🧠 Overview — “With Intermittent Major Depressive Episodes — Without Current Episode”
This specifier is a subtype under Persistent Depressive Disorder (PDD / Dysthymia) in the DSM-5-TR, used to describe patients with a “chronic, long-standing” form of depression who have, at certain periods, dropped down into full-blown Major Depressive Episodes (MDEs). However, at present (at the time of assessment), they are not in one of those severe depressive episodes.
The nature of this condition sits in the middle ground between “chronic sadness as the emotional baseline of life” and “recurrent episodes of major depression.” As a result, the person may appear “better” in the eyes of others, but clinically, the brain is still operating in a depressive mode all the time.
Patients in this group often say things like, “I’ve never really had a period where I felt genuinely energetic or truly happy.” Their depressive mood may not be intense enough to be crying in bed all day like during a full MDE, but they never fully return to a normal baseline either. It’s like walking along a graph line that is consistently lower than the standard emotional baseline of most people — with occasional drops much deeper (during MDEs), and then slowly climbing back up only to a level of “ordinary sadness.”
What differentiates this group from typical Major Depressive Disorder is that their symptoms never fully remit for longer than 2 months. Even when things improve, they still carry a constant sense of emptiness, lethargy, or emotional burnout, as if the brain is stuck permanently in a “low-energy depressive mode.”
In general, their baseline of life is ongoing emotional depletion and a persistently negative worldview (this is referred to as a dysthymic mood). Periods without an MDE do not mean they are happy or normal; they are simply “depressed at a stable level” — a resting phase of depression in which residual symptoms are still continuously present.
Most patients can technically work or socialize, but they do so in a kind of “automatic mode,” like a robot carrying out tasks with no intrinsic motivation. Many live with what is called functional depression: they continue to function, but there is no sense of meaning or genuine satisfaction in their daily routines.
From a brain perspective, the fact that they are not currently in an MDE does not mean their brain has returned to equilibrium. The neural networks involved in emotion are still functioning abnormally — for example, a hyper-reactive amygdala that is overly sensitive to negative cues, and a prefrontal cortex that still cannot fully regulate emotional responses. This means that even without any particular trigger, the person can still feel sad “for no apparent reason.”
This condition is often overlooked because people around them think, “They’ve gotten better now,” after they come out of an MDE. In reality, their cognitive structure and brain chemistry are still functioning at a depressive level. Without ongoing management, there is a very high likelihood that another MDE will occur again.
Epidemiologically, this condition is common in early to middle adulthood, especially among individuals with perfectionistic or self-critical personalities and those who grew up in environments with heavy expectations. They often learn to “keep performing their role” even when their inner emotional life has long since burned out.
In summary, “With Intermittent Major Depressive Episodes — Without Current Episode” describes a form of depression that has never truly gone away. The severity has simply decreased from deep plunges (MDEs) into a more constant, stable level of depression. The patient remains in a state of chronic depressive mode and requires long-term follow-up just like any other chronic illness — no different from managing diabetes or hypertension, except here it is an “emotional chronic disease.”
🎯 Core Symptoms — Main Symptoms
The condition “With Intermittent Major Depressive Episodes — Without Current Episode” represents a complex pattern of depression, because it combines both the “chronic depressive baseline” of Persistent Depressive Disorder (PDD / Dysthymia) and “episodic deep plunges” in the form of Major Depressive Episodes (MDEs) that have occurred in the past. At present, however, the person has returned to a chronic level (PDD phase).Therefore, the symptom picture must be understood on two levels — the baseline layer (PDD) and the superimposed layer (past MDEs), each reflecting different aspects of brain function and emotional regulation.
🔹 Level 1: Baseline Symptoms of Persistent Depressive Disorder
This is the emotional tone that stays with the patient almost all the time; it doesn’t go away, even when they are not in an MDE.Patients often say, “I’ve just been like this for a long time,” without even realizing that this is a depressive condition, because it has become embedded in their habits and worldview.
Common core symptoms (must have ≥ 2 symptoms, persisting ≥ 2 years):
Depressed, dejected, or persistently low mood as the emotional background of life
– Not necessarily crying every day, but feeling as if “nothing is truly bright or joyful” for many years.
– They often say, “I haven’t felt genuinely happy in a very long time.”
Poor appetite or overeating
– The brain’s reward circuitry is dysregulated, causing appetite to fluctuate.
– Some people eat a lot to compensate for inner emptiness, while others lose their appetite almost entirely.
Insomnia or hypersomnia
– The circadian rhythm or biological clock system is disrupted.
– Many wake up frequently at night, or sleep excessively as a way to escape their internal emotional state.
Low energy, fatigue, diminished motivation (low energy / fatigue)
– The brain releases lower levels of serotonin and dopamine, reducing the sense of “wanting to do things.”
– Patients say, “It’s not that I’m crying from sadness — I just have no energy to start anything.”
Low self-esteem, feelings of worthlessness / not being good enough
– Self-schema is distorted by childhood experiences of repeated criticism or invalidation.
– External voices of criticism become internalized and turn into the “voice in their head.”
Poor concentration, difficulty making decisions (poor concentration / indecisiveness)
– The prefrontal cortex is underactive.
– Planning, logical thinking, and sustained attention become noticeably harder.
A pervasive sense of hopelessness, feeling that the future cannot possibly be better
– This is a hallmark feature of dysthymia.
– It’s not just being sad today, but genuinely believing, “No matter what I do, things will never improve.”
Key Psychological Patterns commonly seen in this group
– They often feel, “This is just who I am,” rather than, “This is an illness.”
– They live with functional depression — they can work, but without any real sense of vitality.
– When asked to recall a period of life when they were “not depressed at all,” they often cannot remember, or say, “I don’t even remember what it feels like to feel good.”
– People around them frequently do not notice, because the patient often appears “calm and well-behaved,” even while being chronically down inside.
🔹 Level 2: History of “Intermittent Major Depressive Episodes” (Past Deep Episodes)
Beyond the chronic depressive baseline, patients in this group have experienced full-blown Major Depressive Episodes that were noticeably more intense than their usual state, superimposed on their life at various times.Those periods can be seen as times when “the brain temporarily crashed” — neurochemistry and limbic–prefrontal connectivity became severely imbalanced, leading to a clinical picture similar to full Major Depressive Disorder.
Characteristics of MDEs that may have occurred in the past (must have ≥ 5 symptoms for ≥ 2 consecutive weeks):
– Profoundly depressed mood, nearly all day, almost every day.
– Markedly diminished interest or pleasure in nearly all activities (anhedonia).
– Significant weight loss or gain without intentional dieting, or marked changes in appetite.
– Insomnia or hypersomnia.
– Noticeable psychomotor changes — either agitation or retardation observable by others.
– Fatigue or loss of energy nearly every day, even without heavy activity.
– Feelings of worthlessness or excessive/inappropriate guilt about things beyond their control.
– Diminished ability to think, concentrate, or make decisions.
– Recurrent thoughts of death, wishing to disappear, or suicidal ideation/plan.
But the key point of this specifier is:
At the time of assessment, “there is no MDE currently present” — meaning the symptoms at this moment do not reach the full threshold for Major Depressive Disorder.
However, the brain and behavior remain in a dysthymic base state.
In other words, “the intense episode has resolved, but the depressive tone remains.”
This condition is often compared to a fire that has not completely gone out — even though the flames (the MDE) have died down, the ashes of sadness are still smoldering underneath, ready to flare up again at any time.
📏 Diagnostic Criteria
In the DSM-5-TR, “With Intermittent Major Depressive Episodes — Without Current Episode” is not a separate disorder on its own, but a specifier (a label that describes specific characteristics) of Persistent Depressive Disorder (PDD).Diagnosis therefore requires that the criteria for PDD are met first, and then this specifier is added afterward to describe the course of the illness.
Step-by-step diagnostic process
1. Depressed or dejected mood for most of the day, nearly every day, for at least 2 years (in adults)
– For children/adolescents, the minimum duration is 1 year.
– During this period, there is no interval of more than 2 consecutive months without any symptoms at all.
2. Presence of at least 2 of the following additional symptoms:
– Poor appetite or overeating
– Insomnia or hypersomnia
– Low energy or fatigue
– Low self-esteem
– Poor concentration / difficulty making decisions
– Feelings of hopelessness
3. At least one Major Depressive Episode (MDE) has occurred
– At that time, symptoms met full criteria for Major Depressive Disorder.
– But at present, at the time of assessment, the person is not in an MDE.
– They may still have mild to moderate depressive symptoms consistent with PDD.
4. No history of clear Mania, Hypomania, or Cyclothymia
– This is to differentiate from the Bipolar Spectrum, which is a different category entirely.
5. Symptoms are not primarily attributable to the effects of a substance, medication, or another medical condition
– For example: hypothyroidism, steroid use, or chronic alcohol use.
6. Symptoms cause clinically significant distress or impairment
– For instance: decreased work performance, breakdown in relationships, loss of motivation in life, overall low quality of life.
Additional specifier distinctions within this pattern
Once all the criteria are met, clinicians will add further specifiers to describe the current state of the disorder, such as:
With pure dysthymic syndrome:
No MDE has ever occurred.
With intermittent major depressive episodes — without current episode:
The person has had MDEs in the past, but is not currently in one.
With intermittent major depressive episodes — with current episode:
The person is currently in an MDE.
With persistent major depressive episode:
Symptoms at the level of an MDE have persisted continuously for 2 years or more.
Course Pattern (Illness Course)
This condition typically begins in adolescence or early adulthood and then continues for many years.– There may be periods of slight improvement, but not to the point of complete remission.
– Superimposed MDEs often occur in times of severe stress or major loss.
– The interval between MDEs can be several years, but the underlying PDD remains throughout.
Example of how this might appear in a psychiatric report
Diagnosis:
Persistent Depressive Disorder (Dysthymia), with intermittent major depressive episodes, without current episode
Course: Chronic, fluctuating, onset early adulthood
Severity: Moderate, currently not in MDE
Specifiers: With anxious distress; early onset
Clinical importance of specifying this pattern
Labeling the condition as “without current episode” helps clinicians understand that
the patient still has a chronic depressive condition that requires treatment, even though they are not presently in an MDE.
Treatment planning often emphasizes “maintaining stability” and “preventing relapse” more than acute crisis management.
Ongoing follow-up is crucial because the risk of relapse can be as high as 60–70% over the next few years.
In short:
Patients in this group have not “recovered from depression” — they have simply “returned to a chronic depressive mode.”The brain continues to operate in a depressive state, and long-term care is necessary to prevent recurrent MDEs that can come back at any time.
🧩 Subtypes or Specifiers — Subtypes / Additional Specifiers
For PDD with intermittent MDE — without current episode, additional specifiers can still be layered on, for example:With anxious distress
– Marked anxiety, nervousness, inner tension, or persistent worry present alongside depression.
– Associated with higher risk of relapse and higher risk of suicidal ideation.
With atypical features
– Mood can brighten temporarily in response to positive events.
– Increased appetite and hypersomnia, with weight gain.
– Marked sensitivity to rejection in relationships (rejection sensitivity).
With melancholic features (even if not classic as in pure MDD)
– Near-complete loss of pleasure in almost all activities.
– Mood does not significantly improve in response to external positive stimuli.
– Early-morning awakening, decreased appetite, intense guilt, and psychomotor changes.
With seasonal pattern
– The intermittent MDEs that occur on top of the PDD may follow a seasonal pattern (e.g., in winter).
Early onset / Late onset
– Onset before age 21 = early onset → often associated with personality traits, trauma, and family patterns.
– Onset after age 21 = late onset → more likely to involve biological factors, physical illness, or life events.
With pure dysthymic syndrome vs. with intermittent MDE
– Pure dysthymic syndrome = there has never been an MDE superimposed.
– With intermittent MDE = there have been one or more superimposed MDEs.
And your specific specifier is without current episode = at present, the person has returned to the PDD-level baseline only.
🧬 Brain & Neurobiology — Neural and Neurobiological Mechanisms
This condition reflects a “brain that has learned sadness over the long term.”It is not just about short-lived, acute depressive episodes, but a brain that has gradually adapted until sadness becomes the default emotional mode.
People in this group tend to show brain patterns similar to those with both Persistent Depressive Disorder (PDD) and Recurrent Major Depression (MDD) —
meaning that the structure and connectivity of their brain are dysregulated across multiple systems at once.
🔹 1. Fronto-Limbic Dysregulation — Chronic Breakdown of the Balance Between “Emotion” and “Reason”
The limbic system (especially the amygdala) detects threat, processes emotion, and responds to emotionally salient stimuli.In a healthy brain, when the amygdala is activated, the prefrontal cortex (PFC) sends regulatory signals to calm it down.
In chronic depression, this regulatory system is “disconnected.”
Amygdala: shows hyperactivity to negative signals such as criticism, rejection, or even sad memories
→ This leads the brain to selectively focus on negative information (negative attentional bias).
Ventromedial PFC (vmPFC) and Dorsolateral PFC (dlPFC): show reduced activity
→ The brain is less able to “counterbalance” negative emotions with rational appraisal.
Anterior Cingulate Cortex (ACC): especially the subgenual ACC, often becomes overactive during chronic sadness
→ This locks emotional circuits into an “automatic sadness mode,” even in the absence of a concrete trigger.
The result is that the brain continually interprets neutral or mildly negative situations as “bad” or “failure.”
Even when there is no real threat, it feels as if “the world is hostile” all the time.
🔹 2. Default Mode Network (DMN) Overactivity — A Brain Trapped in Its Own Loops
The DMN is a network that becomes active when we are not engaged in external tasks — such as daydreaming, thinking about the past, or reflecting on ourselves.In chronic depression, the DMN tends to be overactive and over-connected to the limbic system.
This produces persistent rumination — repetitive thinking about failures, regrets, and unresolved emotional issues.
fMRI studies show abnormally high connectivity between the posterior cingulate cortex (PCC) and the medial PFC
→ The brain remains in a self-focused state almost continuously.
The more the person thinks about themselves, the more this activates sadness.
→ This creates a closed loop between “thinking about oneself” and “feeling depressed,” with no obvious exit.
This explains why people with this condition “cannot escape the depressive mode” even when there are no new external problems.
🔹 3. Reward Circuitry Hypoactivity — A Non-Responsive Reward System
The brain’s reward system — particularly the ventral striatum, nucleus accumbens, and ventral tegmental area (VTA) — underlies pleasure, motivation, and the anticipation of positive outcomes.In individuals with PDD plus a history of MDE:
– These regions respond far less to positive stimuli (hypoactivation).
– They do not feel genuinely “excited” or “satisfied” by rewards such as praise, achievement, or rest.
– This phenomenon is called anhedonia — a reduced capacity to experience pleasure.
As a result, life shifts into a mode of “just surviving” rather than “truly living.”
Even when they try, they do not feel that anything they do meaningfully improves their internal state.
🔹 4. HPA Axis Dysregulation — A Stress System Out of Rhythm
The Hypothalamic–Pituitary–Adrenal (HPA) axis regulates cortisol, the stress hormone.In chronic depression, cortisol levels are often persistently elevated or mis-timed (disrupted diurnal rhythm).
– Elevated cortisol can damage the hippocampus → impairing short-term memory and concentration.
– Sleep systems are disturbed → frequent night-time awakenings, nightmares, or oversleeping without feeling refreshed.
– Physical energy drops because the body is stuck in a “constant alert” mode.
This HPA axis dysregulation is closely linked to the “emotional fatigue” commonly seen in PDD.
🔹 5. Neuroplasticity & BDNF Reduction — Loss of the Brain’s Flexibility to Recover
Many studies show that individuals with chronic depression have lower levels of BDNF (Brain-Derived Neurotrophic Factor), a crucial protein for forming new neural connections.– When BDNF is low, the brain becomes “stuck” in existing patterns.
– The longer the depression persists, the more the brain learns negative thinking as an automatic habit.
– Antidepressants (e.g., SSRIs, SNRIs) and certain activities — such as exercise, mindfulness practice, and adequate sleep — can help boost BDNF levels.
This is why treatments that “change lifestyle and behavior” are as important as medication — they directly stimulate neuroplasticity.
🔹 6. Neuroinflammation — Micro-Level Inflammation in the Brain
There is growing evidence that chronic depression is associated with low-grade systemic and neuroinflammatory processes.Cytokines such as IL-6, TNF-α, and CRP are elevated compared to healthy individuals → affecting serotonin and dopamine signaling.
– The brain responds to inflammation by dampening activity in the reward system.
– Patients feel more lethargic, fatigued, and socially withdrawn — a pattern similar to “sickness behavior.”
– Chronic stress and sleep deprivation further amplify inflammation in the brain.
🔹 7. Structural Brain Changes
Longitudinal MRI studies have found:– Reduced hippocampal volume, especially in cases with symptoms lasting more than 5 years.
– Cortical thinning in the prefrontal cortex, impairing emotional regulation.
– Degradation of white matter integrity, particularly in tracts connecting the PFC and limbic regions (e.g., the uncinate fasciculus).
These changes do not necessarily mean the brain is permanently destroyed, but they do indicate that the brain has been “using the depressive pathway” so frequently that it has become the new default network.
🔹 8. Overall Summary of the Brain in This Condition
The patient’s brain is in a state of “learned sadness.”– The limbic system is overactive.
– The cortical systems that support reasoning and regulation are underactive.
– The reward system is blunted.
– Stress and sleep systems are out of balance.
– Structural configurations gradually adapt to “cope with sadness” rather than “recover from it.”
As a result, the brain cannot spontaneously return to a normal baseline, even in the absence of new external stressors — this is the core neurobiological essence of “Intermittent MDE — Without Current Episode.”
⚙️ Causes & Risk Factors — Expanded Risk and Causal Factors
This condition does not arise from a single cause; it emerges from the additive interaction of multiple systems —biological, psychological, and social — collectively forming a biopsychosocial model of chronic depression.
🔹 1. Genetic & Biological Factors
Twin studies suggest that variants in the serotonin transporter gene (5-HTTLPR) contribute to vulnerability to chronic depression.– Individuals with the short allele of 5-HTTLPR are more sensitive to environmental stress.
– Genes related to dopamine (e.g., DRD2, COMT) may also affect the reward system.
– A family history of depression or bipolar disorder increases the risk by about 2–3 times.
In addition, other biological components include:
– Thyroid dysfunction, imbalances in estrogen/testosterone.
– Chronic medical conditions such as diabetes, lupus, and chronic fatigue syndrome.
🔹 2. Personality Predispositions
Individuals with:– High neuroticism — highly reactive to stress and disappointment.
– Perfectionism — setting unrealistically high standards that turn into constant pressure.
– Self-critical personality — tendency to blame themselves rather than appraise problems objectively.
– Avoidant / Dependent traits — relying excessively on external validation.
These personality patterns create a self-critical loop in the brain, aligning with the DMN overactivity seen in this condition.
🔹 3. Early Life Experiences
– Emotional neglect or harsh criticism from an early age.– Early loss of important figures (e.g., separation, parental divorce, or death).
– Physical, verbal, or sexual abuse.
These experiences shape the development of the amygdala and hippocampus towards a “hyper-vigilant threat-detection mode.”
Later in life, the brain tends to interpret even minor cues as threatening, predisposing the individual to chronic depression and a pervasive sense that “the world is unsafe.”
🔹 4. Chronic Stress & Life Events in Adulthood
– Working under intense pressure, burnout, imbalanced relationships, caregiving burden.– Financial problems or feeling “trapped in the same life with no way out.”
Chronic stress dysregulates the HPA axis and reduces neuroplasticity.
Combined with a self-critical personality, this creates a self-perpetuating cycle of thoughts, chemistry, and behavior that steadily erodes well-being.
🔹 5. Medical & Physiological Factors
– Chronic conditions: hypothyroidism, cardiovascular disease, chronic pain, autoimmune diseases.– Certain medications: corticosteroids, isotretinoin, interferon-alpha.
– Deficiencies in vitamin D, B12, omega-3, or sleep disruption due to circadian misalignment.
– Long-term night-shift work or chronic jet lag can also contribute to chronic depressive states.
🔹 6. Social & Interpersonal Factors
– Loneliness and lack of emotional support (social isolation).– Environments that do not validate emotions (“Don’t overthink,” “You’re just being dramatic”).
– Lack of a community or network that understands them, leading the brain to register the message: “I am alone in this world.”
Biologically, this sense of isolation activates stress systems and worsens neuroinflammation in the brain.
🔹 7. Cumulative Risk
This condition usually does not arise from a single “explosive event,”but rather from the accumulation of minor factors over many years, such as:
A sensitive temperament → harsh, critical upbringing → repeated stress exposure → development of chronic depression.
Over time, the brain restructures itself such that “sadness” becomes the default operating mode of the nervous system.
🔹 8. Modern Lifestyle Amplifiers
– Excessive use of social media → constant social comparison → increased mental load.– Continuous multitasking → the brain never enters true recovery mode.
– Sleep deprivation and screen light disrupting circadian rhythms.
These may not be primary causes, but they amplify the brain’s vulnerability, making relapse more likely.
🔹 9. Integrative Summary
– Genes and brain biology → create biological vulnerability.– Life experiences → shape brain structure and its threat-response style.
– Personality and thought patterns → form a negative interpretive style of the world and self.
– Current environment → continually reinforces the same depressive cycles.
Together, these produce the “triangular mechanism of chronic depression,”
or what some neuroscientists refer to as a Depressive Learning System — a brain that has learned to live in sadness and turned it into its fundamental operating mode.
🩺 Treatment & Management — Approaches to Care and Management
Because these individuals have both “chronic depression” and a history of “plunging into MDEs,”treatment must be designed with both the short-term and long-term / relapse prevention in mind.
1) Pharmacotherapy (Medication)
SSRIs / SNRIs / atypical antidepressants
– Used to reduce the chronic depressive tone and lower the chance of future MDEs.
Augmentation strategies (for treatment-resistant / chronic cases)
– For example, adding a low-dose atypical antipsychotic, lithium, or thyroid hormone (in some guidelines).
Maintenance treatment
– Because the person has had recurrent MDEs superimposed on a PDD baseline, many guidelines recommend continuing medication long-term to prevent relapse.
Key point: When symptoms return to “just PDD,” patients often think, “I’m okay now, I don’t need treatment anymore.”
In reality, the relapse risk remains high. Management should be conceptualized like other chronic diseases, such as diabetes or hypertension.
2) Psychotherapy
CBT (Cognitive Behavioral Therapy)
– Identifies chronic negative thinking patterns (core beliefs such as “I am worthless,” “I will always fail”).
– Trains the patient to challenge automatic thoughts and make small behavioral changes that pull the brain out of negative loops.
CBT for Chronic Depression / PDD-specific models
– Focuses on long-term life structure, goal-setting, and reshaping the entire “lifestyle schema.”
– It does not only ask, “What symptoms are present now?” but looks at patterns across the patient’s whole life.
IPT (Interpersonal Therapy)
– Focuses on relationships, communication, and role transitions or interpersonal conflicts.
– Especially helpful when depressive symptoms are tightly linked to interpersonal stress.
Schema Therapy / Psychodynamic approaches
– Digs into early-life patterns, core schemas about worth, trust, and abandonment.
– Suitable for cases where PDD began in childhood/adolescence and is strongly intertwined with personality structure.
3) Lifestyle & Self-Management
– Maintain regular sleep schedules (sleep hygiene).
– Exercise regularly (evidence shows it reduces depressive symptoms and increases BDNF).
– Balanced nutrition, reducing alcohol and substance use.
– Practice mindfulness, breathing exercises, and body scans to pull the brain out of rumination.
– Build daily structure — scheduling activities that provide both a sense of accomplishment and pleasure.
4) Relapse Prevention
Because there is a history of recurrent MDEs:Create a “relapse signature”:
– Identify early warning signs such as:
– Beginning to withdraw from people.
– Disrupted sleep patterns.
– Increasing thoughts like “Nothing has any meaning anymore.”
– Write these down as a checklist for the patient and their close contacts to use.
Plan ahead:
– If early warning signs appear → adjust medication / see the doctor / increase therapy sessions.
– Make a clear agreement with oneself: do not “just wait for it to pass” without taking action.
📝 Notes — Important Clinical Observations
– People in this category often become so accustomed to chronic sadness that they think, “This is just who I am.”
– As a result, they do not view it as an illness → and tend to seek help late.
– The difficulty is that when they are not in an MDE, people around them may think, “They’re fine now,” when in reality, the PDD baseline is still very much present.
Assessment must therefore explore in detail:
– The person’s baseline mood / patterns from childhood onward.
– Past periods where they dropped deeply (MDEs).
In terms of functioning, these individuals often “keep working and living,” but without drive or joy.
– They are not necessarily lying in bed all day, but living in a mode of “surviving, not truly living.”
If left untreated over the long term:
– They are at risk of physical health problems, substance use, relationship breakdown, persistently low quality of life, and intermittent suicidal thoughts.
📚 References — Academic Sources
American Psychiatric Association. (2022). Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR). Washington, DC: American Psychiatric Publishing.
→ Main source defining Persistent Depressive Disorder and the specifier With Intermittent Major Depressive Episodes — Without Current Episode.
Klein, D. N., Santiago, N. J. (2003). “Dysthymia and chronic depression: introduction, classification, risk factors, and course.” Journal of Clinical Psychology, 59(8), 807–816.
→ Describes the chronic course of dysthymia and the pattern of intermittent major episodes (intermittent MDEs).
McCullough, J. P. (2000). Treatment for Chronic Depression: Cognitive Behavioral Analysis System of Psychotherapy (CBASP). New York: Guilford Press.
→ Specialized psychotherapy for PDD with intermittent MDEs.
Nemeroff, C. B. (1998). “The neurobiology of depression: limbic–cortical dysregulation model.” Neuropsychopharmacology, 19(3), 206–220.
→ Classic work explaining limbic–prefrontal circuit dysregulation in chronic depression.
Drevets, W. C., Price, J. L., Furey, M. L. (2008). “Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression.” Brain Structure and Function, 213(1–2), 93–118.*
→ Examines abnormalities in the amygdala, ACC, and prefrontal cortex in MDD/PDD.
Sheline, Y. I., Price, J. L., Yan, Z., Mintun, M. A. (2010). “Resting-state functional MRI in depression unmasks increased connectivity between self-referential networks.” Biological Psychiatry, 67(4), 407–415.*
→ Demonstrates DMN overactivity in chronic depression.
Russo, S. J., Nestler, E. J. (2013). “The brain reward circuitry in mood disorders.” Nature Reviews Neuroscience, 14(9), 609–625.*
→ Explains reduced activity in the ventral striatum and nucleus accumbens in mood disorders.
Pariante, C. M., Lightman, S. L. (2008). “The HPA axis in major depression: classical theories and new developments.” Trends in Neurosciences, 31(9), 464–468.*
→ Core reference on HPA-axis and cortisol dysregulation in depression.
Duman, R. S., Aghajanian, G. K. (2012). “Synaptic dysfunction in depression: potential therapeutic targets.” Science, 338(6103), 68–72.*
→ Supports the concept of reduced neuroplasticity and BDNF in chronic depression.
Miller, A. H., Raison, C. L. (2016). “The role of inflammation in depression: from evolutionary imperative to modern treatment target.” Nature Reviews Immunology, 16(1), 22–34.*
→ Describes low-grade neuroinflammation and its impact on emotional systems.
Cuijpers, P., van Straten, A., Schuurmans, J. (2007). “Psychotherapy for chronic major depression and dysthymia: meta-analysis.” British Journal of Psychiatry, 190, 293–300.*
→ Evidence-based review of psychotherapies for chronic depressive conditions.
Heller, A. S., Johnstone, T., Shackman, A. J., et al. (2009). “Reduced capacity to sustain positive emotion in major depression reflects diminished neural responses in reward circuitry.” PNAS, 106(52), 22445–22450.*
→ Supports reward circuit hypoactivity in chronic depression with superimposed MDEs.
Gotlib, I. H., Joormann, J. (2010). “Cognition and depression: current status and future directions.” Annual Review of Clinical Psychology, 6, 285–312.*
→ Discusses cognitive biases and their neural underpinnings in depression.
World Health Organization (2023). ICD-11: Persistent mood (affective) disorders. Geneva: WHO.
→ Provides the ICD-11 framework for classifying persistent depressive disorders.
Disner, S. G., Beevers, C. G., Haigh, E. A. P., Beck, A. T. (2011). “Neural mechanisms of the cognitive model of depression.” Nature Reviews Neuroscience, 12(8), 467–477.*
→ Links cognitive theory of depression with neurocircuitry.
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