Schizophrenia and Other Psychotic Disorders

Psychoses represent a class of disorganizing experiences and clinical disorders associated with significant impairments in perception (hallucinations), delusions, disorganized behaviors, and “reality testing.”¹ Although some disorders like brief psychotic disorder are short term, many psychotic disorders evolve into chronic conditions associated with significant long-term functional impairment. Delirium and other neuro-medical complications need to be ruled out early in evaluation. Schizophrenia spectrum disorders are characterized by positive and negative symptoms as well as long-term deficits in cognitive, social, and occupational functioning. The DSM-5-TR² and DM-ID-2³ classify psychotic disorders as follows:

• Schizoaffective disorder
• Delusional disorder
• Brief psychotic disorder
• Psychotic disorder due to another medical condition — People with delirium require immediate assessment to treat their potentially life-threatening conditions.
• Psychotic disorder due to substance/medication-induced disorder — Psychotic states and specific disorders can be associated with a wide range of medical, neurological, immunological, pharmacological, and genetic/metabolic disorders, thus requiring appropriate medical work-up and interventions. Late onset psychoses and delirium arise from a wide range of cerebrovascular, neoplastic, chronic medical conditions, and neurodegenerative disorders.
• Catatonia associated with another medical disorder and catatonia specifier — less well recognized but may affect more than 15% of people with ASD.^2,4
• Other specified and unspecified schizophrenia spectrum and other psychotic disorder-psychotic symptoms can also occur with mood, anxiety, and stressors/trauma-related disorders. Co-existing psychosis relates to severity of primary psychiatric disorders and frequently requiring more intensive treatments.

Psychotic disorders lie on a continuum that ranges from short-lived states (experiences that include severe psychological trauma and other ecological events) to severe and persistent mental health disorders with either recurrent or chronic symptoms.⁵ An early age of onset along with neurobiological insults, adverse life events, and co-existing neurodevelopmental disorders (IDD/ASD etc.) influence the developmental trajectory SSD.^6-7 These biopsychosocial events may interfere with early treatment and increase the risk for chronicity and treatment resistance. 

SSDs are complex, polygenic, neurodevelopmental disorders associated with significant clinical heterogeneity. The overlap in symptom presentation of ASD and IDD adds to diagnostic complexity. Like other psychotic disorders, SSDs include positive symptoms (hallucinations, delusions, thought and behavioral disorders, and neuro-motor impairments like catatonia). In the past, treatment approaches focused on these positive symptoms. The observations that negative symptoms and neurocognitive deficits had a greater influence on morbidity and outcome shifted focus towards developing better treatments for these traits.

Table 1: SDD Symptoms and Description²

SSDs are highly heritable, but the effects of other biopsychosocial factors cannot be underestimated. Family, twin, and genetic studies support a stress-diathesis model in which inherited vulnerability interacts with environmental stressors, secondary biological hits, and socio-cultural factors to shape the clinical expression of SSDs. Investigating these elements and their impact is essential to our understanding of SSDs in the context of ASD/IDD.

Description of the Person and Background

MB is a 31-year old female with a ten year history of auditory hallucinations (pictures on the walls talking about her, shadows doing things to her, voices laughing and threatening her), occasional visual hallucinations (monsters dressed in black and white capes), increased social isolation and avoidance, and recurring thoughts of being watched by the police. On multiple occasions, she became extremely agitated for no obvious reason and struck wildly at unseen objects. Her local psychiatrist diagnosed her with treatment resistant psychosis due to other medical condition. She also had a poorly controlled mixed seizure disorder that required multiple anticonvulsants. There was no family history of primary psychiatric disorders. 

MB presents with a complex neurodevelopmental syndrome. Her differential diagnosis is a long one, but her symptoms suggest metamorphosis over the past 5 years. She experienced a stepwise regression that created a major shift in her temperament, personality, social interests, and social-communication abilities. She meets the diagnostic criteria for a psychotic disorder (suggestive of schizophrenia) based on clinical symptoms, duration of functional impairment, and episodic catatonic symptoms. There was nothing in her extensive work-up to suggest underlying metabolic or neurodegenerative disorders. There was no substantiated evidence of abuse, neglect, traumatic brain injury, or adverse drug reactions. There was documentation of failed trials of olanzapine, quetiapine, lucosamide, and multiple mood stabilizers. Extensive interviews with the patient, family, group home staff, vocational staff, and reviews of past psychological, medical, and neurological history suggested “visual hallucinations in early childhood” that waxed and waned over time. Her “psychotic symptoms” markedly intensified during her early twenties.

Examination

The examination reveals short stature, widely spaced eyes, expanded nasal bridge, and palmar creases. Her mental status examination was complicated by her catatonic muteness, and pre-occupation with the ceiling fan. She screamed about a monster riding on the blades mocking her. She had no EPS or dyskinesias, but occasional facial grimacing. Her labs show low serum calcium and mild blood abnormalities, low vit D3 and folic acid levels. Her genetic studies reveal a 22q 11.2-deletion syndrome- velo-cardio-facial Syndrome (VCFS) without DiGeorge’s syndrome. MB’s current treatments include risperidone 2 mg/d, fluoxetine 10 mg/d and valproic acid 1500 mg BID (serum drug level of 105), but no psychotherapies or major ecological interventions. MB has a history of complex partial seizures, surgically corrected tetralogy of fallot (congenital cardiac abnormality), submucosal cleft, moderate ID and previous diagnoses of ADHD, social anxiety, and mild ASD. 

Discussion

MB meets the criteria for treatment resistant schizophrenia-like psychotic disorder but lacks a positive family history for schizophrenia. The intriguing point in this case is the presence of 22q11.2 deletions syndrome. MB presents with core features of this deletion syndrome (large copy number variant or CNV). The most interesting part of the story is the convoluted relationship between VCFS and late-onset schizophrenia-like syndrome. This behavioral phenotype has attracted significant attention as a rare CNV that, while representing only a small fraction of schizophrenia-associated CNVs and single nucleotide polymorphisms, is notable because nearly 30% of individuals with velocardiofacial syndrome (VCFS) develop SSDs. 11-12 There are genes involved that affect early brain development and regulation of neurotransmitters, inflammatory, and mitochondrial activity. The treatment of VCFS in part depends on the length of the VCFS copy number variant (missing genes), the presence of co-occurring ID/ASD, ADHD, and epilepsy (less common) as well as a range of psychosocial factors.

Comprehensive treatment requires a thorough review of medical and family history, past interventions, assessment, differential diagnosis, and careful review of treatment options with close monitoring. Modified cognitive behavioral therapies (CBT), trauma-informed care, family and environmental interventions, and other wellness-based programs are an important part of the treatment plan. The goals of effective non-pharmacological intervention include relapse prevention, enhancing pharmacotherapy, and long-term improvements in resilience and health outcomes.^13-14 

Modified forms of CBT are particularly helpful during premorbid, and prodromal (attenuated psychosis) periods, as well as during maintenance treatment and medication tapering. Family involvement, social support, community services, and employment opportunities are essential components of a comprehensive treatment plan.^15-16 

Effective treatment programs depend on these factors:¹⁷  

• Early intervention: Promptly address prodromal, attenuated symptoms and rapid activation during the first episode of psychosis. Utilize CBT, trauma focused therapy, educational/support interventions to reduce the duration of untreated psychosis and enhance treatment compliance.
• Assess Symptoms: Assess symptom severity and distribution of positive, negative, and cognitive symptoms. Negative and cognitive symptoms often do not improve with pharmacotherapy alone; therapy should focus on cognitive, motivational, and behavioral strategies, which appear more effective in improving these symptoms.
• Goal Attainment: Design cognitive and behavioral strategies to train and support enhanced psychosocial, interpersonal, educational, and occupational programs.
• Community and Social Integration: Organize communities, social networks and activities and work-related programs that focus on developing a sense of personhood, place/belonging, and sense of purpose.

Pharmacotherapies are important but adjunctive to treatment. Since introduced in the 1950’s, antipsychotic drugs (APDs) have improved SSD treatment options. There were many advances in APD technology based on a broader understanding of pharmacokinetics, pharmacodynamics, and pharmacogenomics. These hypothesis-driven modifications still leave us without a cure and facing problems with residual negative symptoms, cognitive impairment, treatment resistance, polypharmacy, and persistent, adverse drug reactions. At the same time, the use of APDs expanded into the realm of generalized drug treatment for a variety of nonpsychotic disorders. Nevertheless, we have learned a few things along the way.^{1, 21-25}

• The recovery rates are better for acute, first episode of schizophrenia if the duration until treatment is short, positive symptoms dominate, and there is rapid response to antipsychotic treatments (improvement by six weeks).
• The outcome is less optimistic when the onset is insidious, there is a long duration until treatment of psychotic symptoms, noncompliance and lack of insight are impaired, EPS occurs with limited improvement, negative and cognitive symptoms dominate, and there are comorbid psychiatric, personality and substance use disorders.
• The definition of treatment resistance is usually 2 or 3 drug treatment failures. Some treatment failures are due to noncompliance or side effects such as EPS/akathisia, significant weight/metabolic syndrome (hyperlipidosis/type 2 diabetes), and cardiovascular side effects.
• In addition to noncompliance, treatment resistance is abetted by undertreated comorbid mood disorders (and OCD), unrecognized EPS (including akathisia), high dosing schedules that can mimic negative symptoms, and substance use.
• Long-acting injectable APDs can reduce noncompliance but still can cause side effects such as akathisia and tardive dyskinesia.
• Diet and exercise education programs, access to enjoyable wellness activities, adequate medical care, smoking cessation, and occasionally metformin can be helpful in reducing health care risks associated with APD treatment.
• APDs should be initiated at low doses, slowly titrated with close attention to drug-drug interactions.
• Clozapine is the most effective treatment for refractory patients. Clozapine requires vigilant monitoring for weight gain, cardiovascular toxicity (myopathy), GI complaints, hematological/stem cell suppression, and serum level dependent forms of epilepsy (myoclonic and other generalized seizure disorder).
• If considering tapering antipsychotics for someone with SSDs then consider implementing nonpharmaceutical supports, variants of CBT, and well-structured, a slow, stepwise, and flexible dose reduction schedule of the antipsychotic. It is essential to have close follow-up, and recognition of the difference between clinical relapse and extinction spurts. Clinicians should very slowly taper to prevent withdrawal, dyskinesia, and other side effects.
• Newer treatments for refractory SSDs are being studied including direct-electrical stimulation, transcranial magnetic stimulation, and novel pharmacological treatments.

Psychotic disorders are complex disorders and require careful assessment in people with ASD and IDD. Psychotherapeutic and social interventions are important parts of a comprehensive treatment plan. The successful treatment of SSDs/psychoses in people with IDD is still a work in progress. This chapter touched on many factors and workable solutions and includes evidence that the first- and second-generation antipsychotics work better for managing acute positive symptoms or assisting in maintenance treatment protocols. However, these same drugs are less helpful for chronic SSD with high levels of negative symptoms and cognitive impairments. 

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