Affective and Mood Disorders

• Affective disorders are also known as mood disorders

• Major depressive disorder (MDD) is a prevalent and significant psychological condition that affects individuals across various demographics. It is characterized by a persistent feeling of sadness or loss of interest in previously enjoyed activities, which can severely impede daily functioning and quality of life. A clinical diagnosis of MDD relies primarily on comprehensive patient interviews where clinicians assess the presence and duration of specific symptoms.

  Additional clinical manifestations of depression often encompass sleep disturbances, such as insomnia or hypersomnia, as well as appetite changes that may lead to significant weight loss or gain.

  Cognitive deficits, which can manifest as difficulties in concentration and decision-making, are common in individuals suffering from this disorder. Energy levels are often markedly reduced, contributing to overall fatigue and lethargy. Alongside these symptoms, pervasive thought patterns may include intense feelings of guilt, a diminished sense of self-worth, and recurrent thoughts of death or suicide, which require immediate and careful intervention.

Treatments

• Antidepressants and mood-stabilizing drugs are the primary treatments for affective disorders
• Major depressive disorder is characterized by symptoms such as depressed mood, loss of interest, sleep disturbances, feelings of worthlessness, and recurrent suicidal thoughts
• Irritability or anxiousness can also be a symptom of major depressive disorder
• Bipolar disorder involves recurrent mood, energy, and behavior fluctuations and extremes Periods of mania alternate or occur simultaneously with depressive symptoms in bipolar disorder
• The manic phase is characterized by elevated mood, inflated self-esteem, increased talking, racing thoughts, increased social or work activity, and decreased need for sleep

Major Depressive Disorder

• Clinical diagnosis is primarily based on patient interviews
• Key diagnostic criteria: Depressed mood for at least 2 weeks, or loss of interest/pleasure in most activities
• Both symptoms can be present simultaneously
• Sleep and appetite disturbances are clinical manifestations of depression
• Cognitive and energy deficits are clinical manifestations of depression
• Common thought patterns include feelings of guilt, sense of worthlessness and suicidal ideation

Medical Comorbidities

• Higher prevalence of coronary artery disease, diabetes, and stroke
• Depression can worsen the prognosis of existing medical conditions
• Depression increases the overall disease burden and decreases quality of life

Pathophysiology of Major Depression

• The historical perspective is the monoamine hypothesis focusing on deficits in monoamine function/amounts
• This contemporary view recognizes that the development of major depression is influenced by a complex interplay of genetic, environmental, and biological factors, particularly highlighting the significance of neurotrophic factors in emotional and cognitive functioning.
• The endocrine system's involvement includes dysregulation of hormones such as cortisol, which can exacerbate mood disorders and contribute to the overall pathophysiology of major depression.

The Neurotrophic Hypothesis

• Focuses on nerve growth factors
• Brain-derived neurotrophic factor (BDNF) is a key player
• Critical functions of BDNF include neural plasticity regulation, resilience maintenance, and neurogenesis promotion
• The mechanism of action involves activation of tyrosine kinase receptor B, affecting both neurons and glia

Evidence Supporting Neurotrophic Hypothesis

• Stress and pain studies show an association with decreased BDNF levels
• Atrophic changes in key brain regions can result from stress and pain
• Affected brain structures include the hippocampus, medial frontal cortex, and anterior cingulate

Human Studies

• Depression markers include decreased BDNF in cerebrospinal fluid and serum
• Lower tyrosine kinase receptor B activity is also a depression marker
• Antidepressants increase BDNF levels as a treatment effect which is seen in potential hippocampal volume restoration
• Contradictory findings:Studies involving BDNF knockout mice are critical for understanding the role of brain-derived neurotrophic factor in depression and anxiety. These mice are genetically modified to lack the BDNF gene, leading to observations of pronounced behavioral changes that mimic symptoms commonly associated with mood disorders. Research has shown that these knockout mice exhibit increased anxiety-like behaviors and cognitive impairments, demonstrating how essential BDNF is for normal neuronal function and emotional regulation. Unexpected responses to social stress in these models highlight the complexity of depression and the necessity for further exploration into how BDNF and related neurotrophic pathways interact with environmental and genetic factors. Such findings contribute to the overall understanding of the neurobiological underpinnings of mood disorders., unexpected responses to social stress, and effects of lateral ventricle BDNF injection
• Genetic factors such as BDNF polymorphisms, mutations affecting anxiety and depression, and treatment responses plays a role

The Monoamine Hypothesis

• It connects depression to deficiencies in serotonin(5-HT), norepinephrine (NE), and dopamine (DA), as well as affecting cortical and limbic regions
• Monoamine is the primary theory in understanding depression mechanisms
• Reserpine studies show that monoamine depletion leads to depression
• Dietary manipulation studies: Tryptophan depletion causes relapse in patients on serotonergic antidepressants
• Catecholamine depletion affects noradrenergic antidepressant responders
• Treatment response patterns involve all current antidepressants affecting the monoamine system
• Treatment includes Enhanced synaptic availability of 5-HT, NE, or DA
• Genetic Evidence points to Serotonin transporter gene polymorphism
• Limitations: Not all studies show altered monoamine levels and some patients show normal monoamine function
• New antidepressants in development target non-monoamine systems, hypothesis incomplete but valuable

Glutamate System in Depression

• Clinical evidence include elevated CSF glutamate, decreased glutamine/glutamate plasma ratios and increased glutamate in frontal/prefrontal cortex
• Structural changes includes Volume changes in glutamate-rich regions, and affecting the amygdala and hippocampus
• Effects of chronic antidepressant use include Reduced glutamatergic transmission and decreased presynaptic glutamate release, as well as affecting hippocampus and cortical areas
• Stress increases glutamate release, antidepressants inhibit stress-induced release

Antidepressant Groups

• Selective Serotonin Reuptake Inhibitors (SSRIs)
• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
• 5-HT2 Receptor Modulators
• Tricyclic antidepressants
• 5-HT receptor modulators
• Tetracyclics & Unicyclics
• Monoamine Oxidase Inhibitors (MAOIs)
• NMDA Receptor Antagonists
• GABAA Allosteric Modulators

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Involves the primary mechanism being the Inhibition of serotonin transporter (SERT)

• First introduced in 1988, Fluoxetine

• Key advantages: Ease of use, Safety in overdose, Good tolerability, Cost-effective, Broad spectrum of uses

• Clinical applications: Major depression, Generalized anxiety disorder (GAD), Post-traumatic stress disorder (PTSD), Obsessive-compulsive disorder (OCD), Panic disorder, Premenstrual dysphoric disorder (PMDD) and Bulimia

• SSRIs selectively block the neuronal reuptake of 5-HT, having much less effect on NA

• Efficacy supports the hypothesis that 5-HT dysfunction plays a significant role in the physiology of depression

• Common Selective Serotonin Reuptake Inhibitors (SSRIs) prescriptions:

• Fluoxetine is for Major depressive disorders, Bulimia nervosa, Obsessive compulsive disorder, and anxiety related personality disorders. Prozac is the trade name.

• Citalopram is for Major depressive disorders, and anxiety disorders. Cipramil is the trade name.

• Sertraline is for Major depressive disorders, and anxiety disorders. Sertra is the trade name.

• Fluvoxamine is for Depressive disorders, and Obsessive compulsive disorder. Luvox is the trade name

• Escitalopram is for Major depressive disorder, panic disorders, GAD, OCD, and social disorders. Cipralex is the trade name.

• Paroxetine is for Major depressive disorder, panic disorders, GAD, OCD, and PTSD. Aropax is the trade name.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Examples: Venlafaxine, Desvenlafaxine, Duloxetine and Levomilnacipran
• Clinical applications: Major depression, Pain disorders, Generalized anxiety, Stress urinary incontinence and Vasomotor symptoms of menopause

Tricyclic Antidepressants (TCAs)

• Current role: Treatment-resistant depression, Pain conditions, Enuresis and Insomnia
• Limitations: Poor tolerability, Difficulty of use, and Lethality in overdose
• Dosulepin is for Major depressive disorders, and depression associated with anxiety. Trade name is Thaden
• Amitriptyline is for Depressive disorders, and pain relief in chronic pain syndromes. Trade name is Trepilene
• Imipramine is for Depressive disorders, Panic disorder, and Enuresis in children over 5. Trade name is Tofranil
• Clomipramine is for Major depressive disorders, cataleptic accompanying narcolepsy, and OCD. Trade name is Anafranil
• Trimipramine is for Major depressive disorders, and Enuresis in children over 5. Trade name is Tydamine

5-HT2 Receptor Modulators

• Medication includes: -Trazodone, containing triazolo moiety, unlabeled as hypnotic with the metabolite m-chlorophenylpiperazine (m-cpp) -Nefazodone, related to trazodone, had a FDA black box warning (2001) for hepatotoxicity, and has limited current use -Vortioxetine, includes multiple receptor activities: 5-HT3, 5-HT7, 5-HT1D antagonist, 5-HT1B partial agonist, 5-HT1A agonist, and is approved for cognitive dysfunction of depression

Tetracyclic and Unicyclic Antidepressants

• bupropion has -Unicyclic aminoketone structure -CNS activating properties -Unique side-effect profile
• Mirtazapine -Tetracyclic structure -Minimal sexual side effects -Piperazino-azepine group

Monoamine Oxidase Inhibitors (MAOIs)

• Historical significance as it was known as the First modern antidepressants (1950s)
• Limited use due to toxicity, food interactions and drug interactions
• Types: Hydrazine derivatives: Phenelzine, Isocarboxazid and Nonhydrazines: Tranylcypromine, Selegiline, Moclobemide

NMDA Receptor Antagonists

• Esketamine
  • First non-monoamine-specific agent
  • Rapid onset (24 hours)
  • Intranasal administration
  • Used in treatment-resistant depression
• Dextromethorphan/Bupropion
  • Multiple mechanisms of action
  • Rapid-acting treatment
  • Combined with bupropion for CYP2D6 inhibition

GABAA Allosteric Modulators

• Emerging Treatments: -Brexanolone
• Neurosteroid antidepressant
• 60-hour IV infusion
• First drug specifically for postpartum depression -Rapid action with durable effect
• In Development:
• Zuranolone, an oral medication for major depression -Ganaxolone, for PTSD treatment

Pharmacokinetics of Antidepressants

• General Characteristics:

  • Rapid oral absorption
  • Peak plasma level between 2 - 3 hours
  • High plasma protein binding
  • Hepatic metabolism
  • Hepatic metabolism

  Renal clearance

Clinical Pharmacology of Antidepressants - Major Depression Treatment

• Acute episodes duration: 6-14 months untreated, 20% of episodes last 2+ years Treatment goals: Complete symptom remission
  • 8-12 weeks initial trial period
  • 30-40% remission with single trial
  • 70-80% remission with sequential strategies Treatment Phases include Acute Treatment
• 1-2 months for maximum benefit Augmentation strategies if needed: -Addition of bupropion -Atypical antipsychotics -Mirtazapine Continuation Phase is between 6 to 12 months with the goal to prevent relapse risk Maintenance Phase should perform long-term prevention, recommended for patients with 2+ episodes in 5 years while 3+ lifetime episodes Bipolar Depression has Limited antidepressant benefit as well as a Risk of manic switch, and Potential cycle acceleration Treatment Effectiveness : Varies by meta-analysis with Generally accepted benefits when combined with psychotherapy for best results

Anxiety Disorders

Panic Disorder

• Recurrent anxiety episodes that are Often unprecipitated and have Avoidance behavior Generalized Anxiety Disorder (GAD)
• Chronic anxiety which are Persistent worrisome thoughts -SSRIs/SNRIs preferred for being More sustainable than benzodiazepines and giving Lower dependence risk

Obsessive-Compulsive Disorder (OCD)

• Serotonergic antidepressants, clomipramine or SSRIs are approved
  • Combined with behavior therapy

Social Anxiety Disorder

• The most common treatment options are SSRIs approved or Venlafaxine with a Higher efficacy than in MDD PTSD
• SSRIs should reduces anxious thoughts and Improves hypervigilance
• Treatment included a Multi-modal treatment

Pain Disorders

• The two Mechanisms are Independent analgesic properties that Affects ascending pain pathways Effective medications include
  • TCAs (historical use) -SNRIs (current preference)
  • Duloxetine
  • Milnacipran (fibromyalgia)

Premenstrual Dysphoric Disorder

• 5% of reproductive-age women suffer from this disorder
• Main treatments are SSRIs, fluoxetine and sertraline Luteal phase treatment that Improves symptom rapidly

Smoking Cessation

• Bupropion is a treatment whose efficacy gives Double quit rate vs placebo and is Comparable to nicotine patches Benefits include Reduced urge to smoke and Fewer withdrawal symptoms that also Lessens the weight gain as it Mimics nicotine effects and affects Dopamine/norepinephrine functions

Eating Disorders

• Bulimia Nervosa treatments are Antidepressants, fluoxetine and reduces binge-purge cycles Anorexia Nervosa
  • Limited antidepressant benefit.refeding is the main treatment

Other Clinical Applications TCAs are mainly recommended to treat Enuresis and Stress incontinence Premature ejaculation Sexual dysfunction is treated with SSRIs or bupropion as well weight management

Adverse Effects of Antidepressants FDA Warning: Increased suicidality risk in patients under 25, as it can give Up to 4% increased suicidal ideation (double placebo rate) No increased risk or reduced risk over age 25, and Particularly reduced risk over age 65

Common Side Effects

• Gastrointestinal: Nausea, and diarrhea improves after the first week
• Sexual dysfunction happens to 30-40% of patients: includes loss of libido Delayed orgasm and Diminished arousal, as well as Headaches and Sleep disturbances can occur Weight gain (particularly with paroxetine) happens

SNRIs and Tricyclic Antidepressants has SNRI-Specific Effects:

Noradrenergic effects: Increases blood pressure and heart rate and CNS activation that can cause insomnia, anxiety, agitation

Venlafaxine increases the Dose-related blood pressure and Duloxetine causes Rare hepatic toxicity

TCA Effects:

Effects of antidepressants can manifest in various ways, including dry mouth, constipation, urinary retention, blurred vision, and confusion. These adverse reactions may stem from the medications' anticholinergic properties. Other notable side effects include orthostatic hypotension, weight gain, and sedation, which can significantly impact a patient's quality of life. Additionally, at higher doses, some antidepressants carry a risk of arrhythmogenic events, potentially leading to cardiovascular complications.

5-HT Receptor Modulators

• Effects include Sedation and Gastrointestinal disturbances Nefazodone can cause Rare hepatotoxicity, or Some cases requiring liver transplant patients
• Vortioxetine causes Dose-dependent GI effects and Sexual dysfunction

MAOIs and Other Classes

MAOI Effects

• Orthostatic hypotension, also known as postural hypotension, is a condition characterized by a significant drop in blood pressure when a person moves from a lying down or sitting position to an upright position. This can lead to symptoms such as dizziness, lightheadedness, and even fainting due to inadequate blood flow to the brain. The condition is often caused by a variety of factors including dehydration, certain medications (such as diuretics and antidepressants), autonomic nervous system disorders, or prolonged bed rest. In elderly individuals, orthostatic hypotension is particularly common and can increase the risk of falls and related injuries. Diagnosis typically involves measuring blood pressure in different positions, while treatment may include lifestyle changes, such as increased fluid and salt intake, wearing compression stockings, and possibly adjustments to medications that contribute to the condition.
• Weight gain
• Highest rates of sexual effects
• Activation/insomnia
• Dangerous food interactions

Other Classes

Tetracyclics: Sedation (mirtazapine)

Bupropion: Agitation, insomnia, anorexia

Vilazodone: Higher GI upset rates

Overdose Risk and Management

• TCAs: cause lethal effects at 1500mg

• MAOIs: causes Severe autonomic effects

• Lower risk exists when SSRIs or SNRIs

• Venlafaxine is usually taken orally, and can be administered independently of food. It is important for patients to follow their healthcare provider's guidance regarding dosage and timing.

• Management includes Cardiac monitoring, and Airway support

• Specific interventions(e.g., sodium bicarbonate for TCAs)

• Concurrent ingestion of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) can lead to a potentially life-threatening condition known as serotonin syndrome. This syndrome is characterized not only by agitation and restlessness but also includes confusion, insomnia, and seizures. Patients may experience severe hypertension and gastrointestinal symptoms, requiring immediate medical attention to mitigate risks.

• At least 2 weeks should lapse between the discontinuation and treatment with either MAOI or an SSRI and the start of treatment with the other drug

• A minimum of five weeks should elapse following the discontinuation of fluoxetine before initiating a new treatment regimen to ensure proper clearance from the system.

• SSRIs should not be taken concurrently with triptans, which are often prescribed for migraine relief, due to the potential risk of serotonin syndrome, a serious and life-threatening condition.