The Realities of Childhood Schizophrenia

PSYCHPEARLS PODCAST

Child and adolescent psychiatrist Abhijit Ramanujam, MD, discusses clinically relevant issues in childhood schizophrenia. Dr Ramanujam is Regional Director of Community Psychiatry, Sacramento, CA.

Transcript edited for clarity. -Ed

Laurie Martin (LEM): How common is schizophrenia in children under the age of 18?

Abhijit Ramanujam, MD: The worldwide prevalence of early onset schizophrenia,that is symptoms prior to the age of 18yrs is estimated to be about 0.5% of the population,whereas childhood onset or very early onset schizophrenia which begins prior to the age of 13, has been estimated to be around 0.04% in the United States.Much less is known about the prevalence of childhood onset schizophrenia internationally.

LEM: Is there an age in which a child is too young to consider a diagnosis of schizophrenia? What do we know about early detection of schizophrenia and how soon can it be diagnosed?

Abhijit Ramanujam, MD: Although there is no official age considered too young for a diagnosis of schizophrenia, we have to keep in mind that childhood-onset schizophrenia that starts before aged 13 years is extremely rare.

Whenever a child is suspected of having schizophrenia, the clinical assessment should include a thorough personal, medication, psychosocial and family history as well as physical examination, neurological work-up, laboratory evaluation, and collateral information from family and schools.

In terms of diagnosis, DSM-5 diagnostic criteria for schizophrenia in childhood and adolescence are the same as those used for adult disorders. They include the presence of significant positive and negative symptoms during a 1-month period (such as delusions or hallucinations, disorganized speech, catatonic behavior, and negative symptoms such as lack of motivation and lack of socialization). Disturbance of functioning in 1 or more major areas and continued signs of disturbance for at least 6 months, as well as the exclusion of other psychiatric or medical diagnoses.

Although the diagnostic criteria used in children are the same as those for adults, there are some key differences in clinical presentation:

• Usually hallucinations are much more common than delusions in youth with schizophrenia as compared to adults. The most common hallucinations are auditory with comments or commands. These are often accompanied by visual and tactile hallucinations.

• Although hallucinations are more common, they are least likely to reported. Many youths may not disclose auditory hallucinations since they are scared that the voices may harm them.There may also be delusions associated with it such as "The voices tell me that they will kill me if I talk about them to anyone."

• Children and adolescents are more likely to exhibit negative symptoms such as being socially aloof or having a flat affect which can sometimes be mistaken for depression or lack of motivation for plain laziness as I have actually heard some of the parents describe it.

• Cognitive decline, in particular verbal memory, attention, and concentration, is significantly affected. Delay in language, motor, and social development, and delay or deviation in developmental milestones may be pronounced as well in childhood-onset schizophrenia; although these delays are not diagnostic, they are commonly observed.

LEM: What are the most commonly confused causes of schizophrenia-like behaviors?

Abhijit Ramanujam, MD: There are many other disorders that can be confused with schizophrenia-like behaviors.

The most common one I see is PTSD. PTSD symptoms can include flashbacks which some patients may describe as auditory hallucinations. Hypervigilance and flashbacks together can often be misinterpreted as paranoia and hallucinations. However, you will notice less disorganized thinking and usually symptoms begin after a traumatic event.

Another area is autism spectrum disorders. Misdiagnosis of autism spectrum disorders as a psychotic disorder also occurs very commonly. Common features such as impairment in social communication can be misinterpreted as negative symptoms of psychosis. Stereotyped use of language seen in autism can be confused with disorganized speech.

It is very important to obtain a thorough developmental history and a baseline thought processes which helps distinguish these 2 diagnoses.

Some patients may have a comorbid diagnosis of autism spectrum disorder and schizophrenia. In these cases, you will see a new onset delusion or hallucination lasting longer than 1 month. Disordered or delusional thinking will be distinctly different from the baseline. We usually notice a significant deterioration of social and general functioning with comorbid diagnoses. I sometimes noticed this in children who have been through multiple foster homes. A baseline thought process is difficult to establish in this case since past history is not readily available. These children are more likely to be wrongly diagnosed as having a disorganized thinking process as opposed to a social communication issue.

Schizoaffective disorder can be a difficult one to differentiate since a psychotic syndrome continues to evolve as a child progresses through the developmental process. Again, a thorough longitudinal symptom assessment would help distinguish the 2.

Major depressive disorders with psychotic features or bipolar disorder with psychosis should also be considered very carefully. Usually in depression with psychotic features, the psychosis is generally seen when the depressive disorder has significantly worsened. Guilt dominates in depressive psychosis. In case of bipolar disorder with psychotic features, you generally see psychosis during severe episodes of mood and not during lucid intervals.

Another area that is very important to remember is that in very young children before the age of 6, anxiety can itself present as hallucinations. Many children with symptoms of anxiety report, "Someone called my name;" they may also report visual hallucinations such as "Mama, I see a shadow every night passing by." Most of these children are healthy and nonpsychotic.

Anxiety-related visual hallucinations are very common in preschool children. Usually in the history, you will notice that there will be a precipitating event such as watching a scary movie or video game that triggered such reactions. Whereas in early-onset schizophrenia, you will notice a decline in cognitive function, attention, and concentration, as well as the presence of negative symptoms which indicate psychosis.

Sometimes, substance-induced psychosis that is secondary to steroid use can present very similarly to a primary psychotic disorder. Urine toxicology screens are very important. It is also important to remember that many of the newer recreational drugs may not be detected in current screens; hence a thorough history will help us distinguish between the 2.

In case of delirium, look for waxing and waning of symptoms or evidence of ingestion of substance or any other metabolic abnormalities, since these are usually seen in delirium and not a psychotic illness.

Other medical conditions may also mimic psychotic symptoms. Those include:

• Seizure disorder

• Medication induced

• Encephalitis

• Autoimmune disorder, such as systemic lupus erythematosus

• Metabolic disorder, such as Wilson disease

CASE VIGNETTES

I am only mentioning the positive pertinent factors in each of the following 3 cases for the sake of brevity. All names and identifying factors have been changed. This is for clinical purposes only.

Case presentation 1: Oppositional or something else?

PR is a 17-year-old boy who initially brought in by his father with chief complaints of “very oppositional, up to something, secretive, and angry.”

The father appeared remorseful due to his "busy schedule" for the last 3 to 4 years. His being away also coincided with a gradual deterioration of his son.

PR refused to talk other than state, "I hate them" [my parents].

Neuropsychological tests, detailed medical examinations, laboratory tests, and a urine drug screen came back negative; the clinical picture became clearer as we obtained collateral information.

The mother described her son demonstrated bizarre behavior. She also hesitatingly disclosed family psychiatric issues (many relatives with schizophrenia), which was initially minimized. “It is a taboo and we do not talk about it,” she said.

His siblings disclosed they are fearful of him "Since he stays up all night and talks to himself. He does not seem like our brother anymore."

School reported he was growing increasingly isolative and suspicious of other kids. His grades kept falling. Teachers also responded behavior that was indicative of PR being internally preoccupied.

The approach of the parents changed from “the boy just needs good disciplining” to a gradual understanding and compliance with the treatment plan.

I will discuss the treatment plan further below. But before that I would like to say that PR is doing much better than he was 3 years ago.

Case presentation 2: “The adopted boy who was ‘psychotic.’”

A was adopted at age 3 and was brought in for an evaluation by his adoptive mother at age 9. The adoptive mother insisted he was “psychotic” and fearful of ingesting food because he thought his mother had poisoned it.

On examination, the boy was found to have significant anxiety, ADHD symptoms, and social communication disorder.

His fear of contamination was misinterpreted as paranoia and delusional. He had also watched a “cold cases” forensic science documentary along with his brother a few months ago which was the precipitating factor. Further information revealed he had a family history of anxiety disorder but no family history of schizophrenia.

Case presentation 3: “My daughter is hearing voices.”

SK is a 7-year-old girl who was brought in for auditory hallucinations. A detailed history revealed a traumatic past (she had witnessed domestic violence). Although currently she lives in a safe environment, she continued to experience flashbacks in the form of auditory hallucinations. There was no family history of psychotic disorders.

After 6 months of cognitive behavioral therapy and trauma-related behavioral therapy, the patient is doing significantly better.

LEM: What are some of the common therapeutic approaches in the treatment of childhood schizophrenia?

Abhijit Ramanujam, MD: We can divide this into 2 sections.

Treatment during the prodromal stage. In this stage, medications are aimed at delaying or stopping progression to psychotic disorder amongst children who are considered high risk or those that have prodromal symptoms, such as disorganized behavior, paranoia or suspicion, or any unusual thought content that is below the threshold of a full-blown psychotic disorder.

Several medications have been tested in clinical trials. Trials of omega-3 fatty acids have shown mixed results. However, although clinical trials are mixed given the positive potential effects as well as the limited adverse effects of omega-3 fatty acids make it a good choice to consider.

Selective serotonin reuptake inhibitor antidepressants have been shown to be helpful in two naturalistic studies but have not been tested in a clinical trial. Initiating SSRIs along with omega-3 fatty acids is a grade 2 recommendation which basically means this is a suggestion, but clinicians could choose a reasonable alternative.

Clinical trials have not found antipsychotics to be efficacious in terms of delaying or preventing progression to psychosis.

Treatment of schizophrenia in youth. Antipsychotics are first-line treatment for confirmed schizophrenia. Several randomized trials have shown that antipsychotics reduce positive symptoms of schizophrenia, such as hallucinations and delusions. Antipsychotics eliminate or reduce the symptoms to a tolerable level in about 70% of the patients with schizophrenia.

Negative symptoms of schizophrenia, such as diminished emotional expression or lack of motivation is a little more difficult to treat.

We generally follow the age guidelines from the indications approved by the FDA in the United States which were based on the age of enrollees in the efficacy trials of antipsychotics in children with schizophrenia. These medications are aripiprazole, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, clozapine, and the first-generation agents, chlorpromazine, haloperidol, and perphenazine.

The current recommendation is to start with a second-generation antipsychotic with lower sedation and fewer problems with metabolic syndrome.

Clinical trials have not consistently found any one antipsychotic more effective than the others except clozapine, but due to adverse effects, it is reserved for use in treatment-resistant schizophrenia.

Hence, clinicians can select 1 amongst the above medications, based on patient age and medication adverse effect profile.

LEM: Can you talk about cardiometabolic risks or any other risks of treatment with antipsychotics, and do they outweigh clinical benefits?

Abhijit Ramanujam, MD: The adverse effect profiles of individual antipsychotic drugs vary widely. Children and adolescents compared with adults are at a high risk of many of the adverse effects associated with antipsychotic use

Common adverse effects associated with second-generation antipsychotics include weight gain and related metabolic effects, sedation, anticholinergic symptoms, elevated prolactin levels and extrapyramidal symptoms, cardiac effects, and sexual dysfunction.

Many of these drugs increase appetite and alter metabolic control. Children who are more vulnerable to these adverse effects are those with pre-existing conditions, such as obesity, diabetes, or elevated cholesterol. Clozapine and olanzapine carry significantly higher risk than other antipsychotics, whereas lurasidone and to an extent aripiprazole are associated with the lowest risk.

Clinicians should conduct routine short and long-term monitoring of weight, waist circumference, blood pressure, fasting glucose, and lipid profile of patients taking any of the antipsychotic drugs. For patients in whom weight gain is a concern, we tend to prescribe lurasidone. Whenever possible, we tend to avoid medication such as olanzapine which has a higher rate of metabolic abnormality.

Tardive dyskinesia is characterized by involuntary movements of the mouth, tongue, face, extremities, or trunk (including lip-smacking, tongue, and jaw movements, and facial grimacing). The symptoms are often initially mild; however, they can progress and become disfiguring or disabling. Tardive dyskinesia risk increases with age, time of exposure to medications, and prior development of extrapyramidal symptoms (EPS).

However tardive dyskinesia is less common in youth compared with adult and older adult populations—0.4% versus 6.8%.^1,2

The risk of tardive dyskinesia in children appears to be the greatest with first-generation antipsychotics with minimal or no risk seen with second-generation antipsychotics.³ Clozapine has not shown to cause tardive dyskinesia. Patients on these medications should be formally assessed for tardive dyskinesia at least annually. Older adults should be assessed every 6 months.

Nausea and sedation are common adverse effects of antipsychotic treatment in all patients, but they often remit over time and should not be considered a reason to terminate treatment. As mentioned earlier although no one antipsychotic is better than the other, for patients with prominent insomnia we tend to use quetiapine.

Clinicians should routinely assess for fall risks in vulnerable population, given that many of these medications cause sedation as well as orthostatic hypotension. Anticholinergic effect, such as constipation, dry mouth, blurry vision, and urinary retention are fairly common. In the case of clozapine sialorrhea rather than dry mouth is common.

Extrapyramidal adverse effects. Second-generation antipsychotics have reduced incidence of akathisia, rigidity, bradykinesia, dysphagia, tremor, and acute dystonic reactions that constitute EPS. Among the second-generation antipsychotics, risperidone carries the highest risk, especially at doses greater than 4 mg/day; elevated risk is also noted with aripiprazole, asenapine, and lurasidone. Quetiapine and clozapine are preferred agents in patients with high risk for EPS. Patients on second-generation agents should be asked about restlessness, slow movements, shaking, and rigidity at baseline and weekly during dose increases.

We usually start with a second-generation antipsychotics because of their lower rates of extrapyramidal symptoms and tardive dyskinesia compared with the first-generation antipsychotics.

Prolactin elevation can occur in both men and women. Accordingly, patients may experience gynecomastia, galacturia, menstrual disturbance sexual dysfunction and infertility. Risperidone and paliperidone are more strongly associated with elevated prolactin. Olanzapine and aripiprazole, clozapine and quetiapine show little or no change in prolactin levels.

Patients on risperidone and paliperidone should be asked about changes in sexual function and abnormal lactation at each visit for 12-week and annually thereafter. A serum prolactin level is indicated if the patient develops signs of sexual dysfunction or galacturia.

Sexual adverse effects that cause dysfunction in all phases of sexual activity are quite common. It seems to be highest on patients who are prescribed risperidone and least amount patients were on aripiprazole. Clinicians are encouraged to ask about sexual functioning initially and at least annually thereafter.

QT prolongation can happen with many of the medications. A corrected QT interval greater than 500 or an increase in QT of 60 or more during antipsychotic treatment indicates significant risk. Ziprasidone appears to have a somewhat greater risk of QT prolongation. Olanzapine and risperidone have been associated with mild QT prolongation but neither carries a specific caution on this issue. Lurasidone and Abilify are the least likely to cause cardiac arrhythmias.

Routine monitoring of ECG with antipsychotics is not usually required in patients without cardiac risk factors. Rarely, cases of myocarditis and cardiomyopathy have been reported with quetiapine, Risperdal, and ziprasidone.

Orthostatic hypotension is frequently observed with clozapine, quetiapine, iloperidone, and paliperidone. This is somewhat less so with olanzapine, risperidone, and ziprasidone. It very rarely occurs with aripiprazole. The symptoms are generally benign and self-limiting but, in some cases, may necessitate a slowing in the rate of dose titration. Seizures have been associated with several second-generation antipsychotics and is dose dependent. Clozapine carries the highest risk among the second-generation antipsychotics.⁴

Some of the less common adverse effects include neuroleptic malignant syndrome, cardiomyopathies, and cataracts. The use of antipsychotics in children should always be started with extreme caution at a low dose and titrated slowly.

LEM: Are there family or genetic factors to consider? What about trauma, sexual abuse, or domestic violence? Do these factors have any effect on children’s propensity to develop early-onset psychosis or psychotic symptoms?

Abhijit Ramanujam, MD: In terms of predisposing factors, genetic vulnerability, environmental factors, obstetric complications, trauma, social adversities, and substance use can all contribute to the risk for acquiring a primary psychotic disorder. Studies have shown the presence of a substance use disorder and co-occurring psychotic symptoms indicate an increased risk for developing a primary psychotic disorder.

Cannabis in particular has the potential to cause psychotic symptoms, although the studies are limited. However, the body of evidence is consistently increasing.

The birth cohort study of patients with schizophrenia reported an association between hypoxia during birth complications and early onset schizophrenia but not of adult-onset schizophrenia. Prematurity was found in 17% of early-onset psychosis in a schizophrenia spectrum disorder study.⁵

Two large systematic studies demonstrate that 30% to 50% of patients with childhood onset schizophrenia had premorbid features of autism or had comorbid diagnoses of pervasive developmental disorders.⁶ However, youth with early-onset schizophrenia frequently showed greater premorbid deficits in attention, learning, and socialization compared with their counterparts with adult-onset schizophrenia.

A meta-analysis reported strong evidence that childhood adversity was associated with an increased risk for psychosis in adults, although psychotic symptoms may also be present in PTSD.^7,8 Twin studies suggest that childhood-onset of schizophrenia may have a substantial genetic component.⁹ A number of psychiatric disorders occur in higher frequency amongst first-degree relatives of children with schizophrenia.

For example, bipolar disorder prevalence is 6% in first degree relatives versus 2.4% in the general population. The same can be said for schizophrenia spectrum disorder: 10% in first-degree relatives versus 3.5% in general population. Anxiety disorders prevalence is 15% in first degree relatives versus 7.3% in the general population.

LEM: Is it too early to talk about long-acting injectable antipsychotic agents, or LAI, treatments?

Abhijit Ramanujam, MD: In terms of long-acting injectable antipsychotics, they have not been sufficiently studied in younger children to recommend their use.

LEM: From a child’s perspective, how do we build a daily routine of taking oral medications? What can one expect when there is a patient stops treatment abruptly?

Abhijit Ramanujam, MD: I strongly recommended a multimodal instead of medication-alone approach for a better outcome. First psychoeducation is key and is best provided early in treatment and frequently reviewed, provide children and their parents or guardian information about the illness, medications, and other interventions. It is highly useful to integrate family members and educate them to better support youth.

There are a few variables in terms of our approach based on the clinical presentation of the patient.

1. Family intervention. For patients with schizophrenia who have had a recent psychotic episode and have significant ongoing contact with family members, we recommend patients and family members receive a family intervention for at least 6 to 9 months. During family intervention, patient's family members receive education about the nature course treatment of schizophrenia.

It also involves correcting the erroneous notion that poor parenting was the cause of schizophrenia. Many parents are left to wonder what they could have done wrong to cause the illness and need help transitioning from the guilt and blame to acceptance and support.

Many times, family members may perceive the negative symptoms of schizophrenia, such as lack of motivation and asociality, as laziness. Furthermore, the clinician should teach early warning signs and explain the importance of medication adherence.

2. If the patient has had multiple relapses of schizophrenia and reside in a particularly stressful family environment, a more intensive problem-solving family therapy has been developed. In these cases, we identify and correct overly hostile and critical parent-patient interaction. Sometimes stressful family dynamics can be mitigated by finding outside rehabilitative activities or supported employment for the patient.

3. For individuals who experience persistent delusions or hallucinations despite adequate trials of antipsychotic medication, we recommend adjunctive treatment with cognitive-behavioral therapy over medication alone (Grade 1B).

The aim is to reduce the intensity of delusions and hallucinations or the subjective distress. It also helps individuals be more proactive in reducing the risk of relapse. It basically involves exploring the subjective nature of the symptoms, gently challenging the underlying assumptions and generating alternative interpretations. Many patients will strongly resist reevaluating delusional believes but one can reduce the related distress. Studies indicate that CBT is effective for chronic schizophrenia.

4. For children with schizophrenia who have deficits and skills needed for everyday activities we usually recommend social skills training along with antipsychotic medications. Social skills training is generally conducted several times a week. Children with observed deficits, such as problems with attention and working memory, should receive age-appropriate vocational skills training. This may include help with placement and support during employment. Therapeutic schools are also an option to educate children who struggle to understand the curriculum in typical school settings due to their illness.

Social skills training is necessary since negative symptoms of schizophrenia such as lack of motivation and lack of socialization do not respond well to medications. The ultimate goal of this training is to provide skills to community-based activities and improve the functioning.

5. For children with schizophrenia who experience persistent cognitive decline such as difficulty concentrating or remembering, cognitive remediation is recommended along with antipsychotic medications. The patient is asked to do simple information processing tasks and once they reach a certain threshold, they will move onto a slightly more complex task. PositScience is a self-contained computer software program that provides cognitive remediation in an outpatient setting. Studies indicate that this approach leads to an overall positive effect.¹⁰

LEM: For clinicians concerned about treating schizophrenia, what advice can you offer?

AR: It is roughly estimated that 13% to 23% of people experience psychotic symptoms at some point in their lifetime.¹¹ Most clinicians will encounter patients with psychosis and thus will greatly benefit knowing how to recognize psychotic symptoms and make appropriate initial evaluation and management decisions.

Prompt diagnosis of schizophrenia and aggressive treatment is necessary to limit impairments in development and learning. Repeated or prolonged psychotic episodes have negative neuropsychological and structural brain defects on patients. Some evidence also suggests that prolonged periods of untreated psychosis may also result in increased resistance to conventional treatments.

Having said that, I encourage optimism and discourage nihilism when it comes to treating schizophrenia. Schizophrenia necessarily does not follow the path of progressive deterioration. The majority of patients respond very well to comprehensive treatment and as many as 20% can be expected to have a full recovery. There is much we can offer patients, and it is valuable to be aware of our current treatment options

References

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8. Kessler RC, Sonnega A, Bromet E, et al. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52(12):1048.

9. Kallmann FJ, Roth B. Genetic aspects of preadolescent schizophrenia. Am J Psychiatry. 1956;112(8):599.

10. Harvey PD, Balzer AM, Kotwickib RJ. Training engagement, baseline cognitive functioning, and cognitive gains with computerized cognitive training: A cross-diagnostic study. Schizophr Res Cogn. 2019;19:100150.

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