Case study: bipolar disorder and catatonia in an adult autistic male with intellectual disability and Phelan-McDermid syndrome (22q13.33 deletion syndrome): psychopharmacological treatment and symptom trajectories

Abstract

Objectives

Individuals with Phelan-McDermid syndrome (PHMDS) appear to be at increased risk of bipolar disorder and catatonia. While previous research indicates that standard pharmacological treatment of both conditions may be effective in individuals with PHMDS, there is limited knowledge concerning treatment when bipolar disorder and catatonia co-occur. Moreover, symptom trajectories during treatment of bipolar disorder and catatonia in this population have been sparsely described.

Methods

Case study describing treatment choices, sequence of interventions, and treatment outcome using standardised checklists, for co-occurring bipolar disorder and catatonia in an adult autistic man with intellectual disabilities.

Results

The current patient was initially diagnosed with a depressive disorder and catatonia. Treatment of catatonia appeared to trigger mania, indicating that catatonia was associated with, and possibly secondary to, affective symptomatology. The successful treatment of catatonia required the discontinuation of antidepressants and the introduction of a mood stabilising drug, in addition to standard catatonia treatment.

Conclusions

The current case demonstrates the importance of considering the treatment of catatonia in the context of co-occurring affective disorder, and vice versa, in individuals with PHMDS. The symptom trajectories and outcomes described add to the current evidence base concerning the treatment of bipolar disorder/catatonia in PHMDS.

Keywords:

• Phelan-McDermid syndrome
• bipolar disorder
• catatonia
• assessment
• treatment
• autism spectrum disorder
• intellectual disability

Introduction

Phelan-McDermid syndrome (PHMDS), or 22q13.3 deletion syndrome (OMIM #606232), is a rare genetic disorder caused by a heterozygous deletion in chromosome 22q13 or a mutation in the SHANK3 gene located within the minimum critical region (Kolevzon et al. 2019; Phelan and McDermid, 2012; Srivastava et al. 2023; Tabet et al. 2017). PHMDS is characterised by autism spectrum disorder (ASD), intellectual disability, speech and language impairments, and hypotonia (Kolevzon et al. 2019; Tabet et al. 2017). Moreover, recent studies have described PHMDS as being associated with risk of neuropsychiatric decompensation/regression and psychiatric illness, in particular bipolar disorder and catatonia (Dhossche et al. 2023; Dille et al. 2023; Kohlenberg et al. 2020; Kolevzon et al. 2019; Landlust et al. 2023; Srivastava et al. 2023; Verhoeven, Egger, and de Leeuw 2020).

Bipolar disorder is characterised by a clinical course of recurring mood episodes (manic, depressive, hypomanic), in which the occurrence of at least one manic episode is necessary for the diagnosis of bipolar disorder type I (American Psychiatric Association, 2013; Carvalho et al. 2020). Pharmacological treatment is often necessary to manage symptoms, and the burden of illness is substantial for many affected individuals (Carvalho et al. 2020). In individuals with PHMDS, bipolar disorder has been described as being associated with irritability, mood cycling or mood dysregulation, sleep disturbance, distractibility, and loss of function (Kohlenberg et al. 2020; Kolevzon et al. 2019; Srivastava et al. 2023).

Catatonia is a psychomotor syndrome (American Psychiatric Association, 2013; Walther et al. 2019) and is associated with a number of medical and psychiatric conditions, including ASD (Ghaziuddin, Andersen, and Ghaziuddin 2020; Rosebush and Mazurek, 2010; Walther et al. 2019). Three patterns have been described in changes in psychomotor behaviour: increased, decreased, and abnormal (Walther et al. 2019). In individuals with PHMDS, symptoms of catatonia have been described to vary, but motor symptoms, negativistic behaviours, and agitation have all been described (Dhossche et al. 2023; Kolevzon et al. 2019; Srivastava et al. 2023). Notably, symptoms of catatonia in individuals with PHMDS have been reported to co-occur with bipolar disorder (Kolevzon et al. 2019), but the nature of this relationship may be complex and remains to be delineated (Dhossche et al. 2023).

Assessment of mental disorders in individuals with PHMDS appears to include similar challenges as assessment in other autistic individuals with intellectual disabilities (Kildahl et al. 2020; Kolevzon et al. 2019; Rysstad et al. 2022; Verhoeven, Egger, and de Leeuw 2020), including verbal communication difficulties, unusual or atypical symptom expressions, lack of appropriate assessment tools, and lack of knowledge in clinicians (Bakken et al. 2016; Deb et al. 2022; Halvorsen, Kildahl, and Helverschou 2022; Halvorsen et al. 2023; Hollocks et al. 2019; Rosen et al. 2018). These challenges involve a risk of diagnostic overshadowing (Reiss, Levitan, and Szyszko 1982), in which symptoms of a co-occurring mental disorder are misattributed to the underlying condition(s), and are therefore not adequately treated (Bakken et al. 2016; Jopp and Keys, 2001; Kildahl, Oddli, and Helverschou 2023). In addition, the assessment of conditions in which symptoms occur in phases, such as bipolar disorder, presents additional challenges because the assessment has to take account of potential symptom cycles or changes over time (Rysstad et al. 2022; Valdovinos et al. 2019). Comprehensive multi-informant assessments including developmental and symptom histories, conducted over time, as well as the use of multiple assessment tools and clinical observation, are likely to be necessary (Deb, Perera, and Rossi 2022; Halvorsen, Kildahl, and Helverschou 2022; Kildahl, Oddli, and Helverschou 2023; Kildahl et al. 2020; Valdovinos et al. 2019).

Previous descriptions of the treatment of bipolar disorder in PHMDS indicate that treatment strategies are generally in line with the guidelines for the treatment of bipolar disorder in the general population (Denayer et al. 2012; Egger et al. 2016; Kolevzon et al. 2019; Srivastava et al. 2023; Verhoeven, Egger, and de Leeuw 2020). This includes the use of mood stabilisers as the first choice and second generation/atypical antipsychotics in combination with anticonvulsants have been associated with good responses in a number of cases (Kolevzon et al. 2019; Rysstad et al. 2022; Srivastava et al. 2023; Verhoeven, Egger, and de Leeuw 2020). However, individuals with PHMDS appear to be sensitive to the side effects of antipsychotics, and monitoring potential side effects is recommended if antipsychotics are prescribed in this population (Kohlenberg et al. 2020; Kolevzon et al. 2019; Rysstad et al. 2022; van Balkom et al. 2023; Verhoeven, Egger, and de Leeuw 2020). As in the general population (Gill, Bayes, and Parker 2020), the use of antidepressants has been described as potentially triggering mania in individuals with PHMDS (Kohlenberg et al. 2020), indicating that antidepressants are not suitable (Kolevzon et al. 2019).

Benzodiazepines are the first choice in the treatment of acute catatonia (Ghaziuddin, Andersen, and Ghaziuddin 2020; Walther et al. 2019), and this seems to also apply to individuals with PHMDS (Kolevzon et al. 2019; van Balkom et al. 2023). Previous findings suggest that catatonia in PHMDS may co-occur with bipolar disorder (Denayer et al. 2012; Kohlenberg et al. 2020; Kolevzon et al. 2019; van Balkom et al. 2023). Because it is recommended to identify and treat any underlying cause of catatonia (Fink, 2013; Rosebush and Mazurek, 2010), the pharmacological treatment of these disorders may need to be integrated and coordinated (Kolevzon et al. 2019).

In order to adequately discern the effects of pharmacological treatment in autistic individuals with intellectual disabilities, it may be necessary to only make one change in treatment or dosage at a time (Deb, Bertelli, and Rossi 2022; Rysstad et al. 2022). When catatonia co-occurs with bipolar disorder, it may be necessary to use two or three medications simultaneously in order to stabilise the symptoms, making it not only challenging to decide what treatment should be attempted but also the sequence and intervals at which it should be introduced. Moreover, not all attempts at treatment are likely to be successful (Kohlenberg et al. 2020; Kolevzon et al. 2019; Rysstad et al. 2022; Verhoeven, Egger, and de Leeuw 2020), indicating that further knowledge on how symptoms of catatonia and bipolar disorder may interact in individuals with PHMDS, particularly during treatment, is important in order to improve the organisation of treatment for these disorders.

Because PHMDS is a relatively recently described genetic syndrome (Tabet et al. 2017), the current literature seems to be based primarily on children, adolescents and younger adults (Kolevzon et al. 2019). This includes the sparse literature on symptom trajectories in the treatment of bipolar disorder (Dille et al. 2023; Kohlenberg et al. 2020; Rysstad et al. 2022; Verhoeven, Egger, and de Leeuw 2020). The current study aims to explore and describe the pharmacological treatment and symptom trajectories of bipolar disorder and catatonia in an adult autistic man with co-occurring intellectual disability and PHMDS. Furthermore, the study aims to illustrate the clinical complexity of this case, including the potential for diagnostic overshadowing during assessment, as well as during the evaluation of treatment outcomes.

Materials and methods

Case study methodology (Yin, 2014) was chosen to allow for more in-depth exploration of pharmacological treatment and symptom trajectories. The study was approved by the data protection officer at the University Hospital of Northern Norway. Written informed consent was obtained from the patient’s legal guardian, and the legal guardian has approved the submitted version of this manuscript. The patient has been anonymised.

Case description

‘Frank’ was 47 years old at the time of the referral. He had been diagnosed with an autism spectrum disorder and mild intellectual disability. PHMDS had been diagnosed when Frank was 43. SNP array analysis (CytoScan HD matrix) showed a 62 kb heterozygote microdeletion in chromosome 22 (arr[hg19] 22q13.33(51,121,452–51,183,870)x1 dn). This microdeletion was confirmed by FISH analysis, and was not detected in the parents. The SHANK3 and ACR genes were at least partially deleted, but since the breakpoints of the deletion are not known, it could not be ruled out that larger parts of the SHANK3 and ACR genes were affected.

Frank is the fourth child of unrelated parents and there are no other developmental issues in his immediate family. In his early development, he met all the gross motor milestones at the expected ages, and had normal vision and hearing. At age ten, he was described as a good football player and played on a team with peers without developmental disabilities. He had some difficulties with fine motor skills and language development, speaking one-word utterances at age 4. At age 11, he spoke in short sentences, though often with grammatical errors, and was reported to frequently misunderstand the utterances of others. At this age, Frank compensated for his verbal language difficulties by pointing and using non-verbal communication strategies.

Frank attended kindergarten from the age of three and received special education from the age of four, focusing on his language development. He started attending primary school with a one-year delay, at age 8, and was described as an active boy who struggled to concentrate. He mastered reading and basic writing, as well as lower level mathematics. Throughout his school years, Frank was described as an anxious child with separation anxiety and tantrums. He was described as being at his best when his mother was present and was able to adapt his surroundings to his needs. If frustrated or angry, Frank displayed self-injurious behaviours, including banging his head against hard surfaces or hitting his head with his hand. Frank was diagnosed with a mild intellectual disability at age 16, scoring just below the threshold of IQ < 70 on the Wechsler Intelligence Scale for Children – Revised (Wechsler, 1974; 1991).

Frank left home at 16, first attending a boarding school for adolescents with developmental disabilities, before moving into a group home and receiving services from professional caregivers in his municipality. In his young adult life, Frank was described as a positive and sociable man. He was described to have friendships with his peers at his day centre/workplace, he enjoyed going to cafés and pubs, listening to music and dancing, as well as going swimming. Frank was described to like his surroundings to be neat and tidy and as needing routines and predictability in his daily life.

Mental health and medical history

According to information from Frank’s medical records, depressive symptoms had first been described by his caregivers at age 23, see Table 1 for timeline. He reported having stomach aches and was described as compulsive and anxious. It was reported that these symptoms coincided with an ongoing conflict between Frank’s mother and his professional caregivers.

Table 1. Timeline of life events, concerns and treatment interventions.

Age	Life events/treatment interventions	Concerns/behavioural changes
20	Lives at care facility, attends day centre/workplace.	Speaks in short sentences. Participates in activities. Appears content.
23	Moves into a new care facility, no change of workplace. Conflict between family and service providers.	Professional caregivers concerned about possible depression.
29	Mother becomes ill. Paroxetine prescribed.	Loss of speech and reduced activity level. Unusual posturing and reduced use of right hand. Loss of adaptive skills.
30		First concerns about possible dementia.
32	Paroxetine discontinued.	Motor rigidity. More focused on routines, needs more assistance. Facial grimacing. Concerns about possible dementia.
35	Referred to neurologist, negative EEG.	Suspected epilepsy.
40–43		Decline in intellectual and adaptive skills. Concerns about possible dementia.
43	Genetic testing. Diagnosed with PHMDS.	Regained some skills, returned to workplace.
46	Loss of two close relatives. Workplace closes due to COVID-19-related restrictions.	Cognitive and motor decline, motor rigidity. Communicates primarily in one-word utterances. Incontinence and confusion. Concerns about possible dementia.
47	Paroxetine 20mg prescribed by GP. Current referral. Mental health assessment initiated (PAC/ABC, see Table 2). Neurological assessment. Brain MRI without pathology.	Incontinence, hypertonia, motor rigidity, disoriented, weight loss of 10 kg, loss of initiative and positive emotions. Concerns about possible dementia
48
March	Paroxetine increased to 40 mg by GP.	Shows more initiative
April		Catatonia diagnosed
4 May		Psychiatric screening reveals symptoms of depression
11 May	Catatonia treatment initiated, lorazepam 1 mg/3.	Language use improved, speaks mostly in two-word utterances. Reduced catatonia symptoms.
26 May	Lorazepam dosage increased to 2 mg/3.	Further improvement of catatonia symptoms
5 June		Improved adaptive skills, more energetic. Mania symptoms reported to have occurred over several days.
7 June	Lorazepam reduced to 1 mg/3.	Increased catatonia symptoms. Mania symptoms somewhat reduced.
8 June	Paroxetine reduced to 20 mg.
16 June	Lorazepam increased to 2 mg/3.	Reduction of mania symptoms.
24 June		Psychiatric screening shows significant symptom reduction (PAC/ABC after six months, see Table 2)
7 July	Paroxetine discontinued.
12 July	Initiated lamotrigine 25 mg. Gradually increased dosage over months.	Mood stabilised, further reduction of catatonia symptoms.
Current situation	Lamotrigine dosage 150mg + 100mg (250mg) Serum level 22.3mmol/L, no side effects. Lorazepam 2mg/3	Speaks in more words, shows more initiative, expresses needs and wishes. Improved adaptive functioning in everyday life. Continent. Mood appears stabilised, absence of mania symptoms/depressive symptoms (PAC/ABC after 1.5 years, see Table 2). Catatonia symptoms remain significantly reduced.

When Frank was 29, his professional caregivers had suspected a possible mental health disorder due to the loss of adaptive skills, and he seemed quieter/reserved and was easily agitated. At the time, Frank was described as twisting/convulsing his entire upper body in a peculiar manner when looking sideways. A reported loss of fine motor skills stated that he had stopped using his right hand.

At 35, Frank was referred to a neurologist because his professional caregivers reported altered responsivity. An EEG showed no signs of epilepsy. Between the ages of 40 to 43, Frank again showed an apparent decline in his intellectual and adaptive skills and early dementia was suspected. He also showed signs of increased aggression and refused to attend his day centre/workplace. The suspicion of dementia was weakened, however, as his condition did not deteriorate and Frank regained some of his skills and returned to his day centre/workplace.

Referral

For the current episode, Frank was referred at age 47 because of suspected dementia. Leading up to this referral, his family and professional caregivers had grown increasingly concerned about his health and behaviour. They reported a gradual deterioration in Frank’s adaptive behaviour, as well as motor and verbal language skills over the course of a year, in addition to a weight loss of 10 kg and an apparent increase in frustration, particularly in situations where perceived demands exceeded his abilities.

A new pair of glasses were reported to improve his balance and gait to some extent, while dental care halted the continuing weight loss. However, even though Frank’s appetite improved after receiving dental care, he did not regain weight. He seemed less interested in activities, showed less initiative, and needed more help and instruction performing familiar tasks. At the swimming pool, Frank started wandering around instead of getting into the water. When the COVID-19 pandemic hit, Frank’s workplace and the café he usually visited once a week closed down for several months. Frank had difficulties managing this change in routine. However, when his workplace reopened, Frank showed little interest and did not attend, and his apparent decline in adaptive skills continued. He still seemed to enjoy passive activities such as watching TV.

As for the decline in his adaptive skills, this was reported to have been ongoing for ten years and to have been more pronounced during the two years leading up to the referral. For instance, Frank was no longer able to brush his teeth, he could not dress himself, use the toilet by himself, use the dishwasher, etc., tasks he had performed independently earlier in his life. He was reported to show signs of confusion and often had difficulties finding his way, even in familiar places, and displayed disorganised behaviours. For instance, Frank would get up in the middle of the night, eat bananas without removing the peel or drink soap, which he had never done before.

Assessment

Frank was referred to a specialised outpatient clinic for adults with intellectual disabilities/ASD and a comprehensive interdisciplinary assessment was conducted by a team comprising a psychiatrist, clinical neuropsychologist, physical therapist, and an intellectual disability nurse. Frank was also examined by a neurologist.

Observation by the physical therapist indicated increased muscle tonus in Frank’s arms and legs, particularly in his arms, and this was more pronounced on his right side. It was noted that Frank frequently grinned, although it did not seem to be associated with positive emotion. Physical pain was suspected as a contributory factor to Frank’s difficulties, and his score on the Chronic Pain Scale for Nonverbal Adults with Intellectual Disabilities (CPS-NAID; Burkitt et al. 2009) was 14, where 10 is the cut-off value. The results indicated burning or superficial pain, particularly in Frank’s right arm, upper back and neck area.

As for his adaptive skills, Frank had a standard score of 20 on the Vineland Adaptive Behaviour Scales, Second edition (Vineland-II; Sparrow et al. 2005), indicating floor effects. It was noted that this was not in line with previous descriptions of his adaptive level of functioning. Screening with the Adaptive Behaviour Dementia Questionnaire (ABDQ; Prasher, Farooq, and Holder 2004) resulted in a score of 89, higher than the cut-off of 78. The reported motor symptoms, including increased muscle tone, were interpreted by the psychiatrist as possible catatonia, retarded type. This was supported by a medical examination identifying catalepsy and waxy flexibility, resulting in a severity score of 20 on the Bush Francis Catatonia Rating Scale (BFCRS; Bush et al. 1996; Oldham, Wortzel, and Francis 2020), indicating likely catatonia. Following this examination, the pain identified on the CPS-NAID was assumed to be catatonia related.

During an attempted neuropsychological examination, Frank did not respond when asked to point at body parts. During a picture-naming task, he verbally and correctly named a car but no other picture. When asked ‘can you eat it?’ to a picture of a banana, Frank nodded, but did not name the banana. When asked about the colour of objects, he responded ‘blue’ to all the pictures. The clinical impression during the examination was that Frank watched and paid attention but frequently did not respond, answered ‘I don’t know’ or answered with an association (e.g. when asked from what animal we get milk, he answered ‘in the morning’). He was not able to name the next number or letter in a sequence, but could correctly point at these in written text.

On mental health measures for people with intellectual disabilities, Frank scored above the cut-off values for pervasive developmental disorder/autism, organic syndrome, and anxiety on the Diagnostic Assessment for the Severely Handicapped-II (DASH II; Matson et al. 1991). On the Reiss Screen for Maladaptive Behaviour (Havercamp and Reiss, 1997; Reiss and Valenti-Hein, 1994), he had an elevated score for physical signs of depression. On the Psychopathology in Autism Checklist (Helverschou, Bakken, and Martinsen 2009; Helverschou et al. 2021), see Table 2, he scored above the cut-offs for general adjustment difficulties, psychosis, depression, and anxiety but not for obsessive-compulsive disorder.

Table 2. PAC and ABC scores at referral and during treatment, with Reliable Change Index (RCI).

	Cut-off	At referral	RCI	After 6 months	RCI	After 1.5 years
Psychopathology in Autism Checklist (PAC)
General Adjustment Problems	2.0	2.6′	4.54*	2.0′	6.80*	1.1
Psychosis	2.3	2.6′	4.57*	2.0	6.85*	1.1
Depression	2.0	3.0′	6.09*	1.7	0.94	1.5
Anxiety	1.8	2.3′	5.60*	1.0	−0.86	1.2
Obsessive-Compulsive Disorder	2.4	1.7	2.65*	1.0	−0.38	1.1
Aberrant Behavior Checklist (ABC)
Irritability		5	−0.34	6	1.71	1
Lethargy		15	4.11*	3	−2.06*	9
Stereotypy		0	−0.65	1	−0.65	2
Hyperactivity		6	0.32	5	0.32	4
Inappropriate Speech		4	−2.55*	8	3.19*	3

Note. Scores on or above cut-off on the PAC are marked by an apostrophe. PAC and ABC were scored in interviews with Frank’s professional caregivers. Norm data for calculation of the RCIs were retrieved from Helverschou et al. (2009) and Halvorsen et al. (2019). Statistically significant RCIs (p < 0.05) are marked by an asterisk.

Because bipolar disorder is associated with PHMDS, further exploration of Frank’s medical history was conducted with the aim of unearthing any previous manic or hypomanic episodes. No examples of such episodes were identified. Frank’s professional caregivers reported that following activities he was particularly enthusiastic about, he could have difficulties regulating his excitement and enthusiasm and would be perceived as more talkative and active, laughing more than he usually did. However, these episodes did not influence the quality of his sleep and he always returned to his habitual state by the next morning.

During one of his previous depressive episodes, Frank had successfully been prescribed an antidepressant, paroxetine. Prior to the current assessment, his general practitioner prescribed this medication again, starting at 20 mg before increasing the dosage to 40 mg. Frank’s professional caregivers noted a partial improvement of his motor symptoms, depressive symptoms, and his adaptive skills at initiation, as well as when the dosage was increased.

In the diagnostic formulation, it was concluded that Frank met the criteria for a major depressive disorder and catatonia. Because of its trajectory, catatonia was assumed to be associated with the depressive disorder.

Treatment

In order to evaluate any changes in treatment, only one change was made to Frank’s pharmacological treatment at any time (Deb, Bertelli, and Rossi 2022). Frank appeared to be in pain, and the response to catatonia treatment with benzodiazepines is often rapid and would help verify the diagnosis (Sienaert et al. 2014). Moreover, retarded and untreated symptoms of catatonia can switch to a malignant state (Edinoff et al. 2021; Walther et al. 2019), which in rare cases can be lethal (Edinoff et al. 2021). Thus, treatment of catatonia was chosen as the most urgent pharmacological intervention. While electroconvulsive therapy (ECT) has shown positive effects on catatonia (Lloyd et al. 2020), as well as on mood disorders (Kolar, 2017), ECT was not considered as the primary treatment due to legal restrictions on its use in people with limited capacity to consent in Norway.

The treatment of choice for catatonia, lorazepam (Pelzer, van der Heijden, and den Boer 2018; Walther et al. 2019), was initiated at 1 mg three times daily. The following day, Frank’s caregivers reported a striking effect on his motor function, as well as his speech and language use. No side effects were observed. Severity score on the BFCRS was 7, indicating likely catatonia, but was reduced from the score of 14 during assessment (Bush et al. 1996; Oldham, Wortzel, and Francis 2020). After 14 days, the dosage was increased to 2 mg three times daily, resulting in a marked behavioural change. He became increasingly active, repeatedly stating that he wanted to go out to cafés, etc. He became more talkative and started talking to strangers in a loud and intense manner, laughed a lot, and periodically shouted. Frank’s mood seemed to be elevated and he showed signs of disorganisation. He seemed irritable, expressing frustration when his wishes or demands were not met, and he showed sexualised behaviours that clearly differed from his habitual state. Finally, Frank developed difficulties sleeping and wandered around his apartment during the night, demanding to go out. Using the Young Mania Rating Scale (YMRS; Young et al. 1978; see also Rush, First, and Blacker 2008) with his caregivers as proxy informants, Frank scored 26 (range 0–60), indicating a moderate manic episode.

Because the increased dosage of lorazepam was suspected to have triggered an apparent manic episode, the dosage was reduced to 1 mg three times daily. The previous muscle rigidity and motor symptoms returned to some degree, but it was decided to maintain this reduced dosage until symptoms of mania had been alleviated. To relieve the mania symptoms, Frank’s professional caregivers were informed about environmental strategies to reduce them, including reducing stimuli and re-establishing his sleeping pattern. The paroxetine dosage was reduced from 40 mg to 20 mg and a plan for discontinuation was formulated. While these measures helped re-establish Frank’s sleeping pattern, his mania symptoms persisted in a less intense form, varying somewhat from day to day. The YMRS score in this period was 15, in line with a mild manic episode. Following the discontinuation of paroxetine, the lorazepam dosage was again increased to 2 mg three times daily. This had a clear effect on Frank’s motor symptoms and muscle rigidity but did not increase or otherwise appear to affect the remaining mania symptoms.

Following two more weeks of persistent mild mania symptoms, it was decided to initiate a mood-stabilising drug. Antipsychotics were avoided due to the catatonia (Sienaert et al. 2014; Srivastava et al. 2023; Verhoeven, Egger, and de Leeuw 2020) and an anticonvulsant was chosen, in line with the current expert consensus recommendations for PHMDS (Srivastava et al. 2023; van Balkom et al. 2023). Lithium was ruled out because Frank had difficulties taking blood tests (Nederlof et al. 2018). Because symptoms of depression had been predominant in Frank’s life, lamotrigine was chosen over sodium valproate. In addition, the receptor affinity of lamotrigine has been suggested to have a potentially favourable effect on symptoms of catatonia (Ellul and Choucha, 2015; Konstantinou, Papageorgiou, and Angelopoulos 2021).

Lamotrigine was introduced at 25 mg, and gradually increased over several months to 250 mg, with plasma concentration of 22.3mcgmol/L. No significant side effects were observed, the remaining mania symptoms were alleviated, and a mood-stabilising effect was reported. The PAC and the Aberrant Behavior Checklist (ABC; Aman et al. 1985; Halvorsen, Myrbakk, and Martinussen 2015) were used to monitor treatment response, as previously described by Rysstad et al. (2022), see Table 2. Following the increase of lamotrigine dosage to 250 mg, no PAC scale was over the cut-off, and the score on lethargy/social withdrawal on the ABC was significantly reduced from referral. The YMRS score was 1, indicating no remaining symptoms of mania. While still indicating likely catatonia, the BFCRS severity score was further reduced from 7 to 5 (Bush et al. 1996; Oldham, Wortzel, and Francis 2020).

Results

Following catatonia treatment with lorazepam, Frank appeared to develop symptoms of mania. It was understood that these had potentially been triggered by the use of paroxetine, but that they were overshadowed by catatonia and only became observable when the catatonia was treated with lorazepam. Following these observations, the diagnosis was changed from a major depressive disorder to a bipolar disorder.

One year after initiating the combined treatment of lorazepam and lamotrigine, the symptoms of catatonia are still significantly reduced and the affective symptoms remain stabilised. This reduction is also apparent from his PAC scores, see Table 2, and Frank has gradually regained more of his adaptive skills during this year. Nevertheless, his current intellectual and adaptive skills remain significantly reduced compared to his described functioning in his teenage and early adult years. At that time, he was diagnosed with a mild intellectual disability, while his current functioning is more in line with a severe intellectual disability.

Discussion

The current case demonstrates the importance of considering the treatment of catatonia in the context of a co-occurring affective disorder, and vice versa, in autistic individuals with intellectual disabilities and PHMDS. This is of importance as the respective conditions may be related, and their respective treatments may affect each other. These findings add to the current evidence base for the treatment of mental disorders in PHMDS, and are in line with previous recommendations that antidepressants should be used with caution in this population. Moreover, the current findings are in line with previous accounts that anticonvulsants may be an effective treatment for bipolar disorder in autistic people with intellectual disabilities and PHMDS, including when used in conjunction with treatment for catatonia. Assessment scales especially adapted for this population (e.g. PAC and ABC), as well as more conventional assessment tools (e.g. YMRS) were helpful in the assessment and monitoring of treatment. Finally, these findings highlight the importance of conducting genetic assessments in autistic people with intellectual disabilities who present with potential symptoms of a mental health disorder.

The phenotypes of people with PHMDS show a high degree of variation, including their profiles of co-occurring difficulties (Dhossche et al. 2023; Kolevzon et al. 2019; Landlust et al. 2022; Phelan and McDermid, 2012; Srivastava et al. 2023; Tabet et al. 2017), highlighting the importance of establishing a baseline for each individual’s functioning in assessment and treatment of co-occurring difficulties. In the current case, the timeline, as displayed in Table 1, was helpful in establishing this baseline, including potential loss of functioning during different life stages and aided the clinical team in making the diagnoses of catatonia and bipolar disorder. Moreover, this timeline proved helpful in systematic evaluation of treatment effects and delineating the treatment of the co-occurring catatonia and bipolar disorder. Establishing such a baseline for each individual is important in assessment and treatment of mental health problems and other co-occurring difficulties in PHMDS, and is in line with recent PHMDS guidelines (van Balkom et al. 2023), as well as for mental health assessment in people with intellectual disabilities more broadly (Deb et al. 2022; Kildahl, Oddli, and Helverschou 2023).

For the current patient, the introduction of catatonia treatment using lorazepam seemed to trigger mania symptoms. However, this only occurred during ongoing treatment with the antidepressant paroxetine, and an increase in lorazepam dosage following discontinuation of paroxetine did not increase mania symptoms. It has previously been stated that antidepressants have the potential to trigger a manic switch in patients with bipolar disorder and PMDHS (Verhoeven, Egger, and de Leeuw 2020). For the current patient, this manic switch only became evident when lorazepam was introduced. No direct interactions between lorazepam and paroxetine have been registered, and we are not aware of any indications that this combination may trigger mania in other patients without an underlying bipolar disorder (Dinsmore, 2010; Hashimoto et al. 2021). While hyperactivity may be a potential side effect of lorazepam in people with intellectual disabilities, mania is not a registered side effect (Kalachnik et al. 2002). Moreover, mania symptoms did not increase at the same dosage of lorazepam after paroxetine had been discontinued. Thus, a possible explanation is that the manic switch occurred prior to the introduction of lorazepam, independent of catatonia, but that this manic switch was not observable due to the catatonia. In addition, psychological and environmental factors may have contributed to exacerbating the symptoms of mania. When the patient regained his motor functions and seemed more interested and motivated to participate in activities, his professional caregivers were happy to oblige, which may have led to the patient suddenly having access to an overly stimuli-rich environment.

The complexity of this case, including the reported symptom trajectories, illustrates the challenges that many clinicians, professional caregivers, and family members face in the treatment of mental health disorders in autistic patients with co-occurring intellectual disabilities. These findings underline the importance of having a well-defined treatment strategy, in which the sequence of treatment interventions is well-planned and communicated, as well as properly implemented. The case further illustrates the importance of using antidepressants with caution in people with PHMDS and affective disorder and, if used, closely evaluating the treatment effects and potential side effects (Kohlenberg et al. 2020; Kolevzon et al. 2019). The current case indicates that this is particularly important in the context of co-occurring catatonia and lorazepam treatment.

In the current case, lamotrigine was chosen as the primary mood-stabilising agent due to previous descriptions of its effectiveness in people with PHMDS (Kolevzon et al. 2019; Rysstad et al. 2022; Srivastava et al. 2023; Verhoeven, Egger, and de Leeuw 2020), its inclusion as a treatment of choice by the expert consensus group for the treatment of affective disorder in PHMDS (Srivastava et al. 2023), and because it is well tolerated and especially suitable for patients with bipolar disorder in which depressive symptoms predominate (Hashimoto et al. 2021). Moreover, while the pathophysiological mechanism for catatonia is not yet fully understood, current theories suggest that neurotransmitter-related mechanisms, including increased levels of glutamate and decreased levels of GABA, may be involved (Edinoff et al. 2021; Ellul and Choucha, 2015). It has therefore been suggested that pharmacological treatment targeting both neurotransmitter systems may be suitable for the treatment of more treatment-resistant forms of catatonia. Lamotrigine and acamprosate are examples of existing medications that dually target these neurotransmitter systems (Dinsmore, 2010; Kalk and Lingford-Hughes, 2014). Thus, lamotrigine may be particularly suitable for the treatment of bipolar disorder in PHMDS when co-occurring with catatonia.

As described in previous cases (Kohlenberg et al. 2020; Rysstad et al. 2022), evaluating treatment interventions can be challenging and may require a systematic approach to obtaining standardised information about symptom development. In the current case, the use of the ABC and PAC to monitor depressive symptoms and evaluate potential treatment effects was perceived as helpful and it supported clinical decision-making. Moreover, even though it was used in a non-standardised way, with proxy informants rather than self-report, the YMRS was perceived as helpful in monitoring the presence and severity of the patient’s mania symptoms. BFCRS (Bush et al. 1996; Oldham, Wortzel, and Francis 2020) was helpful for evaluation of catatonia during assessment, as well as during treatment evaluation.

Finally, the current case highlights the importance of genetic assessment and etiological diagnosis. Prior knowledge that the patient had PHMDS enabled a more targeted assessment of existing symptoms, in line with existing knowledge concerning specific risks appearing to be associated with the syndrome. Of special importance are the treatable conditions of bipolar disorder and catatonia which, when left untreated, can significantly impact the quality of life for the patient and their family. In the current case, the first occurrence of an apparent neuropsychiatric regression was described as occurring at the same time as the suspected first depressive episode. While neuropsychiatric regression may occur during different developmental stages and be associated with different causal mechanisms in PHMDS (Dille et al. 2023; Kolevzon et al. 2019; Srivastava et al. 2023; van Balkom et al. 2023), further research is needed to disentangle the relationship between such regressions and mental health disorders in this population. In particular, knowledge concerning the potential reversibility of such regressions in the context of mental disorders is important, as some previous accounts have described individuals regaining their previous level of functioning (Rysstad et al. 2022; Verhoeven, Egger, and de Leeuw 2020), while others have not (Kohlenberg et al. 2020).

In sum, these findings highlight the importance of further research on the neuropsychiatric regressions that appear in individuals with PHMDS, in particular the phenomenology and different causes of these regressions. Such knowledge may improve access to appropriate treatment and increase the likelihood that treatment interventions are more targeted and appropriate for each specific individual. There is a need for further research on treatment of bipolar disorder and catatonia in these individuals, including studies delineating some of the complexities that appear to be common in individuals with PHMDS, as well as the characteristics and trajectories of catatonia. Clinical implications include the helpfulness of establishing a baseline of previous symptoms and functioning during assessment, as well as establishing a ‘current’ baseline for ongoing systematic evaluation of treatment interventions. Finally, the current study highlights that although they have complex and co-occurring difficulties; interventions to improve the mental health quality of life for individuals with PHMDS are available, even if the appropriate interventions sometimes need to be identified through a process of trial and error.

The current study has several limitations. The study concerns a single case and is not generalisable. The findings concerning the potential mechanisms in development and manifestations of mania are limited insofar as they are based on observational data. Finally, while the treatment of bipolar disorder and catatonia was perceived by the clinicians and professional caregivers as successful, the patient was not able to offer his views on the effects of treatment.

Conclusion

This case demonstrates the importance of considering the treatment of catatonia in the context of the treatment of co-occurring affective disorder, and vice versa, in autistic individuals with intellectual disabilities and PHMDS. Even if dementia was suspected, catatonia and bipolar disorder were treatable in the current patient, allowing him to regain some level of adaptive and communicative skills, as well as access to activities that positively affected his quality of life. However, the patient has not fully regained his previous level of functioning, underscoring that the relationship between neuropsychiatric decompensation/regression, loss of skill, and mental disorder in individuals with PHMDS is not yet fully understood.

Acknowledgements

The authors thank ‘Frank’, his family and his professional caregivers for allowing us to write this paper and for contributing in their individual ways. The authors also thank the Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway for their help with interpreting and describing the results of the genetic assessment.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The current study concerns a single case. There is no available data to share beyond the data reported in the paper.