Response to Treatment in 3q29 Deletion Syndrome-Associated Psychosis: A Mini-Review

3q29 deletion syndrome is associated with various developmental abnormalities, including speech and motor delays, mild to moderate intellectual disability, autism spectrum disorder, subtle facial dysmorphism, and structural posterior fossa defects, in addition to numerous medical issues. A variety of neuropsychiatric symptoms may also occur, such as anxiety, attention deficit hyperactivity disorder, and psychosis [1]. Not only can psychosis occur, but 3q29 deletion syndrome may confer the greatest risk for schizophrenia of any copy number variation (CNV), with at least 20–40% of individuals expected to develop the illness [1, 2]. Moreover, the age of onset may be younger than in general schizophrenia populations [1].

While numerous candidate genes have been proposed (e.g., DLG1 and PAK), the genetic basis of the phenotype remains unknown, including with respect to the development of psychotic symptoms [1]. As such, there are currently no available therapies that address the underlying pathophysiology of the disorder [1], and the treatment approach to psychotic symptoms is largely based on a small number of published case reports/series or extrapolated from general schizophrenia populations. However, as antipsychotic treatment response in 3q29 deletion syndrome has not been systematically reviewed, the aim of this mini-review was to do so.

In December 2022, a PubMed search was completed using the term:

“3q29” in combination with “psychosis”, “psychotic”, “hallucination”, “delusion”, “paranoia”, “paranoid”, or “schizophrenia”. The search yielded 62 results (Fig. 1). The abstracts and reference lists of all results were reviewed, and 44 articles of potential relevance were retrieved and assessed for eligibility. Only English language articles that reported the use of psychotropic medications in psychotic individuals diagnosed with 3q29 deletion syndrome were included in the review. Ultimately, five articles that collectively described eight individuals were deemed eligible.

Details regarding the individuals’ psychiatric symptoms and response to treatment are described below, whereas their developmental and medical histories (where available) are included in Table 1. Additionally, the proportions of patients who responded to treatment (to varying degrees) are outlined in Table 2.

Sagar et al. [4] described a 16-year-old male who developed tics, “obsessive compulsive behaviours,” stereotyped movements, and choreoathetosis at two years of age. At around age four, he received a diagnosis of pervasive developmental disorder – not otherwise specified, while Sydenham chorea and paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections were also considered. At some point, he also received diagnoses of obsessive compulsive disorder and autism. At age five after developing “chicken pox,” he was described by his mother as being in an “odd psychotic state” that involved him covering his ears and seeing “things on the wall moving,” as well as an alleged inability to recognize his mother. He “misinterpreted noises” and experienced auditory hallucinations that involved “a clock ticking inside his head,” as well as visual hallucinations; all of which reportedly prevented him from leaving his house. While his medication history and response to antipsychotic treatment were not described in detail, the authors reported that he had been trialed on a “long list of typical and atypical antipsychotics, antidepressants, and mood stabilizers” and that his auditory hallucinations “responded to antipsychotic medications.” Additionally, the authors reported that after being on many medications, he “improved” on loxapine. While no dose was provided, the authors stated that he was on “16% of the maximum recommended dose.” However, his “perseveration, obsessions, and compulsions” worsened at age 16, and he was cross-titrated to quetiapine 150 mg/day as loxapine “no longer controlled his symptoms.” While his symptomatic response to this switch was not described, he experienced an unusually severe antipsychotic withdrawal dyskinesia (described in detail in the article), resulting in an Abnormal Involuntary Movement Scale score of 25.

Malt et al. [5] described a 29-year-old female who experienced early-onset psychosis and was eventually diagnosed with “paranoid schizophrenia with persisting hallucinations.” She had “recurrent psychoses from age 14” with frequent psychiatric admissions. While she exhibited only a partial response to antipsychotic therapy, no further details regarding the nature of her symptoms or the particular antipsychotic medications trialed were provided.

Harner et al. [6] described an affected 57-year-old woman with treatment-resistant schizophrenia (“paranoid subtype”) and early-onset dementia. Her first psychiatric admission occurred at 19 years of age following a sexual assault, and her psychotic symptoms included auditory hallucinations of “threatening voices,” Capgras delusions involving concerns that her family had been replaced by imposters, and paranoia. She was subsequently readmitted to hospital at the ages of 23, 24, and 26 years. While medication non-adherence had historically been an issue, by 29 years of age, she had become compliant with her treatment and her auditory hallucinations subsided. However, “she remained delusional, asocial, and unemployable.” Medication trials up to that point included fluphenazine decanoate, perphenazine, and risperidone. Fluphenazine provided “moderate symptom relief,” despite persistent disorganization of thought and behaviour, paranoia, and Capgras delusions. Her symptoms worsened after discontinuing her medication at the age of 32, prompting another psychiatric admission. Treatment with 35 mg/day of oral haloperidol as well as 100 mg/three to four days of haloperidol decanoate did not improve her symptoms over the course of six weeks, and she was transferred to a state psychiatric hospital. As “adequate trials” of olanzapine and aripiprazole were also ineffective, clozapine was initiated (and titrated to a dose of 425 mg/day) with “modest improvements,” despite severe, albeit “stable,” persisting hallucinations and delusions that never remitted. Specifically, her agitation and hallucinations lessened but did not resolve entirely, while her delusions and social functioning did not improve. Around the age of 56, she began to exhibit cognitive decline, prompting a trial of donepezil, which was eventually discontinued. While specific negative symptoms were not described in detail, at the time of recruitment into the study, her Positive and Negative Syndrome Scale (PANSS) negative subscale score was reported to be 18/49, with symptoms of blunted affect, social withdrawal, difficulty in abstract thinking, lack of spontaneity, and stereotyped thinking. Comorbid psychiatric issues included hoarding, excoriation, and OCD behaviours, as well as anxiety. At the time of the assessment, her medication regimen included aripiprazole 15 mg/day, risperidone 1 mg/day, prochlorperazine 15 mg/day, clozapine 275 mg/day, buspirone 15 mg/day, sertraline 50 mg/day, and lorazepam 20 mg/day.

Nawa et al. [3] described four affected individuals diagnosed with schizophrenia. The first patient was a 55-year-old female who experienced insomnia and social anxiety at 18 years of age before developing psychotic symptoms at age 20 after patent ductus arteriosus surgery. Her psychotic symptoms included persecutory delusions as well as auditory hallucinations, and she was described as being irritable. While her symptoms reportedly initially remitted with outpatient antipsychotic treatment, she relapsed for unclear reasons, and her psychotic symptoms became increasingly treatment-resistant. At the time of her assessment at age 55, her symptoms included “severe positive symptoms” and thought disorganization, as well as “elevated, expansive mood” and “increased speech,” despite remaining on paliperidone 12 mg/day, quetiapine 650 mg/day, chlorpromazine 150 mg/day, and valproate 1,000 mg/day. As a result, she was described as having treatment-resistant schizophrenia, but clozapine was not trialed as it was thought that her cognitive impairment and disordered thought process would have made it difficult to “manage her medication.” Severe negative symptoms were also described, including avolition, asociality, affective flattening, and social withdrawal, in addition to cognitive impairment, as mentioned.

The second patient was a 46-year-old male with autistic features who developed auditory hallucinations, persecutory delusions, “monologue,” and agitation at age 27. He was also described as having manic symptoms, including “irritability” and grandiosity. His psychotic symptoms did not “significantly” improve with antipsychotic treatment, and he had been hospitalized nine times. At the time of the assessment, he was taking aripiprazole 6 mg/day, haloperidol 12 mg/day, levomepromazine 180 mg/day, zotepine 150 mg/day, and valproate 800 mg/day. He also exhibited “persistent negative symptoms” including avolition and social withdrawal. While he met criteria for treatment-resistant schizophrenia, clozapine had not been trialed.

The third patient was a 17-year-old female with autistic features who experienced a brief psychotic episode at age 12, characterized by grandiosity and persecutory delusions. She gradually socially withdrew thereafter, and at age 14, she exhibited a “disturbance” of consciousness and bizarre behaviour. As she was found to have an ovarian cyst, anti-NMDA receptor encephalitis was suspected, and although she underwent an ovariectomy, steroid therapy, and antipsychotic treatment, her psychotic symptoms did not entirely remit. Her auditory hallucinations and disorganized behaviour worsened at age 17, and she was described as being agitated and stuporous, even with ongoing antipsychotic treatment, which included olanzapine 15 mg/day and risperidone 6 mg/day. Lithium and valproate were also tried, but as her symptoms did not improve “sufficiently,” she was diagnosed with treatment-resistant schizophrenia. Clozapine was initiated, and her symptoms gradually improved. Lamotrigine was also started for seizures. At the time of the study, her medications included clozapine 400 mg/day, lithium 300 mg/day, and lamotrigine 100 mg/day. While it is not clear if she achieved full remission, the authors noted that she was able to attend high school “without clinically significant symptoms.”

The fourth patient was a 30-year-old female who experienced her first psychotic episode at age 15, characterized by auditory hallucinations, persecutory delusions, and aggressive behaviour. Treatment with olanzapine 20 mg/day, blonanserin 16 mg/day, and valproate 400 mg/day did not lead to significant improvement in her symptoms, and she was hospitalized four times. She was diagnosed with treatment-resistant schizophrenia, and clozapine 450 mg/day led to an improvement in her symptoms. However, after four years of clozapine therapy, she developed leukopenia and neutropenia, and clozapine was discontinued, which resulted in a worsening of her psychotic symptoms, despite “antipsychotic treatment.” As such, clozapine was reinitiated and lithium was added. Her psychotic symptoms gradually improved, and there had been no recurrence of neutropenia. While her negative symptoms were not described, her PANSS negative subscale score at the time of the assessment was 41. While her total score was 156 (positive = 36; negative = 41; general = 79), it is unclear when this was completed with respect to the initiation of clozapine.

Lastly, Quintero-Rivera et al. [7] described a 10-year-old female with a history of autism, who developed auditory hallucinations by age 10, as well as “anger rages” and aggressive behaviours. Her diagnosis was “bipolar disorder with psychotic features versus schizophrenia.” While her response to treatment was not described, her case is mentioned here for the sake of completeness, as the authors noted that she was taking psychotropic medication and was under the care of a psychiatrist.

Of the seven individuals whose response to treatment was described, it is notable that with respect to non-clozapine antipsychotic medications, four of whom had a poor response and only three had a partial (or temporary) response, while none had a good and enduring response. However, the designation of “poor” versus “good” response to treatment may be overly simplistic, as the degree of symptomatic improvement in response to various medications was often only vaguely described in the articles. Moreover, in numerous cases, initial improvement on a given medication was not sustained, further complicating the issue.

Regardless, based on these results, it appears that 3q29 deletion syndrome may not only be associated with an increased risk of psychosis, and possibly early-onset psychosis [1], but also treatment-resistant psychosis. This possibility is congruent with findings from previous studies that have demonstrated an association between the presence of clinically relevant CNVs and treatment resistance in schizophrenia [8, 9]. Although this association may in part be directly related to CNV-specific pathophysiological changes relevant to treatment resistance, it may also be indirectly mediated by the increased prevalence of neurodevelopmental disorder phenotypes in this population [9].

Nonetheless, it is worth noting that among the individuals included in this review, treatment response was not obviously dependent on the presence or absence of a comorbid developmental disorder. For example, while six out of eight individuals were intellectually disabled, autistic, or both, the only two (presumably) neurotypical individuals experienced severe psychotic symptoms and were diagnosed with treatment-resistant schizophrenia, despite one responding well to clozapine [3]. Moreover, the third patient described by Nawa et al. [3], and one of the only two individuals who exhibited a good response to treatment (clozapine, in particular), was described as having autistic features, mild dysmorphism, and suspected epilepsy.

While only three patients described in the literature have been trialed on clozapine, two of whom seemingly had a good response to treatment and one had a partial response. With this in mind, and as was previously noted by Nawa et al. [3], dysfunction of non-dopaminergic pathways in the brain may be responsible for the development of psychotic symptoms in 3q29 deletion syndrome. In particular, as one of the leading candidate genes, DLG1, is involved in the regulation of glutamate receptors [10], clozapine may be more effective in this population compared to other antipsychotic medications, given its interaction with the glutamate system [3, 11].

While the use of clozapine is often limited by its side effect profile and the need for regular blood work, given the results of this review, clozapine should strongly be considered for use in affected patients, provided they are otherwise medically appropriate and meet criteria for treatment-resistant schizophrenia. However, given the increased risk of seizures in 3q29 deletion syndrome [1], patients should be carefully screened in this respect prior to the initiation of clozapine, given its propensity to lower seizure threshold. Relatedly, postictal psychosis should always be ruled out before a primary psychotic disorder diagnosis is made, given that the treatments for the two conditions obviously differ.

In conclusion, 3q29 deletion syndrome-associated psychosis may be particularly treatment-resistant. As such, clozapine should be considered, provided other antipsychotic trials have failed. However, given that only four articles have described medication response in this population, there is a need for more published case reports/series to help better understand treatment response and guide clinical decision-making before more firm and specific recommendations can be made. In support of this, Sullivan and Owen [12] have convincingly outlined the critical importance of publishing systematic case reports that incorporate longitudinal data, including response to treatment, in the field of neuropsychiatric genetics. Doing so has the potential to yield numerous benefits, including with respect to helping guide therapeutic approaches in genetically unique patients [12].

The only grant currently held by Mark Colijn is a “Clinical Research Fund” seed grant (CAD 20,000) through the University of Calgary for the study of anti-neuronal cell surface antibodies and rare genetic variation in treatment-resistant schizophrenia. Mark Colijn otherwise has no conflicts of interest to report.

The author did not receive any funding related to the preparation of this manuscript.

Mark Colijn was the sole author of this paper and was responsible for the development, research, and writing of the manuscript.