Depression Treatments

Confirming Diagnosis

It's important to confirm that the patient's symptoms are indeed due to depression and not something else. Differential diagnosis is critical to rule out other potential causes, including:

  • Medical conditions: Hypothyroidism (TSH, T4), B12 and folate deficiencies, anemia (CBC), electrolyte imbalances (CMP). Other investigations may include brain imaging (CT or MRI) to rule out brain tumors, strokes, or traumatic brain injuries, infections such as HIV or syphilis, and other endocrinological disorders, such as Cushing's syndrome or Addison's disease.

  • Substance use: Obtain a thorough history of substance use, including alcohol, illicit drugs, and prescription medications. Urine drug screens may be necessary. Withdrawal or intoxication from drugs or alcohol can mimic depression.

  • Psychiatric conditions: Bipolar disorder must be ruled out because administering antidepressants to someone with bipolar disorder in a depressive episode can induce mania or rapid cycling. Anxiety disorders, personality disorders, and psychotic disorders should also be considered.

Diagnostic Hierarchy

There's a diagnostic hierarchy in medicine and psychiatry that should be followed, especially when a patient presents for the first time with symptoms of depression:

  • Rule out organic or medical causes through comprehensive blood tests (B12, folate, thyroid function, LFTs, U\&Es, CBC, CMP). Consider other tests based on clinical suspicion (e.g., HIV, syphilis, Lyme disease).

  • Consider substance use by obtaining a detailed substance use history and ordering urine drug screens and/or blood alcohol levels.

  • Rule out other psychiatric conditions, especially bipolar disorder by inquiring about any history of manic episodes or psychosis and family history. Use screening tools such as the Mood Disorder Questionnaire (MDQ).

Severity of Depression

When diagnosing depression, it's important to consider the degree of severity. Severity can be categorized as mild, moderate, or severe. This involves assessing:

  • The intensity of symptoms using standardized rating scales.

  • The impact on the person's ability to function in various domains (e.g., work, social, personal care).

  • The number of symptoms present based on diagnostic criteria (DSM-5 or ICD-10).

Tools like questionnaires (e.g., Ham-D, BDI, PHQ-9, GAD-7) can be used to quantify the severity of depression and track treatment response.

Causes and Contributing Factors
Biological Factors:

  • Genetics: Family history of depression increases the risk. It's a Polygenic risk rather than a specific gene. Specific genes such as the serotonin transporter gene (5-HTTLPR) have been implicated, but the evidence is not conclusive.

  • Neurotransmitters: Imbalances in serotonin, noradrenaline, and dopamine. Other neurotransmitters such as glutamate and GABA are also implicated.

  • Other biological factors: B12 deficiency and other vitamin deficiencies (e.g., vitamin D), chronic illnesses, hormonal imbalances.

  • Medical Conditions: Diabetes, cardiovascular disease, chronic pain syndromes, autoimmune disorders, Parkinson's and other neurological syndromes.

Psychological Factors:

  • Childhood trauma or abuse, Adverse Childhood Experiences (ACEs).

  • Stressful life events such as job loss, relationship problems, financial difficulties.

  • Cognitive factors such as negative thinking patterns, low self-esteem, and learned helplessness.

  • Personality traits such as neuroticism and perfectionism.

  • Coping mechanisms: Maladaptive coping strategies such as avoidance, substance use, or self-harm.

  • Attachment style: Insecure attachment patterns developed in childhood.

Social Factors:

  • Low socioeconomic status, unemployment, poverty.

  • Relationship problems, social isolation and loneliness.

  • Lack of social support, discrimination and marginalization.

  • Cultural factors: Cultural norms and values that stigmatize mental illness or discourage help-seeking.

  • Environmental factors: Exposure to violence, trauma, or natural disasters.

Biological Theories of Depression
Monoamine Theory

The monoamine theory suggests that depression is caused by a deficiency in one or more of the monoamine neurotransmitters (serotonin, noradrenaline, and dopamine) in the brain. Most current antidepressants work by increasing the levels of these neurotransmitters in the synaptic cleft. However, the earliest mentions of research in this area comes from TB drugs because they improved patients' moods.

  • Serotonin: There are approximately 14 types of serotonin receptors, and antidepressants affect most of these receptors, leading to a variety of effects, including side effects. SSRIs (Selective Serotonin Reuptake Inhibitors) selectively block the reuptake of serotonin, increasing its availability in the synaptic cleft.

  • Noradrenaline and Dopamine: These neurotransmitters are also implicated in depression, and some antidepressants target these systems. SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors) block the reuptake of both serotonin and noradrenaline. Dopamine is involved in reward, motivation, and pleasure, and some antidepressants (e.g., bupropion) increase dopamine levels.

Other Biological Factors

  • Glutamate: Imbalances in glutamate levels may contribute to depression. Glutamate is the primary excitatory neurotransmitter in the brain, and abnormalities in glutamate neurotransmission have been implicated in depression.

  • Hormones: Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis, as evidenced by a positive DST (dexamethasone suppression test) in some patients, have been observed. Increased cortisol levels are often found in depressed patients.

  • Inflammation: Some studies have found elevated levels of inflammatory markers in people with depression, such as cytokines (e.g., IL-6, TNF-alpha). Inflammation can affect neurotransmitter function and contribute to depressive symptoms.

  • Neuroplasticity: Reduced rates of neuroplasticity and neurogenesis are found in people with depression, which is the ability of the brain to form new connections and adapt. BDNF (brain-derived neurotrophic factor) is a protein that supports neuroplasticity, and reduced levels of BDNF have been found in depressed patients.

Diagnosis and Treatment
Guidelines for Treatment

  • Mild Depression: The NICE guidelines recommend against using antidepressants for mild depression. Instead, low-intensity therapy (e.g., guided self-help, psychoeducation) and lifestyle advice are recommended. Watchful waiting may also be appropriate.

  • Moderate to Severe Depression: Antidepressants are generally recommended, along with psychological therapies such as cognitive behavioral therapy (CBT), interpersonal therapy (IPT), or psychodynamic therapy.

Antidepressants

  • Tricyclic Antidepressants (TCAs): Older antidepressants (e.g., amitriptyline, imipramine) that are effective but have significant side effects (e.g., dry mouth, constipation, urinary retention, orthostatic hypotension) and are dangerous in overdose. TCAs block the reuptake of serotonin and noradrenaline.

  • Selective Serotonin Reuptake Inhibitors (SSRIs): Newer antidepressants (e.g., fluoxetine, citalopram, sertraline, paroxetine, escitalopram) that are generally better tolerated with fewer side effects. Common side effects include nausea, insomnia, sexual dysfunction, and weight gain. SSRIs selectively block the reuptake of serotonin.

Other Antidepressants

  • Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs): Affect both serotonin and noradrenaline (e.g., venlafaxine, duloxetine). SNRIs block the reuptake of both serotonin and noradrenaline.

  • Monoamine Oxidase Inhibitors (MAOIs): Inhibit the enzyme that breaks down monoamines (e.g., phenelzine, tranylcypromine). MAOIs are effective but have significant dietary restrictions (tyramine) and drug interactions.

  • Melatonin Agonists: Target melatonin receptors (e.g., agomelatine). Agomelatine is a melatonergic antidepressant that can improve sleep and mood.

  • Ketamine: A newer antidepressant that works differently from traditional antidepressants by not affecting monoamines. Ketamine is an NMDA receptor antagonist that can provide rapid relief of depressive symptoms.

Switching Antidepressants

If a patient experiences side effects or does not respond to an antidepressant, it may be necessary to switch to a different one. It's generally recommended to try each antidepressant for at least 6-8 weeks at a therapeutic dose before switching and try a medication from a different family to maximize chances of success. Cross-tapering may be necessary to avoid withdrawal symptoms or drug interactions.

Treatment-Resistant Depression

Treatment-resistant depression is defined as depression that does not respond to two or three different antidepressants. In these cases, other treatments may be considered, such as:

  • Combining two antidepressants (e.g., SSRI + bupropion).

  • Augmentation with other medications (e.g., lithium, thyroid hormone, atypical antipsychotics).

  • ECT (electroconvulsive therapy). ECT is a highly effective treatment for severe depression, especially when other treatments have failed.

  • Neuromodulation techniques (e.g., TMS, DBS, VNS). TMS (transcranial magnetic stimulation) is a non-invasive brain stimulation technique that can be used to treat depression. DBS (deep brain stimulation) and VNS (vagus nerve stimulation) are more invasive techniques that involve implanting electrodes in the brain or neck.

  • Psychotherapy. Continued psychotherapy can help patients develop coping skills and address underlying psychological issues.

Holistic Approach

It's important to treat the patient holistically, addressing other factors such as social support, lifestyle, and co-morbid conditions.

  • Lifestyle modifications can include exercise, healthy diet, sleep hygiene, and stress management techniques.

  • Addressing co-morbid conditions such as anxiety, substance use, or medical problems can improve treatment outcomes.

  • Treat early to avoid poor outcomes such as chronic depression, disability, and increased risk of suicide.

Synaptic Diagram and Mechanism of Action

Different antidepressants affect different parts of the synaptic diagram. SSRIs, by way of example, block the reuptake transporter. The reuptake transporter usually takes the serotonin neurotransmitter from the synapse and brings it back to the presynaptic neuron.

Factors to Consider When Prescribing

  • Patient preference and values

  • Associated problems and co-morbidities

  • Side effects and tolerability

  • Previous response to antidepressants

  • Family history of treatment response

  • Overdose risk and safety

  • Drug interactions

  • Cost and availability

Take Home Message

  • Know the diagnosis of the patient and use diagnostic criteria (DSM-5 or ICD-10).

- Other medical and psychiatric conditions need to be ruled out first through comprehensive evaluation.