Bi-Polar & Disruptive Dysregulation Disorder (DMDD)

Bi-Polar & Disruptive Dysregulation Disorder (DMDD)

Bipolar spectrum disorders affect an estimated 4% of children and adolescents. Presentation often involves cycles of both major depressive symptoms, and episodes of abnormally elevated mood (mania, hypomania). Young children who have a family history of bipolar disorder, or who exhibit symptoms of depression, anxiety, or behavior dysregulation, may be at an increased risk for developing pediatric bipolar disorder.

Disruptive Mood Dysregulation Disorder (DMDD) is classified as a depressive disorder, with symptoms of chronic persistent irritability and physical or verbal outbursts. DMDD was first utilized as a diagnosis in 2013, when it was included in the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Prior to 2013, individuals who would now be diagnosed with DMDD were often described as having “severe mood dysregulation”. DMDD is estimated to occur between 0.8% to 3.3% of children and adolescents, and prevalence varies by age group. Youth with DMDD have prominent irritability, but do not experience some of the other features of mania seen in those with bipolar disorders. 

Diagnosis and management of bipolar disorders and DMDD frequently involves coordination between a primary care provider and psychiatrist, or other behavioral health professional. Individuals with DMDD and bipolar disorder commonly experience comorbid psychiatric disorders, such as attention-deficit/hyperactivity disorder (ADHD), anxiety disorders, oppositional defiant disorder (ODD) or substance use disorder and require ongoing monitoring. Symptoms can be disruptive to relationships at home, school and in the community, and may be exacerbated by adverse or traumatic life events. Both DMDD and bipolar disorder are chronic disorders that manifest differently throughout the lifespan, and symptoms may be managed through the use of medication and psychotherapy. Medication management and adherence is often a challenge for patients with these disorders due to an inherent lack of self-recognition of symptoms, and reluctance to engage in treatment (pharmacologic and non-pharmacologic).

Myths vs. Facts about Bipolar Disorder and DMDD

Fact: Symptoms of bipolar disorder are more extreme and persistent than typical mood swings, and long-term treatment is recommended. Even with proper treatment, people with bipolar disorder may experience severe symptoms that impair their ability to work or complete daily tasks.

Fact: Mood disorders, such as DMDD and bipolar disorders, manifest differently depending on age. Pediatric bipolar disorder can be diagnosed as early as age six. Genetics and environmental factors are associated with an increased risk of developing pediatric bipolar disorder. However, bipolar disorder is rare in young children and a proper diagnosis should be made before treatment is enacted.

Fact: Individuals experiencing a manic or hypomanic episode often demonstrate a loss of inhibition and are at risk of making impulsive or reckless choices that are harmful to themselves or others. They may also experience concurrent depression, symptoms of psychosis, or feelings of irritability and restlessness during these cycles.

Fact: While symptoms suggestive of DMDD or bipolar disorder may result from use of alcohol or drugs, these disorders do not develop as a direct result of substance use. However, substance use disorders are more prevalent in youth diagnosed with mood disorders like DMDD and bipolar disorder.

Screening and Assessment

Primary care providers who suspect a patient of having DMDD or bipolar disorder should begin by ruling out any medical conditions that may be causing the symptoms. Next, a comprehensive assessment is completed, which may include a combination of gathering observations from parents, teachers, and other caregivers about the youth over the course of the previous 12 months, as well as implementing standardized rating scales. Standardized rating scales are neither definitively diagnostic, nor a definitive indication of a specific condition. The intent is to determine if the symptoms experienced by the child are contributing to their social, emotional, behavioral, academic, or work challenges.

Parents should be asked to report abnormal and persistent issues with behavior, sleep, energy level, depression and/or irritability. Distinct episodes of severely elevated mood or irritability that are significantly different from what is expected for the child’s developmental stage should be noted. Some accompanying symptoms that may be present during these episodes, such as racing thoughts, agitation, increased and out-of-character talkativeness, disorganized thoughts, or decreased need for sleep (without feeling tired after minimal sleep) may signal that specialty assessment for bipolar disorder is warranted.

One of the most used specialty assessments for bipolar disorder in children and adolescents is the Youth Mania Rating Scale (YMRS). This is an 11 item, self-reported assessment that specifically focuses on behaviors, thoughts, and moods over the previous 48 hours. The YMRS is a useful tool for clinicians to further assess the possibility of mania or hypomania in clients presenting with symptoms.

Youth with DMDD experience chronic severe irritability without distinct episodes of mania. Irritability may be characterized by a consistent angry or sad mood that is present in more than half of the child’s waking hours. Reacting to frustration or negative stimuli with outbursts of excessive physical or verbal aggression on three or more days per week in addition to irritability should prompt assessment for DMDD.

Meet Joseph

Joseph is a 10-year-old male with no past medical or psychiatric history who presents to the primary care practitioner's (PCP) office for worsening behavioral outbursts. Joseph’s mom reports that he is easily angered and has a “screaming fit” about four times per week. During these “fits,” Joseph will often yell, cry, punch walls, and destroy objects. Last week, one of these episodes ended with Joseph physically attacking his father for the first time. These episodes first started about 6 months ago, although his mom cannot identify a specific trigger. Joseph’s mom denies any period in which these episodes stopped occurring. Joseph’s episodes can last 15 to 60 minutes and afterwards he is calm and apologetic. His mom also reports that he is quick to anger about small things and seems grumpy all the time. His mom has not noticed any anxiety, nervousness, sadness, or loss of interest. He sleeps 8-9 hours per night without difficulty. In the office, Joseph is calm and cooperative, but mildly irritable when asked questions. He reports that people just make him angry and that he has trouble calming down. Vanderbilt forms completed by his mother and teacher are not concerned for ADHD. Joseph also scored low on the GAD-7 and PHQ-9, which suggests that both anxiety and depression are the unlikely diagnosis for his presenting behavior.

Given the low scores on the GAD-7 and PHQ-9, along with the disruptive and violent behavior that Joseph is presenting with, the suspected diagnosis is DMDD. Upon diagnosis of DMDD, Joseph is referred to psychotherapy and to psychiatry. He follows up in the PCP's office monthly until he is seen by a psychiatrist. During the PCP visits, the doctor teaches relaxation techniques and suggests coping skills that Joseph can use when upset. His PCP also discusses behavioral management techniques with his mom, including setting positive rewards for good behavior and firm limits around physical aggression. Furthermore, the PCP has communicated with Joseph’s therapist to best coordinate care and reinforce skills. 

Joseph is eventually able to be seen by a psychiatrist who confirms the diagnosis of DMDD. His outbursts are improving with behavioral techniques but can still be severe at times. The psychiatrist starts him with 2 mg of aripiprazole at bedtime, which significantly improves his irritability and aggression after about four weeks. 

Six months later, Joseph returns to the office for his well-child check. He continues to see both his psychiatrist and therapist. His mom reports that he is much happier and only has outbursts one to two times per month. Upon review of his chart, the PCP notes normal values for monitoring labs recommended for his ongoing use of aripiprazole. Joseph’s weight continues to be at the same percentile as prior to medication use and his blood pressure is within normal limits. 
 

Meet Christina

Christina is a 16–year-old female patient with no past medical or psychiatric history who presents to the pediatrician’s office for irritability and difficult behaviors. Her mom reports that Christina has not been sleeping very well and has been up most nights for the past eight days. Christina has been skipping classes at school and her mom caught her “making out” with a boy she just met. Christina had been yelling at everyone in the home and destroyed her own room yesterday when she became upset over what her dad made for dinner. Last weekend she stole her mom’s credit card and bought $1200 worth of clothes online. When her mom tries to confront Christina about her symptoms, Christina gets tearful and emotional, but quickly returns to being bright and energetic. These behaviors are very out of character for her. Her mom also notes that Christina had anger issues for one-month last year, but this improved on its own and she went back to being her regular self. In the office, Christina is talkative and goes from one subject to another. She confirms that she has not been sleeping much but reports not feeling tired. She denies the use of drugs and alcohol and is not on any medication. When asked about her behavior, she says that nothing is wrong with her and that her mom is overreacting. She also says that she does not think she needs to go to school any longer because she has a secret job as a model with Calvin Klein. 

Christina is referred to the Emergency Room for suspected bipolar disorder, as she is displaying signs of mania, including delusional thinking. She was admitted to the psychiatric hospital for further management and stabilization. 

Christina returns to the pediatrician’s office one month after being discharged from the inpatient psychiatric unit. Her mom reports that she has been sleeping 7-8 hours per night and is no longer having emotional outbursts. She has also been more like herself, and no longer engaging in risk taking behaviors. During hospitalization, Christina started on risperidone with the dose titrated up to 1 mg twice daily. She responded quickly to the medication but reported stiffness in her arms and legs. Her new psychiatrist added benztropine to help with side effects. The pediatrician completes a lipid panel to have CBC, CMP, and HbA1C checked. The pediatrician notices that Christina has had minor weight gain and discusses diet considerations and lifestyle modifications with her and her mom.
 

Clinical Pearl: The Role of PCP's

Often, symptoms that appear to be consistent with bipolar disorder or DMDD evolve into clearer pictures of other mental health disorders such as anxiety, depression, or PTSD. Due to this complexity, the role of the primary care provider is often to detect the presence of a mental health condition causing significant functional impairment with symptoms consistent with bipolar disorder or DMDD and connect these patients with specialty care, rather than to make a definitive diagnosis or single-handedly manage the care of patients with bipolar disorder or DMDD.

 

Psychosocial Assessment 

Parents and the patient should be interviewed together and then separately. This provides the patient and parents an opportunity to discuss the history and symptoms with the provider without the influence of one another. Examples of provider questions to use during these interviews include:

  • Suicide:
    • “Sometimes when I meet teens that are feeling down, they feel like life is not worth living. Has this ever happened to you?”
    • If so, “Did you ever have thoughts of ending your own life?”
    • If so, “Did you ever develop a plan? What was it?”
    • If so “Did you act on those plans? Have you ever tried to end your life before
    • Learn More
  • Self-harm:
    • “Have you ever tried to hurt yourself?” Examples: withholding food, pulling out hair, burning, cutting.
  • Homicide:
    • “Have you ever had thoughts about hurting others?”
  • Substance use:
    • “How often do you drink alcohol? Smoke or vape? Use prescription medications (stimulants, opioids, sedatives) not prescribed to you? Use marijuana, cocaine, hallucinogens, any other substances?”
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  • Mania:
    • “Have you ever had a period of time, at least within the last few days, in which you felt super happy or irritable, had a lot of energy, slept very little, and/or had racing thoughts?”
  • Psychosis:
    • “Have you ever felt like your mind was playing tricks on you? Heard or seen something that you weren’t sure if it was really there?”

 

Clinical Pearl: Gather General Information

Even when it may be difficult to pinpoint a specific psychiatric diagnosis, a patient’s primary care provider can help children and families a great deal by gathering information about symptoms and how these are impacting domains of functioning in the child’s life. General categories of life to inquire about include the impact of symptoms on academic or occupational functioning, family life, and social relationships and activities. Together with screening for safety concerns (suicidal ideation and behavior, aggressive behavior), this information can help clarify acuity and enable mental health providers seeing patients referred by the primary care provider to begin treatment on an initial visit.

Clinical Pearl: Psychosis in Mood Disorders

Hallucinations (e.g., having auditory or visual perceptions without accompanying external sensory stimuli), delusions (fixed false beliefs), and disorganized thinking are features of psychosis, but these are not specific to a single psychiatric diagnosis. Patients, families, and providers may be acquainted with the fact that psychotic symptoms are associated with conditions like schizophrenia, but in young people, hallucinations are more often associated with mood disorders (depression or bipolar disorder) or a history of trauma rather than with schizophrenia Given how challenging the diagnosis and treatment of young people with psychosis can be, the role of a primary care provider is primarily detection, clarifying impairments related to symptoms, assessing safety concerns, and connecting the patient to mental health care.

Diagnostic Features

Bipolar disorder is characterized by distinct periods of elevated or irritable mood- mania or hypomania- and periods of significantly depressed mood. Manic or hypomanic symptoms may include inflated or “grandiose” self-esteem, decreased need for sleep, psychomotor agitation, increase in goal directed behaviors and behaviors that have the potential for negative consequences, such as unrestrained buying, increased talkativeness, racing throughs, and distractibility. Depressive symptoms may include loss of interest or pleasure in activities, decrease or increase in appetite, loss of energy, feeling of worthlessness or guilt, difficulty concentrating or making decisions, recurrent thoughts of death or suicide. Hypomanic symptoms are differentiated from manic symptoms based on intensity and functional impairment, with manic symptoms being more severe. For instance, if symptoms of elevated mood are severe enough to require hospitalization or significantly disrupt academic, occupational, or other social functioning, mania is likely present rather than hypomania. In individuals with bipolar disorder, there has been at least one episode of mania or hypomania, with at least one episode of significant depression. While some children and adolescents may have episodes of mania or hypomania that are shorter than those seen in adults, the presence of mania/hypomania symptoms which last at least several days to weeks at a time significantly increases the likelihood that a bipolar disorder is present.

DMDD is characterized by an inability to control emotions, temper tantrums that happen three or more times a week on average, and angry or irritable mood between tantrums. In individuals with DMDD, these symptoms have been present before the age of 10, although the diagnosis may be made between ages 10 and 18 based on symptoms seen at that time, together with information about symptoms having been present before age 10. This diagnosis is not used for children younger than 6 years of age.
 

Differential Diagnosis

Many symptoms of Bipolar depression are like symptoms of other disorders. Those disorders may include anxiety, ADHD, ODD, depression, conduct disorder, or substance abuse. No one symptom is used to diagnosis bipolar depression. 

Furthermore, children who are experiencing symptoms of DMDD and bipolar disorders should also be screened for common comorbid disorders such as ADHD, ODD, and anxiety to determine an accurate diagnosis and appropriate plan of care.

Treatment

A multi-modal approach involves management strategies that include non-medication interventions and medication interventions. 

Shared decision-making can encourage children, teens, and caregivers to have a voice in their care.  The Ohio Minds Matter Shared Decision-Making Toolkit is a guide for youth and families to take an active role in their treatment, prepare for their appointment, consider treatment options, document their symptoms, and describe their goals.

 

Shared Decision Making

 

 

Non-Medication Management

Psychotherapy is a key component of treatment for both bipolar and DMDD. Psychotherapy is recommended to be used with psychopharmacology as part of a multimodal treatment plan to manage symptoms associated with these disorders.

  • Individual therapies such as cognitive-behavioral therapy (CBT), dialectical behavioral therapy (DBT), and interpersonal therapies are evidence-based treatments for symptoms of depression.
    • CBT and DBT address negative thought patterns that can affect mood, behavior, and emotional self-regulation.
    • Interpersonal therapies (e.g., family therapy, school-based or community interventions) can help youth improve family and peer relationships through Interventions aimed at communication and problem solving.
  • Patients and families should be provided with education about common symptoms, prognosis, treatment options and management strategies. Family and social relationships may be adversely affected by the disorder. Family should be included in interventions that support communication and problem solving or provide peer support.
  • Parents of children with DMDD can support symptom management through the use of parent training techniques such as the Positive Parenting Program.
  • Older youth are more likely than younger age groups to benefit from more individualized therapies that help them learn how to identify and manage their own problematic thoughts and behaviors.

 

Clinical Pearl: Provide Immediate Support

While most youth with bipolar disorder or DMDD will benefit from specialty care, primary care providers can help support patients and families as they work to get connected to that care. Primary care providers should also monitor acuity and the need for referral to a higher level of care. In less acute situations, primary care providers can continue to encourage patients and families by reinforcing things the patient and family are doing to keep safe (such as restricting access to lethal means of suicide in patients who are having significant suicidal thoughts) and helping the patient and family identify coping skills that can be used when in crisis. When symptoms of mania, depression, aggression, psychosis, or suicidal thoughts and behaviors are prominent and beyond the ability of caregivers to manage, it may not be possible to maintain patients safely outside of a hospital setting until stabilization has occurred.

Medication Management Principles

Pharmacologic agents used for bipolar disorder are typically one of three distinct types: mood-stabilizing antipsychotic medications, anticonvulsants, or lithium. Pharmacotherapy with these agents may entail greater risk of adverse side effects than other common psychiatric medications, especially over time. In cases where there are barriers to accessing specialty care and the level of impairment due to symptoms is great, primary care providers may initiate pharmacotherapy with these agents or continue agents that were started by other prescribers. They should maintain a low threshold for seeking consultation with specialty prescribers in cases of diagnostic uncertainty, significant comorbidity of mental health conditions, significant acuity and functional impairment, and significant medication adverse effects. See the Prescribing Principles of Psychotropic Medications.

 

Second-Generation Antipsychotic Medications

The relevant history of this class of medication dates to the 1950s at which time agents such as chlorpromazine (Thorazine) and haloperidol (Haldol) were developed and initially used to treat schizophrenia. These and similar agents are often referred to today as “first-generation antipsychotic medications.” More recently, other agents that are also effective for schizophrenia but that have differences in mechanism of action and side effect profile have been termed “second-generation antipsychotics” (SGAs), or sometimes “atypical antipsychotics.” The first SGA developed, clozapine, is used to treat a select group of patients with treatment-resistant schizophrenia, but subsequent SGAs, such as olanzapine, risperidone, quetiapine, and aripiprazole, have been used as “mood stabilizing” medications in individuals with bipolar disorder, as well as for other symptoms and conditions.

By far the most common adverse effects of SGAs are their metabolic effects. Specifically, there is a high frequency of increased appetite, weight gain, and associated health complications resulting from these medications. For this reason, it is important that youth being prescribed SGAs be routinely monitored for weight and BMI increases beyond what is expected based on growth curves, along with laboratory monitoring of fasting blood glucose, cholesterol, and triglycerides. [Please see the chart below for more detailed information on the recommended metabolic monitoring protocols.] Prescribers should identify children who have been prescribed multiple SGAs to assess safety and consider a more appropriate prescribing regimen.

Antipsychotic Medication Aid

Recommended monitoring for metabolic adverse effects in individuals who are taking second generation (atypical) antipsychotic medications is described below:
 

  Baseline 3 months after starting Every 6 months Annually
Complete Blood Count/differential X     X
Fasting Basic Metabolic Panel (electrolytes, BUN and creatinine, and glucose) X     X
Fasting Glucose     X X
Liver Function Tests (AST, ALT) X X   X
Fasting Lipid Panel (Total Cholesterol, LDL, HDL, Triglycerides) X   X X
Height/weight/BMI X X X X
Pulse/Blood Pressure X X   X

(Adapted from Correll CU. “Assessing and maximizing the safety and tolerability of antipsychotics used in the treatment of children and adolescents.” J Clin Psychiatry. 2008;69 Suppl 4:26-36.)

Another type of adverse effect related to SGA use is movement abnormalities. These are sometimes called “extrapyramidal symptoms” (EPS) and occur less frequently with the use of SGAs than with the use of first-generation antipsychotics. EPS is a broad term which encompasses several distinct types of medication effects. In acute dystonic reactions, there is involuntary contraction of muscles (within the face, extraocular muscles, neck, extremities, or sometimes other parts of the body) which can be uncomfortable and frightening; anticholinergic agents (diphenhydramine or benztropine) may be used to reverse acute dystonia. In akathisia, patients experience an internal feeling of restlessness and a compelling urge to move. In tardive dyskinesia, involuntary movements (especially affecting the face and mouth, but sometimes other parts of the body) develop after treatment with an antipsychotic medication, and this may occur months or years into treatment (“tardive”) in individuals who did not initially display these movements. In withdrawal dyskinesia, similar movements may develop in patients who stop taking antipsychotic medication or who switch from one agent to another. In neuroleptic malignant syndrome (NMS), a rare side effect of antipsychotics, severe muscle rigidity is associated with fever and tachycardia. Laboratory findings show increased creatine kinase and white blood cell counts. Patients with suspected NMS should be seen emergently because the condition, while rare overall and especially rare with SGAs, is potentially life-threatening.

Additional adverse effects of SGAs for the primary care provider to be aware of are sedation, hyperprolactinemia (especially with risperidone and paliperidone use), and QTc prolongation (especially with ziprasidone use).

 

Anticonvulsant Medications:

Primary care providers are likely familiar with anticonvulsant medications because of their use in individuals with epilepsy. Anticonvulsants are sometimes used to treat mood disorders in youth including valproate, carbamazepine, oxcarbazepine, lamotrigine, and topiramate. While a detailed discussion of adverse effects of these agents is outside the current scope of this website, important issues for the primary care provider to be aware of are drug-drug interactions/effects on drug metabolism in individuals taking valproate or carbamazepine, fetal anomalies in individuals who become pregnant while taking valproate or carbamazepine, risk of Stevens-Johnson syndrome in individuals taking lamotrigine (the appearance of a skin rash in these individuals requires evaluation), and reduced appetite and cognitive effects from topiramate.

 

Lithium

Individuals taking lithium are at risk for renal insufficiency, especially if they become dehydrated or take medications which interact with lithium, such as ibuprofen and other NSAIDs. They are also at risk for hypothyroidism. For these reasons, it is recommended that BUN, creatinine, and TSH are followed for patients taking lithium. Other adverse effects can include nausea, diarrhea, tremor, and polyuria. These can also be signs of lithium toxicity.

When to Refer to Specialty Care

The Standard of Care is to Refer to Specialty Care

Patients with significant functional impairment from bipolar disorder or DMDD require care from one or more specialty mental health providers. All of these patients should be connected with a mental health provider who can continue to assess the condition, provide anticipatory guidance, treat as necessary, and assist patients and families in stabilizing crises. Primary care providers with experience treating Bipolar and DMDD or those who face timely lack of access to specialty pharmacotherapeutic management, may be in a situation considering initiation of pharmacotherapy. In general, management of patients with significant mood dysregulation should remain with specialty care, given the diagnostic challenges, adverse effects from agents used, diagnostic uncertainty, the potential emergency of serious adverse effects from agents used, and the risk of symptom exacerbation from pharmacotherapeutic treatment choice (e.g., worsening of manic symptoms from antidepressants).

In general, primary care providers should prioritize assessing acuity, e.g., the degree of functional impairment due to symptoms and possible safety concerns, in order to triage the urgency of referral to specialty care.

Ongoing Management

  • Primary care providers should stress the importance of treatment adherence and relapse prevention to patients and families. Patients may be averse to medication treatment and promote relapse through noncompliance. Stress, sleep deprivation and substance use may also contribute to relapse. Patient overall status should be monitored through scheduling regular follow-up visits. Provider interactions that build a therapeutic relationship and support treatment compliance benefit both the patient and family. 
  • Mood disorders affect both academic and social development in the school environment. Families of young children with these disorders should be advised to seek school consultation to determine if an individual education plan (IEP) or specialized education program is needed to support academic growth.
  • Providers may need to consult with other service systems, such as juvenile justice or social services, depending on youth and family circumstances. Helping the youth obtain community-based services that allow them to stay in their preferred home environment may require coordination with other care providers.
  • Some youth will require referrals to intensive services to address their complex care needs in order to maintain them at home, due to the severity of their symptoms or presence of complicating environmental stressors.

OhioRISE

Frequently Asked Questions (FAQs)

Youth with DMDD will experience irritability that is persistent and causes impairment across multiple settings (e.g., home, school, with peers). Irritability in DMDD differs from typical behavior due to being chronic, inappropriate to the situation and not in accordance with the child’s developmental level.

Symptoms of DMDD and Bipolar disorder in children can change throughout the lifespan and be exacerbated by comorbid disorders, environmental risk factors, and psychosocial stressors. As children with DMDD age, outbursts and severe irritability may lessen and symptoms of anxiety or depression may become more prevalent. Bipolar disorder is often diagnosed in adolescence and young adulthood when symptoms that resemble those seen with adult presentations of bipolar disorder begin to peak. Bipolar symptoms are typically most severe between the ages of 15 and 30 years.

Children who experience severe symptoms of mood disorders that impair their ability to concentrate, carry out daily tasks, or function socially can meet criteria for having a disability. School-based interventions like an Individualized Learning Plan (IEP) or 504 plan may be established with the home school district to provide support and accommodations designed to meet academic and social development goals.

References

  1. Mürner-Lavanchy, I., Kaess, M., & Koenig, J. (2021). Diagnostic instruments for the assessment of disruptive mood dysregulation disorder: A systematic review of the literature. European Child & Adolescent Psychiatry. https://doi.org/10.1007/s00787-021-01840-4
  2. Shain, B. N., & Committee on Adolescence. (2012). Collaborative role of the pediatrician in the diagnosis and management of bipolar disorder in adolescents. Pediatrics, 130(6), e1725–e1742. https://doi.org/10.1542/peds.2012-2756
  3. Tang, M. H., & Pinsky, E. G. (2015). Mood and affect disorders. Pediatrics in review, 36(2), 52–61. https://doi.org/10.1542/pir.36-2-52