% of the patients achieved an improvement rate of 56% in the symptoms w ith amo- barbital treatment (McCall et al. 1992). When the literature is reviewed, numerous case reports and prospective studies conducted in the last 20 years reported an improvement rate of 60 -80% in the symptoms within hours and days with the parenteral a nd oral use of benzodiazepines, such as lorazepam. In a study included 13 acute catatonic patients showed an improvement in catatonic symptoms by 60% within 10 minutes with 2 mg intravenous lorazepam treatment (Bush et al. 1996). Catatonic patients are tr eated as inpatients in order to determine and treat the un- derlying psychiatric or other medical conditions, and to follow up complications that may arise due to catatonia such as aspiration pneumonia, venous thromboembolism, constipation and urinary retent cially the cases of malignant catatonia may be life -threatening and these patients require close follow -up and monitoring in terms of vital signs such as body temperature, blood pressure, and pulse. So me severe cases may require intensive care monitoring (Mann et al. 2005). Dehydration, malnutrition, deep vein thrombosis, pulmonary embolism, extremity contractures, excitation and impulsive behaviors are the medical conditions that should be followed up and prevented in catatonic patients. In the treatment of catatonia, it is necessary to rapidly determine and treat the un- derlying medical condition. Catatonia is commonly seen in patients with mood disor- ders and psychotic depression hospitalized at psych iatric clinics. Catatonia may also be seen in patients with psychotic disorder and autism spectrum disorder (Mukaddes and tious, metabolic and neurological diseases (Fink and Taylor 2009, Daniels 2009). In such cases, the treatment of the underlying medical condition is of first priority. Dopa- mine antagonists should be used with caution in catatonic patients since they may aggravate the picture. The first -generation antips ychotics have not been shown to have a significant effect in the treatment of catatonia (Hawkins et al. 1995). Although there are studies reporting the efficacy of the second -generation antipsychotics in the treat- ment of catatonia, all antipsychotics may a ggravate catatonia (Francis 2010, Erol et al. 2013). Clozapine is the most appropriate agent because of its lower dopaminergic antagonist effect. There are also publications reporting that olanzapine and aripiprazo- le, a dopamine partial agonist, can be eff ective (Beach et al. 2017). The use of antipsyc- hotic drug in catatonic patients is a risk factor for the development of NMS. Especially in patients with a history of catatonia and dehydrated patients, the use of parenteral and high -dose antipsychotic poses a greater risk (Berardi et al. 2002). Antipsychotics are contraindicated in cases of malignant catatonia. The first treatment option in patients with malignant catatonia is ECT (Falkai et al. 2006). In these cases, a benzodiazepine should immediately be initiated, and during

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Asan 266 Psikiyatride Güncel Yakla˜˚mlar – Current Approaches in Psychiatry this process, consent for ECT should be obtained from the patient himself/herself or his/her relatives and required consultations should be performed immediately before the treatment. If there is no significant improvement in the pict ure within 24 -48 hours, benzodiazepine treatment should be discontinued and ECT should immediately be initiated. The case reports published in the literature report that not initiating ECT in malignant catatonia within 5 days after the onset of symptoms in creases mortality (Freudenreich et al. 2011). Again, the case reports published in the literature reported that 9 (89%) out of 11 malignant catatonia cases responded to ECT, and 2 (40%) out of 5 malignant catatonia cases responded to benzodiazepine treatme nt (Hawkins et al. 1995). Therefore, ECT is the gold standard in the treatment of malignant catatonia. In other cases, the choice of treatment should be based on the patient’s clinical condition. According to the treatment algorithms of the American Psychi atric Association and the World Federation of Societies of Biological Psychiatry, benzodiazepine treatment or ECT may be preferred depending on the urgency of the patient’s clinical condition. ECT should be preferred in cases of refusing to eat -drink, seve re weight loss and dehydration, and benzodiazepine treatment should be preferred in milder pictures. Although it is not recommended by the treatment algorithms as a standard practice, numerous studies report that the combination of ECT and benzodiazepine t reatment is also effective (Petrides et al. 1997, Espinola -Nadurille et al. 2007). However, it should be kept in mind that the antiepileptic effect of benzodiazepines may reduce the efficacy of ECT in this combination. Among the benzodiazepines, the most commonly studied agent is lorazepam. The- re are also cases successfully treated with alprazolam, diazepam, clonazepam and mida- zolam (Delisle 1991, Benazzi 1991, Hung and Huang 2006, Bozkurt et al. 2016). In a study included 104 cases of catatonia, it was re ported that benzodiazepine monotherapy exhibited improvement in 70% of the cases, while this rate was 79% with lorazepam (Hawkins et al. 1995). If a positive response is observed after the first dose of loraze- pam, the chance of success for the treatment is higher (lorazepam challenge test). Pati- ents with comorbid bipolar disorder and depression respond better to benzodiazepines than schizophrenia patients. In cases of chronic catatonia occurs with schizophrenia, response is obtained at higher doses (lorazep am> 6 mg/day). According to the clinical experience, response to benzodiazepines arises within a week in cases of excited and retarded catatonia. ECT should be considered in cases where response is not obtained within this period. It has been reported th at 60% of patients who do not respond to benzodiazepine benefit from ECT. Another superiority of ECT is that it treats the underlying psychiatric disorders such as psychotic disorder, bipolar disorder and psyc- hotic depression along with catatonic symptoms (Armstrong et al. 1999). Alternative treatment modalities have been investigated for patients who do not respond to benzodiazepine or ECT or do not accept ECT. There are case reports reporting that valproate (Yoshida et al. 2005), memantine (Carpenter et a l. 2006), amantadine (Babington and Spiegel 2007), topiramate (McDaniel et al. 2006), carba- mazepine (Kritzinger and Jordaan 2001) and bromocriptine (Tang et al. 1995) are useful in catatonic symptoms. Clinicians should be careful with dopaminergic agents such as amantadine because of the risk of exacerbating the underlying psychotic symp- toms. There are a limited number of publications reporting that transcranial magnetic stimulation may be an alternative treatment option (Hawkins et al. 1995). Glutamate

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267 Catatonia Psikiyatride Güncel Yakla˜˚mlar – Current Approaches in Psychiatry ant agonists (amantadine, memantine) and an anticonvulsant may be used in cases where there is no response to benzodiazepine and ECT. As the last option, a combina- tion of lorazepam and a second -generation antipsychotic agent such as olanzapine and clozapine, o r aripiprazole, a partial agonist, should be tried. Dantrolene, a calcium channel blocker, was tried especially in the treatment of malignant catatonia and NMS but it was not found to be effective. Although there is no sufficient number of studies showing the long -term prognosis of catatonia, it is generally considered to have a good prognosis. The long -term prognosis of catatonia generally depends on the course and severity of the underlying psychiatric disorder or other medical conditions. The cases assoc iated with mood disorders and toxic -metabolic causes usually improve by treating catatonic symptoms and underlying pathology. Catatonia may become chronic in some schizophrenia patients; however, cases of chronic catatonia are rare nowadays because of the widespread use of antipsychotic drugs. In cases of malignant catatonia, mortality rates up to 20% have been reported (Fink and Taylor 2003). Even if it does not result in death, these patients may develop permanent cognitive impairment, apathy syndro- me an d limb strictures. In cases of catatonia, the risk of recurrent catatonia increases. In a case series of 5 patients, it was reported that catatonia recurred within 5 -20 months. In these cases, it was found that motor symptoms of the patients were similar i n recur- rent episodes and responded to the same treatments (Francis et al. 1997). Therefore, questioning the history of catatonia and treatment response may be a guide for treat- ment choice. In cases of periodic catatonia, maintenance ECT is an appropriate a nd effective method. In the literature, there is a case report in which the patient was suc- cessfully treated with 4 -year maintenance ECT (Bulbul et al. 2013). Conclusion Catatonia is an independent neuropsychiatric syndrome that may occur with various med ical conditions and psychiatric disorders. Despite numerous studies to date, no catatonia -specific genetic, structural, neurochemical etiology has been found. In neurot- ransmitter studies, a decrease in GABA -A and dopaminergic activity and an increase in glutamatergic activity were reported. The clinical manifestation is heterogeneous. Alt- hough there is a significant reduction in the incidence of chronic catatonia seen with schizophrenia due to the widespread use of antipsychotics today, the number of acute catatonia cases are more than assumed, and the diagnosis is frequently overlooked by clinicians. In cases of malignant catatonia with autonomic instability and changes in consciousness, mortality rates up to 20% may be seen. In cases of malignant catatonia , the most appropriate approach for the treatment is initiation of ECT without wasting time, and in other cases, the administration of benzodiazepine (especially lorazepam) and ECT depending on the severity of table. The first generation antipsychotics has not been shown to have any significant benefit in catatonia. It should even be kept in mind that these agents may aggravate catatonia and lead to NMS. Information on the use of second -generation antipsychotics is contradictory. Glutamate NMDA antago- nists, antiepileptics and second -generation antipsychotic -lorazepam combination can be tried in cases when there is no response to lorazepam or ECT. To date, numerous studies have been conducted on the nature, clinical characteris- tics, pathogenesis of catatonia and its place in classification systems. Catatonia was reclassified under a separate heading in the DSM -5 as a result of studies showing that

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