Persistent Depressive Disorder

Etiology

Biopsychosocial conceptualizations postulate that depression is a multifactorial disease state caused by biological, social, psychological, and spiritual factors.[4] Risk factors for persistent depressive disorder may include genetics, epigenetics, prior mental illness, neuroticism, high anxiety states, sense of self-worth, psychological health, trauma, life stressors, and social determinants of health.[5] However, depressive symptoms are heterogeneous, and there are few studies investigating participants who were healthy at baseline. Studies of the onset and recurrence of depressive symptoms are scarce.[6] 

Antecedents of chronic depression include greater childhood adversity and maltreatment, childhood loss of a parent, higher rates of chronic depression in relatives, and earlier onset of depression.[1] There are high rates of comorbidity between PDD and borderline personality disorder, which is a risk factor for PDD, suggesting that the disorders may share etiological factors such as genetics, temperamental vulnerability, interpersonal stress, or childhood maltreatment. During their lifetimes, individuals with PDD experience a higher number of traumatic events.[7]

Results from one PDD study showed that depressed patients did not show deficits in decoding the affective states of others but may have difficulties in managing another person's negative emotional state. Individuals with PDD may be hypersensitive, feel overwhelmed by emotional situations, and develop empathic distress and empathic concern. Empathic distress was correlated with depression severity. Patients with PDD reported significantly more interpersonal problems and more childhood maltreatment, including increased levels of physical abuse, emotional abuse, emotional neglect, and total childhood maltreatment than healthy controls.[8] Interpersonal problems may lead to lower perceived social support, weaker social ties, and prolonged loneliness.[9]

Epidemiology

PDD was a new diagnosis in the DSM-5 in 2013 that combined dysthymia and chronic major depressive disorder.[1] Due to its relative newness as a diagnostic category, the epidemiology of PDD has not been well-studied. The DSM-5 Text Revision (DSM-5-TR) estimated the 12-month prevalence for dysthymia to be approximately 0.5% and 1.5% for chronic major depressive disorder. 

Results from a study of 3720 patients in Zurich found the prevalence was 15.2% for PDD with persistent major depressive episodes, 3.3% for PDD with pure dysthymia, and 28.2% for major depressive disorder.[10] According to the DSM-5-TR, the 12-month prevalence of major depressive disorder in the United States is approximately 7%, with a higher prevalence in women and steeper rates in youth than in older groups. The prevalence of major depressive disorder may vary 8- to 9-fold globally. Estimates of depression may be low in older adults due to the misattribution of depressive symptoms to physical disorders that increase with age.[11]

Pathophysiology

The pathophysiology of persistent depressive disorder is unknown. No studies of PDD exist, and older studies of dysthymia and chronic major depressive disorder have not been replicated.[1] Early research implicated serotonergic abnormalities, immune system dysregulation, neuroendocrine alterations, and sleep alterations. Only a few gene studies are available, flawed by the small study sizes and the absence of replication attempts and genome-wide approaches. Brain imaging has not demonstrated any firm conclusions about brain structure or neural network function in PDD, although the prefrontal cortex, anterior cingulate, amygdala, and hippocampus have been implicated.[1][12][13][14][15][16] Polysomnographic abnormalities may exist in PDD.

History and Physical

History 

PDD is often overlooked. In diagnoses, obtain a careful history and conduct a mental status examination. Assessing risks of harm to oneself or others and considering the influence of substance use are critical components of this assessment, as those with PDD have a higher risk of suicide. Collateral information from family members or close contacts is helpful. The primary objectives are to eliminate the possibility of other medical or psychiatric conditions and confirm the diagnosis based on the DSM-5-TR.

The following are essential elements of the history:

• History of present illness: Take a chronology of symptom presentation and predisposing, precipitating, and perpetuating factors, particularly mood, sleep, appetite, energy, self-esteem, concentration, decision-making capacity, and hopelessness. Review other psychiatric symptoms and comorbid diagnoses, especially if acute depressive episodes are preceded or followed by low-grade depression. Obtain a relevant negative history that could help differentiate PDD from other medical or psychiatric conditions. Using a screening tool, such as the one-question persistent depression screener, in conjunction with other depression screening instruments, can be a way to detect PDD.[17][18]
• Past psychiatric history: Include previous manic or depressive episodes, hospitalizations, treatments (including electroconvulsive therapy), adherence to treatments, the effects and adverse effects of medication, and any history of suicidality (ideas, plans, or attempts, including details), self-injury, or aggressive ideas or behavior. A life chart or timeline may help elucidate a pattern of depressive symptoms.
• Substance use history: Ask about the use of tobacco, alcohol, cannabis, or other substances.
• Medical history: Include medical illnesses, allergies, treatments, surgeries, parity, and other relevant health information, such as neurological conditions and sleep issues. Ask about diagnoses such as Parkinson disease, multiple sclerosis, syphilis, human immunodeficiency virus/acquired immunodeficiency syndrome, brain lesions, heavy metal toxicity, delirium, and metabolic or endocrine disorders.
• Medications: Ask about all medications and their indications.
• Family history: Include a family history of psychiatric illness, treatment and response to treatment, and history of suicidal or aggressive behaviors in biological relatives.
• Personal and social history: Language preferences, life circumstances, relationships, children, employment history, cultural views on psychiatric illness, stressors, trauma history, access to weapons, and legal concerns are important.
• Developmental history: Ask about any complications during childbirth, early development, history of trauma and abuse (including head trauma), and education.

Physical Examination

The physical examination should be performed with sensitivity to any trauma history. Vital signs such as blood pressure and heart rate are crucial in identifying underlying health issues. A comprehensive examination covers the neurological, cardiovascular, and respiratory systems. A dermatological examination helps detect signs of substance use or skin infections.

Mental Status Examination

ThemMental status examination (MSE) for PDD should include the following:

1. Appearance and behavior: Patients may present with disheveled attire, reflecting a lack of self-care. Assess for psychomotor retardation. Patient responses can vary from being cooperative to being withdrawn.
2. Speech: Assess for rate and tone.
3. Mood and affect: Individuals may describe their mood as depressed, sad, or "down in the dumps." Affect can be constricted.
4. Thought content: Assess for hallucinations and delusions.
5. Thought process: Inferred from the patient's speech. Is the patient clear and coherent?
6. Risk: Assess current suicidality (ideas, plans, access to weapons), self-injury (ideas or behaviors), and aggressive ideas or behaviors.
7. Cognition: Assess for orientation to person, place, and date.
8. Insight and judgment: Insight varies, with some patients partially aware of their condition while others lack insight. Judgment may be impaired, affecting the ability to make decisions.

No laboratory or radiologic studies currently exist for diagnosing PDD.

Diagnostic criteria for persistent depressive disorder

According to the DSM-5-TR, the following are the diagnostic criteria for persistent depressive disorder:

A. Depressed mood most of the day, more days than not, for at least 2 years.

B. At least 2 of the following 6 symptoms:

1. Poor appetite or overeating
2. Insomnia or hypersomnia
3. Low energy or fatigue
4. Low self-esteem
5. Poor concentration or difficulty making decisions
6. Feelings of hopelessness

C. During a 2-year period (1 year for children or adolescents), the individual has never been without the symptoms in Criteria A and B for more than 2 months at a time.

D. Criteria for a major depressive disorder may be continuously present for 2 years.

E. There has never been a manic or hypomanic episode.

F. The disturbance is not better explained by a schizophrenia spectrum or other psychotic disorder.

G. The symptoms are not attributable to the physiological effects of a substance or another medical condition.

H. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

A patient may meet the criteria for PDD and major depressive disorder at the same time, in which case a separate diagnosis of major depressive disorder should be made. The DSM-5-TR identifies specifiers to describe if the PDD is with a pure dysthymic syndrome or with a persistent major depressive episode, with anxious distress or atypical features, in partial or full remission, early onset or late onset, and severity (mild, moderate, or severe).[19] Dysthymia is maintained as a diagnosis in the International Classification of Diseases, 11th Revision.

Evaluation

A thorough assessment of patients presenting with mental health symptoms involves ruling out medical and biological causes of symptomatology. While routine laboratory screening of an otherwise healthy patient with symptoms of depression is of questionable diagnostic value, the following laboratory tests are commonly ordered to support medical decision-making: complete blood count, comprehensive metabolic panel, urine pregnancy test, urine toxicology screen, human immunodeficiency virus testing, rapid plasma reagin, vitamin B12, folate, and a thyroid panel. Symptoms and patient history guide additional testing.[20][21][22] 

Treatment / Management

Treatment success in PDD may be lower due to delays in diagnoses (and starting treatment), patient hopelessness, and inadequate treatment duration. Individuals with PDD may have histories of adverse childhood events, which are risk factors for chronic, early-onset depression; those with trauma histories may have better success with targeted therapies such as the cognitive behavioral analysis system of psychotherapy. Previous studies of psychotherapy for dysthymia showing less efficacy may be flawed by the low number of sessions provided. Studies of patients with chronic depression have shown better outcomes with longer duration of psychotherapy and higher numbers of sessions.[1][23] (B3)

There is little research on the efficacy of medication or psychotherapy in PDD. One 2014 meta-analysis of studies of patients with pure dysthymia, chronic major depressive symptoms, and various forms of chronic major depression demonstrated that fluoxetine, paroxetine, sertraline, moclobemide (not approved for use in the United States), imipramine, ritanserin (not approved for use in the United States), amisulpride (only available in intravenous solution), and acetyl-l-carnitine (a dietary supplement) were more effective than placebo. Interpersonal psychotherapy (IPT) alone was less effective than IPT with medication. The studies of cognitive behavioral analysis system of psychotherapy with medication were inconsistent. There was insufficient evidence for several treatments, such as mirtazapine, venlafaxine, and psychodynamic psychotherapies.[24] Although there was not a clear benefit for combination treatment, the use of medication and psychotherapy together resulted in higher response rates and improved functioning.[1][25][26][27][28][29][30][31](A1)

New models of treatment are under consideration for PDD, taking into consideration not only symptom modification but also improving mentalization capacity, developing empathy, increasing motivation, overcoming avoidance, social skills, healing trauma, addressing hopelessness and helplessness, and reducing comorbidities.[1] One case study showed the efficacy of the mood stabilizer lamotrigine, with remission of symptoms for over 2 years.[32] The American Association of Child and Adolescent Psychiatrists Clinical Practice Guideline suggests cognitive behavioral therapy or interpersonal psychotherapy as treatment for persistent depressive disorder. There was insufficient evidence available about the benefits or harms of selective serotonin reuptake inhibitors for PDD in children and adolescents.[33] (A1)

Differential Diagnosis

According to the DMS-5-TR, the differential diagnoses for PDD are:

• Major depressive disorder (MDD): If the criteria are met for major depressive disorder during the time period for PDD, the additional diagnosis of MDD should be made.
• Other specified depressive disorder: There may be individuals who do not meet the criteria for either PDD or MDD but do have depressive symptoms lasting more than 2 years.
• Bipolar I and bipolar II disorders: A history of a manic or hypomanic episode excludes a diagnosis of PDD, and the individual should be assessed for bipolar I disorder or bipolar II disorder.
• Cyclothymia: If an individual has hypomanic symptoms that do not meet the criteria for a hypomanic episode and has a depressed mood for at least 2 years, the appropriate diagnosis would be cyclothymia.
• Psychotic disorders: Depressive symptoms that occur only during the course of a psychotic disorder would not warrant a diagnosis of PDD.
• Depressive or bipolar and related disorder due to another medical condition: This is the proper diagnosis if an individual's depressive symptoms are attributable to another medical condition, for example, multiple sclerosis.
• Substance/medication-induced depressive or bipolar and related disorder: If a substance such as a drug of abuse, a medication, or a toxin is judged to be the cause of the depressive symptoms.
• Personality disorders: These are characterized by enduring patterns of inner experience and behavior and commonly co-occur with PDD, in which case both can be diagnosed.

Pertinent Studies and Ongoing Trials

There are several areas for additional research:

• Further validation of the diagnosis of persistent depressive disorder
• Preferential use of medication, psychotherapy, or combination therapy
• Treatment effect modifiers such as family characteristics
• Effects of other psychotherapies, such as psychodynamic psychotherapy, attachment-based therapy, or family therapy
• Use of antidepressant medications or other psychotropic medications such as ketamine
• Use of interventional treatments such as transcranial magnetic stimulation or electroconvulsive therapy
• Use of lifestyle interventions such as exercise
• Effectiveness of treatments in minoritized populations
• Effectiveness of treatments in populations with developmental disorders
• Integrating mental health, medical treatment
  • For example, results from one study found high rates of persistent depressive disorder and major depression among patients undergoing human immunodeficiency virus testing.[33][34]

Prognosis

Even before the COVID-19 pandemic, depressive and anxiety disorders featured as leading causes of burden globally, despite the existence of intervention strategies that can reduce their effects.[35][36] The prognosis of PDD is similar, if not worse, than that of major depressive disorder. Outcomes of a 10-year study suggest that persistent depressive disorder is independently associated with greater severity of depression, anxiety, and somatic symptoms in individuals with major depressive disorder in comparison to individuals with major depressive disorder without PDD.[37] 

Complications

Persistent depressive disorder (PDD) negatively affects social and occupational functioning in varying ways, which can be as great or greater than a major depressive disorder. PDD is associated with an increased risk of suicidal outcomes. The symptoms of PDD are much less likely to fully resolve in a given period. Individuals with PDD are at higher risk of personality disorders and substance use disorders. Significant associations were found in inpatients with PDD between childhood emotional abuse and suicidal behaviors (including suicide attempts).[38] 

In one study, results showed that the suicide risk in those with sleep disorders was 1.429 times higher than in those with no sleep disorders, and people with PDD exhibited a 7.195 times higher risk of suicide compared with those without PDD. Those with sleep disorders and PDD exhibited a 1.174 times higher risk of suicide compared to those with no sleep disorders.[39]