Cotard’s syndrome is a psychotic disorder in which one experiences delusions that their limbs and/or organs have fallen off/out or have completely disappeared [10] . They also may claim that they are dead, hence why it is also called ‘Walking Corpse syndrome’. The signs of this may be that someone is claiming that they have lost their limbs or that their organs do not exist, when, in fact, they are all intact and unharmed. They may also be very paranoid, depressed, and anxious. The causes of this syndrome are unknown, but there is a theory that a part of the brain called the fusiform face area loses connection with the amygdala, causing a loss of recognition when someone with this syndrome looks in the mirror [10] . This leads to the delusion that they are dead or are missing parts of their body.

Alice in Wonderland Syndrome (AIWS) is characterized by visual hallucinations and interpreting distortions in the visual field [11] . The symptoms of this disorder are incorrect perception of speed, distance, and most commonly, size. People with this disorder may perceive objects or people in their visual field to be larger or smaller than they really are. They may even perceive different ‘auras’ to them [11] . There is no known direct cause for this disorder, however, there is a large correlation between AIWS and other neurological conditions, such as migraines, brain tumors, and severe headaches, as will be examined later in this review.

Catatonic Schizophrenia/Catatonia is characterized by its negative symptoms, such as waxy flexibility, motor rigidity, verbal rigidity, and more [12] . These people are known to stay frozen in odd positions for hours or days on end. They also tend to have insomnia, anxiety, and depression associated with it. The causes of this disorder are unknown, but like all categories of schizophrenia, there is data that supports the idea of hereditary/genetic causes of this disorder [12] .

I am choosing to review these psychiatric conditions because of their uniqueness and rarity. Since they are so rare, there are very few studies divulging into the treatment options for these disorders. Thus, I wish to expand their knowledge base.

The aim of this scientific literature review is to provide more information about current and upcoming treatments for marginalized, rare psychiatric disorders. Since these disorders are so infrequently documented and diagnosed, they often do not have many studies done on them and have a smaller basic knowledge basis. So, it is important to provide accurate information about them and their treatments. Cotard’s syndrome was first documented in 1880 by Jules Cotard. Even though this disorder, as well as Alice in Wonderland Syndrome and Catatonic Schizophrenia, was discovered so long ago, there is still little research done on them. They are also often treated as side effects of other neurological and psychiatric disorders, so they are often unnoticed or unmentioned. Thus, the aim of this review is to treat these conditions as their own disorders and discuss their treatments, and to fill the gap of information. These treatments include medications, therapies, lifestyle changes, and surgical intervention.

In Cotard’s syndrome, there seems to be a lack of African and Latino overall populations present in research studies. The countries of the studies collected include Japan, the United States, the United Kingdom, and India. Thus, there are quite a few gaps of information present based on this demographic. Furthermore, there seems to be more research and case studies done on women with Cotard’s syndrome than men. Thus, Africans, Latinos, and men seem to be underrepresented demographics in studies of Cotard’s syndrome.

In Alice in Wonderland Syndrome, it is seen that this syndrome is especially discussed only as a side effect of other neurological conditions, such as migraines, tumors, and cluster headaches. Furthermore, there seems to be a lack of women represented in these studies. In the studies chosen, the countries of origin included Japan, Turkey, Italy, and Egypt. Thus, we are missing demographic information from Africans, Latinos, and Europeans. Furthermore, it is important to note that the majority of Asian studies conducted on all 3 disorders are from Japan (and occasionally India). Thus, a wide majority of European people and Asians are also underrepresented in these studies.

In Catatonic Schizophrenia/Catatonia, there seems to be a large amount of research done in Japan. Over half of the research studies chosen are from Japan. Here, once again, we see an underrepresentation of Africans, Latinos, and Europeans. The countries of origin of the articles done on this disorder are the United States, Japan, India, and Turkey. Thus, we can see Japan taking the lead in researching all 3 of the disorders of interest for this scientific literature review. There does not seem to be a significant gender inequality in research done on Catatonic Schizophrenia/Catatonia (Table 1).

Ctard’s Syndrome (Databases: PubMed and Google Scholar):

I chose the same databases (PubMed and Google Scholar) for researching and finding articles of Alice in Wonderland Syndrome. The searches included were “Alice in Wonderland Syndrome treatment” and “AIWS treatment” (Table 2). The articles were again, further narrowed based on their inclusion of discussion sections of the treatment(s) used and the patient responses to the treatments, as well as if alternatives were offered. These studies mainly included case studies, testing out drugs (clinical trials) to see if they alleviate symptoms of Alice in Wonderland Syndrome. Furthermore, the results were limited to having been published from 2010 to 2023, as were the parameters for Cotard’s Syndrome.

The filters, once again, excluded any other systematic reviews, articles in any language other than English (unless translated to English), and studies only involving humans (no trials done on animals). Other than this, the parameters also only fit free articles (which is why PubMed and Google Scholar were the databases of interest).

I chose the same databases (PubMed and Google Scholar) for researching and finding articles of Alice in Wonderland Syndrome (Table 3). The searches included were “Alice in Wonderland Syndrome treatment” and “AIWS treatment.” The articles were again, further narrowed based on their inclusion of discussion sections of the treatment(s) used and the patient responses to the treatments, as well as if alternatives were offered. These studies mainly included case studies, testing out drugs (clinical trials) to see if they alleviate symptoms of Alice in Wonderland Syndrome. Furthermore, the results were limited to having been published from 2010 to 2023, as were the parameters for Cotard’s Syndrome (Table 4 and Table 5). The filters, once again, excluded any other systematic reviews, articles in any language other than English (unless translated to English), and studies only involving humans (no trials done on animals). Other than this, the parameters also only fit free articles (which is why PubMed and Google Scholar were the databases of interest).

I chose the same databases for research and inclusion of articles on Catatonic Schizophrenia/Catatonia (PubMed and Google Scholar (Table 6)). The searches included were “Catatonic Schizophrenia treatment” and “Catatonia treatment.” The articles were narrowed based on their inclusion of discussion sections of the treatment(s) used on the patient(s) and the responses to it. Once again, this includes any alternatives or new testing drugs (clinical trials) to see if people respond to such treatments. Furthermore, the results were limited to have been published from 2011 to 2023. This is slightly different from the other disorders, which have been published since 2010. The Catatonia articles were meant to be

the same, published since 2010, but ended up not being included in the final picked papers, unlike AIWS and Cotard’s syndrome. The filters were the same as before only including testing on humans (if clinical trial), excluding systematic reviews, excluding articles that were not in English (unless they were a translated English version), and only free articles (Figure 3 and Figure 4).

Research demonstrates that there are a variety of symptoms associated with Cotard’s syndrome, the majority including symptoms of suicidal ideations and restricted mobility. One of the most prominent symptoms are the claims of not having certain limbs, organs, or claims of being dead. Along with these more significant, defining symptoms are more common ones, such as depressed mood, nihilistic behavior, anxiety, motor rigidity, loss of appetite, suicidal idealations, and insomnia. As seen in the [13] (Mughal et al., 2013) study, the patient exhibited symptoms of suicidal feelings, claims of having a rotting corpse, claims of her limbs falling off, and psychosomatic induced immobility. In another case study, by [14] (Grover et al., 2010), the patient exhibited symptoms of claimed lycanthropy (that her bones were converting to pig bones and treat she and her children overall were turning into pigs), claimed God was punishing her for skipping prayers and religious pilgrimages, and decreased sleep/insomnia due to her anxiety. Thus, a great deal of anxiety is also associated with Cotard’s syndrome, similar to Illness anxiety disorder. Furthermore, in another study by [15] (Grover, et al., 2014), a patient exhibited decreased appetite, nihilism, hopelessness, feelings of sin and guilt, delusions of catastrophe, poverty, and persecution. He believed he had an illness he could spread that caused cancer, which was his reasoning for his suicidal intent. Thus, we can see that there are quite a few delusions involved with all of these studies as well.

The research done on Cotard’s syndrome and the articles chosen support evidence that Electroencephalography (ECT) was the major tool used to treat this disorder. ECT is usually used as a last resort to treating disorders, which signifies the severity and rarity of Cotard’s syndrome. Thus, ECT was a major theme displayed throughout articles discussing the treatment of Cotard’s syndrome. For example, in a case study of a woman with Fronto-Temporal Dementia (FTD) who was experiencing symptoms of Cotard’s syndrome, the patient responded to 18 ECT sessions very well [3] . She claimed that she did not have her intestines, stomach, lungs, and even claimed that she was dead. However, during and after her ECT, her overall psychotic symptoms and delusions eventually stopped. Her associated sluggishness and claims of missing organs diminished completely. One side effect seen through this exhibit of ECT and many others is that there was a fluctuation in mental health. Patients often experience depressive symptoms fluctuating throughout the ECT treatment, but they often disappear by the end of the treatment. Another widely used therapy for Cotard’s syndrome is antipsychotic (olanzapine), antidepressant, and ECT combination therapy. In the Mughal, Menezes study, a patient who experiencing nihilism, suicidal idealizations, claims of feeling like a rotting corpse, and psychosomatic induced motor rigidity, had completely resolved her symptoms with antipsychotic, antidepressant, and ECT combination therapy [13] . The patient felt much happier as well as attended to her personal hygiene, and her motor disability was completely repaired. Similar results were seen in the Weiss study which used Olanzapine (an antipsychotic drug) which successfully alleviated all symptoms of Cotard’s syndrome [16] .

Overall, the most commonly used treatments for Cotard’s syndrome include ECT (electro-convulsive therapy), Lorazepam (an anti-anxiety medication), and Olanzapine (an antipsychotic medication), or a combination of an antidepressant, anti-anxiety medication, and ECT.

The only side effects mentioned in the articles are mood and mental health fluctuation, which was exhibited in the Kobayashi case study [2] . While Cotard’s syndrome commonly has depression as a side effect, the use of ECT sometimes worsens it or causes bipolar-like symptoms, in which changes in mood are frequent and unexpected, as seen in the case study mentioned.

The articles selected demonstrate that the symptoms associated with Alice in Wonderland Syndrome are mainly pertaining to the visual field. These symptoms are also associated with other disorders. Alice in Wonderland Syndrome itself is often presented as a symptom of some other neurological disorder. For example, in the Tunç, Başbuğ study, the patient had a history of migraines and severe headaches as a child, along with a maternal family history of them [18] . Her AIWS symptoms were suspected to have arisen because of these migraines, as a symptom. Furthermore, in the Uca, Kozak study, the patient had a history of cluster headaches, another neurological condition inducing AIWS [19] . Finally, in the Mastria study, a patient who had glioblastoma (a type of brain cancer) experienced symptoms of AIWS [21] . However, his symptoms disappeared after his tumor was removed and went into remission, suggesting that the AIWS symptoms were only present due to the severe neurological condition. Because of the severity of these neurological disorders and their wide range of symptoms, it is commonly seen that distortions in the visual field may arise, such as micropsia (seeing things smaller than they actually are), macropsia (seeing things larger than they actually are), and perception of inaccurate colors or ‘auras’, as mentioned in the Tunç, Başbuğ study [18] .

The actual symptoms of Alice in Wonderland Syndrome, as mentioned before, mainly include micropsia, macropsia, perception of different colors, distorted sense of speed or time, distorted perception of size, migraines, headaches, depressed mood, and distorted body image. As seen in the Yokoyama study, severe and consistent periods of depression, altered body image, and altered perceptions of speed and time were frequent in the patient [17] . Furthermore, the patient also portrayed interesting symptoms of a lack of empathy and value. He was able to know the value of money and people but not feel it. Other than this, as the Tunç, Başbuğ study suggests, the patient experienced frequent misconceptions of size and auras [18] . She claimed that she saw her father’s head as large and having a blue aura. Finally, the Uca, Kozak study also suggests that the patient experienced distortions of speed, color, and size minutes before his migraine attacks [19] .

The research done on the treatments of Alice in Wonderland Syndrome supports the evidence that Valproate (an anti-epileptic drug) is the most effective. Most of the articles chosen had a variety of different treatments, yet Valproate was the only one that reappeared multiple times. First, the Uca, Kozak study treated their patient with Valproate for 3 months, which yielded improved clinical conditions through a complete loss of headaches (thus removing all associated AIWS symptoms, in this case, visual hallucinations) [19] . Therefore, we can see that Valproate is mainly used as an attempt to relieve the cause of AIWS, the neurological disorders (migraines and headaches). Valproate was also used to treat the patient in the Hamed study, which was prescribed to the patient for a long duration of time and will likely continue for the rest of their life to reduce the severity of the headaches [20] . Lastly, Valproate was also used to treat the glioblastoma patient in the Mastria study [21] . After prescription of Valproate as well as the neurosurgery and drug chemotherapy for the cancer, the patient’s symptoms completely vanished and had no other recurrences of AIWS symptoms.

Overall, it is clear that Valproate is the most commonly used treatment for AIWS, but only applies to cases in which AIWS is associated with some other neurological condition, such as headaches, migraines, or tumors.

There seem to be no significant or notable side effects to the use of Valproate mentioned in the articles chosen. The overall impact seems to be positive and effective within a few months of treatment.

The research exemplifies that Catatonic Schizophrenia/Catatonia’s symptoms are widely associated with motor rigidity and psychosomatic-induced motor retardation. These include widely negative symptoms of schizophrenia, such as waxy flexibility, mutism and the flat effect. Wavy flexibility means that patients with Catatonia often are able to stay frozen or completely still in odd positions for as long as days at a time. The flat effect signifies a lack of emotion and expression variability. As seen in the Chen study, the patient experienced catalepsy, mutism, agitation, grimacing, hyperthermia, and motor rigidity as symptoms of their Catatonia [22] . The patient had been diagnosed with Catatonia ten years prior, but his symptoms showed no improvement from the use of benzodiazepines and antipsychotics. Thus, his motor rigidity was able to last for long periods on end with no effective treatment up until then. Furthermore, according to the Nomura study, the patient experienced strong motor rigidity in the upper and lower limbs, as well as verbal rigidity [23] . Thus, the physical and verbal rigidity and lack of expression are significant in Catatonia patients. This physical rigidity can also have associated effects. For example, in the Kate study, the patient experienced oral cavity drooling, nihilistic delusions, depression, restlessness, and fever [24] . Thus, depression and oral cavity drooling are common symptoms or associated symptoms of Catatonia. Furthermore, uncontrolled urination, inability to maintain personal hygiene, and anxiety are also common effects. In the Hagikura, Inada study, the patient experienced uncontrollable large periods of urination as well as dehydration and weight loss because she would refuse to eat or drink anything due to her severe state of immobility [25] . This also meant that she refused to take medicines orally, which led to alternative methods being proposed for her treatment. In the Ohi study, the patient experienced hyperthermia, immobility, hypertension, and profuse sweating [26] . We can see that hyperthermia and associated body impairments are frequent in Catatonia patients. Finally, in the Unal cohort study, the majority of the patients experienced symptoms of negativism, withdrawal, waxy flexibility, and associated mood disorders or fluctuations [27] .

It is also important to note that quite a few patients had been diagnosed with Catatonia for years, or even decades, prior and were in remission. However, because of psychosocial stressors (i.e. in the Ohi study, the patient stopped taking his medication for Catatonia because of a major life stressor) [26] .

The articles selected overall support the effectiveness of ECT (electro-convul- sive therapy) and benzodiazepine therapy in combination, as well as rTMS (rapid transcranial magnetic stimulation). benzodiazepines used to treat Catatonia had already been an established, common first-base treatment for newly diagnosed patients. However, it is not always effective and sometimes loses its effectiveness over time, which is why ECT and rTMS are now widely discussed treatments as well. According to the Kate study, which used rTMS as their method of treatment, all of the patient’s symptoms of verbal/motor rigidity had diminished, and her Bush Francis Catatonia rating score (BFCR) score had dropped from 32 to 9 by the end of treatment [24] . The patient was able to speak fluently again by the end as well. Furthermore, as the Ohi study discusses, the patient was treated with a variety of treatments but mostly with diazepam (a benzodiazepine drug) which resulted in his remission [26] . The diazepam treatment resulted in the patient’s ability to move again and stop drooling (which was a side effect of his prior severe motor rigidity). The patient’s motor flexibility completely returned by the end of his hospital stay. Not only this, but the Unal study provides concrete evidence of the effectiveness of benzodiazepines in combination with ECT [26] . Since the study is a cohort study and involves multiple (57) people with Catatonia, it provides results that are generalizable to the population of Catatonia patients. The treatment of benzodiazepines and ECT in combination yielded a 100% successful recovery in all Catatonia patients over a span of eight years. Thus, it is evident that benzodiazepines and ECT are largely successful in treating Catatonia.

It is also important to mention alternative treatments used to treat special cases of Catatonia. For example, in the Hagikura, Inada study, the patient’s Catatonia was so severe that they refused to take drug treatment orally, as she refused to open their mouth [25] . Thus, in Japan, the blonanserin patch (an antipsychotic transdermal patch that can be applied on the skin) was used. The blonanserin patch was first globally approved for use in Japan in 2019. The patch proved to be effective, as the patient resolved her Catatonic symptoms within two weeks of administration. The patient was able to open her mouth, communicate verbally, and develop better motor control.

There do not seem to be any significant side effects of benzodiazepines and ECT in combination that were mentioned. However, the blonanserin patch yielded larger, uncontrollable amounts of urination and profuse sweating. Overall, the blonanserin patch proved effective in subsiding the symptoms of Catatonia, however, it also led to larger amounts of liquid secretion from the body (urination, sweating).

It is clear that ECT is a very popular mode of treatment for both Cotard’s Syndrome and Catatonic Schizophrenia/Catatonia. This is likely because of the fact that they both include psychotic symptoms. Furthermore, the symptoms themselves presented seem to share similarities across all 3 disorders. For example, all 3 disorders result in some sort of depression, depressed mood, anxiety, and mood swings. This is also likely due to the severity and rarity of the disorders chosen. Furthermore, both Alice in Wonderland Syndrome (AIWS) and Cotard’s syndrome involve delusions and hallucinations, as they share similar symptoms of distorted perceptions of reality. In fact, Type 1 of AIWS follows a similar pathway as Cotard’s Syndrome does. Type 1 of AIWS is defined as people feeling as though their own body parts are changing in size, while Cotard’s syndrome is defined as feeling as though their body parts are missing or dead.

Furthermore, insomnia also seems to be a side effect of all 3 disorders chosen. Once again, because of the highly debilitating nature of the disorders chosen, they are known to cause insomnia. This is also because of the associated symptoms of all 3 disorders. For example, patients with Cotard’s syndrome are often stuck in odd, difficult positions which may inhibit their ability to relax and sleep. Furthermore, patients with AIWS often experience neurological pain such as headaches, migraines, or tumors which may contribute to their lack of sleep. Lastly, Cotard’s syndrome typically results in substantial anxiety about being dead or dying, which may also contribute to the development of insomnia.

It is also significant to note that the majority of the studies conducted on all 3 disorders were done in Japan (5 out of 16 articles), and that Latin America and Africa are not represented in any of the articles searched for. Thus, Latinos and Africans are a widely underrepresented demographic in studies of Cotard’s syndrome, AIWS, and Catatonia.

From this data, it can be concluded that ECT seems to be the most common mode of treatment, currently, for Catatonia and Cotard’s Syndrome. However, it is more common for benzodiazepines, antipsychotics, and or anticonvulsants to be used to treat Alice in Wonderland Syndrome. The most common one seen is Valproate, which is originally used to prevent seizures or the manic mood swings of bipolar disorder.

There seem to be quite a few geographical areas that are underrepresented in the studies conducted on Cotard’s Syndrome. As mentioned before, there are no studies included or found that have been conducted on people of African or Latino ethnicity or descent. This demographic discrepancy may be attributed to the lack of resources funded to do research in these regions or the lack of resources available to get the treatments required for people of African and Latino backgrounds. There seems to be a high density of studies from Asia, including Japan and India. There are also studies from the United States and the United Kingdom. Furthermore, in regards to gender, there seems to be more women with Cotard’s syndrome that are studied than men (4 women, 2 men included in the article studies). Thus, men and people of Latino and African backgrounds are underrepresented demographics in the studies of potential treatments for Cotard’s syndrome.

The same geographical areas are underrepresented in studies of Alice in Wonderland Syndrome. The Latino and African communities are, once again, underrepresented in these studies. There also seem to be more men represented in studies of AIWS than are women (4 men, 1 woman identified in the studies). Thus, women and people of Latino and African backgrounds are underrepresented demographics in the studies of the current and upcoming treatments for AIWS. The articles chosen originate in Japan, Turkey, Egypt, and Italy.

Furthermore, it is important to note that the majority of patients of AIWS had an associated neurological disorder that caused or influenced the development of their AIWS symptoms. For example, in the Tunç, Başbuğ study, the patient had a history of migraines [18] . In the Uca, Kozak study, the patient had a history of cluster headaches [19] . In the Matria study, the patient had a brain tumor. All of these neurological conditions are believed to have caused the onset of AIWS symptoms in the patients. Thus, their AIWS symptoms often subsided as their associated neurological conditions diminished in severity.

It is also important to note that many of the patients of AIWS have a personal history of neurological disorders, but not a family history of them.

The same geographical areas are underrepresented in studies of treatments for Catatonia. The Latino community and African community are, once again, an underrepresented and understudied demographic. The countries that are represented in the studies conducted include the United States, India, Japan, and Turkey. Interestingly enough, Japan was represented in half of the articles (3 out of 6) chosen for Catatonia. Furthermore, there are roughly an equal number of men and women represented for studies of Catatonia, so there is little or no discrepancy in gender in these studies.