LOW MOOD / DEPRESSION: The Pathology of the Spirit

Initial Impression & Probable Syndromes

We must first broaden our view. "Low mood" is a symptom, not a diagnosis. It arises from:

1. Primary Major Depressive Disorder (MDD): A discrete neuropsychiatric illness, often recurrent.

2. Depressive Syndrome Due to a General Medical Condition: Where the low mood is a direct physiological consequence of another disease (e.g., hypothyroidism, cancer, stroke).

3. Adjustment Disorder with Depressed Mood: A maladaptive, disproportionate response to an identifiable psychosocial stressor.

4. Bereavement / Normal Grief: A non-pathological, expected response to loss, though it can evolve into MDD.

Why this differentiation is critical: The management of thyroid-induced apathy is levothyroxine, not just an SSRI. Missing the medical cause is a profound failure.

The "Mental List": Beyond "Feeling Sad" – The Diagnostic Criteria

We use structured criteria (like DSM-5/ICD-11) not as a checklist, but as a framework to understand the depth and pervasiveness of the syndrome. The core question is: "Is this a change from the person's usual self, causing functional impairment?"

Question / DomainWhat It Asks (SIG E CAPS Mnemonic)Why It's Critically ImportantPathophysiological / Clinical Link

1. Mood Core (S)Sleep: Change in pattern?Insomnia (especially early morning awakening) or hypersomnia are cardinal neurovegetative signs.Disruption of circadian rhythms and monoamine (serotonin, norepinephrine) regulation. A hallmark of biological depression.

2. Mood Core (I)Interest: Loss of pleasure/interest (Anhedonia)?Anhedonia is the cornerstone. The inability to enjoy what once gave pleasure distinguishes pathological depression from simple sadness.Dysfunction in the brain's reward pathways (mesolimbic dopamine system, prefrontal cortex).

3. Mood Core (G)Guilt / Worthlessness: Excessive or inappropriate?Differentiates pathological self-loathing from normal regret. Can reach delusional proportions.Linked to cognitive distortions and hyperactivity of the brain's self-referential/emotional processing networks.

4. Energy (E)Energy: Fatigue, loss of energy?Profound, pervasive fatigue not relieved by rest. This is biological fatigue, not just tiredness.Associated with HPA axis dysfunction (high cortisol), altered metabolism, and monoamine depletion.

5. Cognition (C)Concentration: Diminished ability to think or indecisiveness?"Brain fog." Impacts work and daily life. A key symptom of executive dysfunction.Prefrontal cortex and hippocampal impairment; can be objectively measured on neuropsychological tests.

6. Appetite (A)Appetite: Significant increase or decrease?Weight change >5% in a month. Another neurovegetative sign pointing to biological dysregulation.Hypothalamic dysregulation affecting hunger/satiety centers.

7. Psychomotor (P)Psychomotor: Agitation or retardation?Observable by others. Patient may speak/walk slowly or be unable to sit still.Reflects profound disturbances in basal ganglia and motor cortex circuits.

8. Suicidality (S)Suicidal Ideation: Thoughts of death or suicide?The ultimate psychiatric emergency. Must be asked directly, compassionately: "Has it gotten so bad that you've thought of harming yourself?"Result of overwhelming psychic pain, hopelessness, and impaired problem-solving.

Deep Dive: The Pathophysiology of Major Depressive Disorder

This is not a "chemical imbalance" in a simplistic sense. It is a systems-level failure.

• Epidemiology: Lifetime prevalence ~15%. More common in women, those with family history, and following major stressors.

• Pathophysiology Stepwise:

  1. Genetic Vulnerability & Stress Interaction: Stressful life events trigger changes in susceptible individuals.

  2. Neurotransmitter Dysregulation: Not just serotonin. Norepinephrine, dopamine, GABA, and glutamate systems are all involved. It's a network problem.

  3. HPA Axis Hyperactivity: Chronic stress leads to excessive Cortisol (the "stress hormone"), which is neurotoxic, particularly to the hippocampus (involved in memory and mood regulation). This creates a vicious cycle.

  4. Structural & Functional Brain Changes: Reduced volume in the hippocampus and prefrontal cortex. Altered connectivity in emotional processing networks (amygdala hyperactivity, prefrontal hypoactivity).

  5. Inflammation: Elevated pro-inflammatory cytokines (IL-6, TNF-α) are now recognized as a key player. They can induce "sickness behavior" (fatigue, anhedonia) and blunt neurotransmitter function.

• Natural History (if untreated): Episodes typically last 6-12 months but can become chronic. Risk of recurrence is high (~50% after first episode, rising with each subsequent episode). Mortality: Significantly increased risk of death from suicide and comorbid medical conditions (cardiovascular disease).

In my experience, the most telling presentation is not the tearful patient, but the one who sits slumped, answers in monosyllables, with flat affect, who says, "I just don't care about anything anymore, Doctor. I have to force myself to eat." That is anhedonia and neurovegetative shutdown—the very essence of the biological syndrome.

Schematic Diagnostic Approach ("The Clinic Workup")

Rule out the organic, then address the psychic.

• First Visit (The 15-Minute Evaluation):

  1. Focused History: Use SIG E CAPS. Ask directly about suicidality: "Do you have thoughts of ending your life?" Assess function: "Is this affecting your work, family life?"

  2. Physical Exam: Look for signs of medical illness (e.g., thyroid eye signs, Cushingoid features, Parkinsonian tremor).

  3. Mental Status Exam: Document affect (flat, constricted), thought process (slowed), thought content (hopelessness, guilt, suicidality).

• Basic Labs (The "Medical Mimics" Panel):

  • Complete Blood Count, ESR

  • Thyroid Function Tests (TSH, Free T4) - Non-negotiable.

  • Vitamin B12, Folate

  • Basic Metabolic Panel (electrolytes, calcium, glucose)

  • Consider: Morning cortisol, HIV test, syphilis serology if indicated.

• Secondary/Specialist-Driven Assessment:

  • Structured Diagnostic Interview by Psychiatrist.

  • Neuroimaging (MRI): Only if focal neurological signs, onset in older age, or atypical features are present.

Principles of Management: A Staged Approach

• Non-Pharmacological (First-Line for Mild-Moderate):

  • Psychoeducation: Explain it as a real illness, not a weakness.

  • Lifestyle Prescription: Regular aerobic exercise (potent neurogenesis stimulator), sleep hygiene, structured routine.

  • Psychotherapy: Cognitive Behavioral Therapy (CBT) is gold-standard. Addresses the cognitive distortions that fuel the mood disorder.

• Pharmacological (For Moderate-Severe, or failure of therapy):

  • First-Line: Selective Serotonin Reuptake Inhibitors (SSRIs) e.g., Sertraline, Escitalopram.

  • Mechanism: Initially block reuptake, leading to complex downstream changes in gene expression, neuroplasticity (e.g., increased BDNF - Brain-Derived Neurotrophic Factor), and ultimately, hippocampal regeneration over weeks.

  • Key Monitoring: Warn about initial worsening of anxiety/agitation (first 1-2 weeks). Emphasize 4-6 weeks for full therapeutic effect. Monitor for activation of suicidality in young adults (Black Box Warning).

  • Duration: Continue for 6-9 months AFTER remission to prevent relapse. Long-term maintenance may be needed for recurrent disease.

• Referral Threshold:

  • Immediate Psychiatric Emergency Referral: Active suicidal or homicidal ideation with plan/intent.

  • Urgent Psychiatric Referral: Treatment-resistant depression, psychotic features (delusions, hallucinations), bipolar features, complex comorbidity (e.g., personality disorder).

Clinical Pearls & Caveats

• A Pearl: "Depression is the great masquerader." It often presents to the internist as chronic fatigue, unexplained somatic pain (headaches, backaches), or irritable bowel syndrome. Always screen for anhedonia and neurovegetative signs in patients with persistent, medically unexplained symptoms.

• A Caveat: Never start an antidepressant without assessing for Bipolar Disorder. Ask: "Have you ever had a period of elevated mood, decreased need for sleep, racing thoughts, and impulsive behavior?" Triggering a manic episode with an antidepressant is a serious iatrogenic harm.

• The Long View: Depression is a chronic, relapsing disease for many. The goal is not just remission of the current episode, but functional recovery and relapse prevention. The therapeutic alliance is paramount. As I often tell my patients, "We will treat this with the same seriousness and partnership as we would diabetes or hypertension."

In essence, evaluating low mood requires a dual vision: the meticulous eye of the physician ruling out organic mimics, and the empathetic ear of the healer listening to profound human suffering. It is where our role as internists is most holistic.

Dr. Asif Malik