DEPRESSION by qingyunliuliu


• Also known as Affective disorders – includes
  depression, elation or both
• 2 groups:
  - Unipolar disorders: single recurrent episodes of
  - Bipolar disorders: periods of elation alternating
    with depression
• Is a normal response to defeat, disappointment or
  adverse event,
• But when goes out of proportion and continues past
  point at which people begin to recover – major
• Characterized by lowered mood and loss of interest
  or pleasure in activities that are normally enjoyable
• Major depression has a point prevalence of approximately 3 to 5
  percent in males and 8 to 10 percent in females, and lifetime
  prevalence about twice the point prevalence; it is more common in
  populations with higher prevalence of medical illness.
• Peak onset for major depression is in the fourth decade. Although
  most depression episodes remit spontaneously or with therapy, the
  recurrence rate approximates 90 percent.
• Depression is a risk for all-cause mortality, both associated with
  underlying diseases and due to suicide
• Cause is unknown
• Genetic factors - Polymorphisms in the
  promoter region of the serotonin transporter
  gene (5HTT) have been associated with the
  incidence, severity, and treatment
  responsiveness of depression (see Depression:
  Epidemiology and pathogenesis – Uptodate .com)
• Neurotransmitters
• Monoamine neurotransmitters, particularly
  norepinephrine (NA) and serotonin (5HT) have a
  major role
• Many other neurotransmitters and neuromodulators
  (eg, dopamine, acetylcholine, the protein p11,
  endocannabinoids and the CB1 receptor, and substance
  P) also play a role in depression
• Monoamine hypothesis suggests that depression is due
  to depletion of monoamines especially NA and 5HT
• HPA axis
• Many depressed patients have hyperactivity of
  the hypothalamic-pituitary-adrenal cortex axis
  believed due to centrally-mediated
  overproduction of corticotropin releasing
  hormone (CRF)
 General medical conditions causing or contributing
   to major depression ('Secondary Depression')
• Drugs and Poisons - Alcohol, beta blockers, steroids, opiates,
  barbiturates, withdrawal from cocaine and amphetamines, heavy
  metal poisoning, cholinesterase inhibitors, cimetidine,
  chemotherapy agents
• Metabolic/Endocrine Hyper and hypothyroidism, severe anemia,
  hyperparathyroidism, hypokalemia, hyponatremia, Cushing's
  disease, Addison's disease, uremia, hypopituitarism,
• Infectious Diseases TuberculosisHIV, pneumonia, postinfluenza,
  tertiary syphilis, encephalitis, and post-encephalitic states
• Neurodegenerative and Demyelinating Diseases Alzheimer
  disease, multiple sclerosis, Parkinson disease,
• Other: strokes, post-traumatic brain injury syndromes, cerebral
  tumors, cancers chronic inflammatory or auto-immune
  disorders, congestive heart failure
      Diagnostic criteria for major
• DSM IV criteria (refer to notes)
• A major depressive syndrome or episode manifests with five or more of the
  following symptoms, present most of the day nearly every day for a minimum
  of two consecutive weeks. At least one symptom is either depressed mood or
  loss of interest or pleasure.
• Depressed mood
• Loss of interest or pleasure in most or all activities
• Insomnia or hypersomnia
• Change in appetite or weight
• Psychomotor retardation or agitation
• Low energy
• Poor concentration
• Thoughts of worthlessness or guilt
• Recurrent thoughts about death or suicide
       When to start treatment
• Treat if accepted diagnostic criteria are met > 2
• Although drug treatment is often used first, non
  drug therapy is useful to consider
• Sever depression (suicidal ideas) warrants
  hospital pschyatric management
        Non drug - Psychotherapy
• Psychodynamic psychotherapy — relies on developing patient insight, with
  better understanding about why problems existed and how to avoid similar
  problems in the future;
• Cognitive therapy - assumes that a patient's symptoms (eg, anxiety and
  depression) arise from misperceptions and attitudes about the world and
  themselves. Teaches patients to identify and respond to their dysfunctional
  thoughts and beliefs, using a variety of techniques to change thinking, mood,
  and behavior.
• Behavioral therapy — Treatment attempts to alter behavior by systematically
  changing the environment that produces the behavior, leads to changes in
  thoughts and emotions.
• Exposure-based behavioral treatment — Exposure based treatment utilizes
  gradual, systematic, repeated exposure to the feared object or situation to
  desensitize patients with anxiety disorders to the feared stimulus.
   Cognitive behavioral therapy
• CBT combines principles of both behavioral
  and cognitive therapy.
• CBT focuses simultaneously on the
  environment, behavior, and cognition.
• Patients learn how their thoughts contribute to
  symptoms of their disorder, and how to modify
  these thoughts.
• An example from cognitive therapy may illustrate the
• Having made a mistake at work, a person believes, "I'm
  useless and can't do anything right at work."
• Believing this, in turn, tends to worsen his mood.
• The problem may be more worsened if the individual
  reacts by avoiding activities and then behaviorally
  confirming his negative belief to himself.
• As a result, a successful experience becomes more
  unlikely, which reinforces the original thought of being
• In therapy, identify "problem cycle," and the efforts of
  the therapist and client would be directed at working
  together to change this.
• This is done by addressing the way the client thinks and
  behaves in response to similar situations and by
  developing more flexible ways to think and respond,
  including reducing the avoidance of activities.
• If, as a result, the client escapes the negative thought
  patterns and destructive behaviors, the feelings of
  depression may, over time, be relieved.
• The client may then become more active, succeed more
  often, and further reduce his negative feelings.
            Treatment of Depression -
Initial theories based on monoamine theory implying a relation
   between mood and cerebral intrasynaptic concentrations of
   serotonin (5HT) and noradrenaline.
   Current thinking considers depression to be as a result of
   dysregulation of neurotransmitters.

Effective treatments involve:
• drugs that inhibit pre synaptic neuronal reuptake of serotonin or
  noradrenaline (reuptake inhibitors)
• Drugs that inhibit the oxidative transformation of these amines
  by monoamine oxidase (MAO)
          Treatment of Depression -
Reuptake inhibitors
1. Tricyclic antidepressants (TCAs)
2. Selective serotonin reuptake inhibitors (SSRIs)
3. Serotonin noradrenergic reuptake inhibitors (SNaRIs)
4. Noradrenergic and specific serotonergic antidepressants

Enzyme Inhibitors

1. Monoamine oxidized inhibitors MAOIs
2. Reversible inhibitors of monoamine oxidase A (RIMAs)

                Drug choice
• 50% of adult patients respond to antidepressant
• All anti-depressants are approx equal in efficacy
  however patient response and different adverse
  events determine choice
• TCAs, SSRIs, mirtazapine and moclobemide can
  be regarded as first line (AMH 2009)
      Tricyclic Antidepressants
– Amitriptylline, Imipramine, Doxepin
- Inhibit reuptake of NA, 5HT into presynaptic
- Cheap, od dosing
- Sedative effects – insomnia
- Pain relief property as well
- Precautions: close angle glaucoma, epilepsy, cardiovascular
- Cardiovascular: adverse effects on conduction, ppt or exacerbate
  angina, prolong the QT interval increase risk of arrythymia.
- Adverse effects:
  - Anticholinergic effects (dry mouth, blurred vision,
   constipation, flushing)
  - Postural hypotension
  - Sedation
  - and sexual dysfxn (impotence, loss of libido), weight gain
- Fatal in overdose – avoid in suicidal patients
- Elderly: confusion, delirium
- Avoid use with MAOIs
    Selective Serotonin reuptake
          inhibitor (SSRIs)
- Paroxetine, Fluoxetine, Sertaline, Citalopram
- Selectively inhibit 5HT uptake
- NO AntiChol effects, sedative effects, CV
  events, weight gain
- Safe in overdose, use in elderly
- o.d dosing allows compliance
- Does not seem to interact with alcohol
• SSRIs are usually taken in morning to minimize
  insomnia, fluvoxamine and paroxetine can cause
• Adverse effects – nausea, agitation and anxiety,
  headache, insomnia, weight gain
• Adverse effects more frequent and severe at higher
  doses – start low triturate slow
• High rates of sexual dysfunction - reversible on
• Can cause SIADH and hyponatremia (monitor patient
  esp elderly)
• Drug interactions as SSRIs inhibit CYP450 enzymes
 Irreversible Monoamine oxidase
• Phenelzine, tranylcypromine
• Irreversibly block MAOA and MAOB increasing
  monoamine levels in brain
• Usually second line agents (useful in atypical
  depression, psychotic depression)
• Low anti-cholinergic and sedative effects
• Insomnia common – taken in morning or before
• Postural hypotension – dizzy upon standing
• Sexual dysfunction
 Irreversible Monoamine oxidase
• Dietary restrictions – avoid tyramine rich foods
• Tyramine rich foods – matured out of date cheese, salami,
  protien extracts, yeast extracts (Vegemite), soya bean extracts,
  bean pods, pickled herring.
• Leads to hypertensive crisis or ‗cheese effect‘ – possibly
  accumulation or release of NA
• Symptoms – throbbing headache, rapid prolonged rise in BP
  leads to intracranial hemorrhage or acute cardiac failure
• TX: medical emergency, sodium nitroprusside or hydralazine or
  clonidine (nifedipine, amlodipine)
 Irreversible Monoamine oxidase
• Patients advised to keep list of tyramine rich
  foods and avoid intake while on this medicine
  and for 2 weeks after stopping
• Also to avoid use with sympathomimetic agents
  in OTC cold & flu preparations
    Reversible MAOA (RIMA)
- Reversible MAOA inhibitor resulting in
  increased levels of NA, 5HT and DA in brain
- Moclobemide (Amira, Aurorix)
- Not sedating, no hypotension, no diet
  restrictions (except in higher doses)
- Free of CV, AntiChol effects c.f TCAs and
- Low lethality in overdose
- Nausea vomiting, dizziness, insomnia common
- Agitation, excitation
Other antidepressants
       Venalfaxine, Duloxetine
- Serotonin and NA Reuptake inhibitors (SNRI)
- Short half life bd dosing, ER prep
- No Antichol, weight gain, safe in OD
- NV, sexual dysfxn, dose related hypertension
  monitor BP
- ↑ chance of discontinuation smx when stopped
- Not used in children, adolescents ↑ risk of self
-Tetracyclic antidepressant shares most of TCA
- block alpha2 adrenergic receptors, NA and H1
-↓ AntiChol/CV effects, safe in overdose c.f TCA
-More sedating
-Reversible neutropenia: stop if sore throat or signs
of infection
-Avoided in seizure patients
- Nefazodone (sever liver damage, not available)
• Bupropion has significantly fewer adverse effects
  related to sexual dysfunction than SSRIs, and may
  be particularly effective for patients who are
  lethargic, not associated with weight gain.
• Mirtazapine, a mixed serotonin-norepinephrine
  antagonist, is sedating. It has efficacy equivalent to
  SSRIs and may have a role in the treatment of
  patients with insomnia and depression, causes
  more weight gain than SSRIs
   Side effect profiles of major antidepressant
                    Sedative   Antimuscarinic   Hypotensive
TCA                 ++         ++               ++

SSRIs               neg        neg              neg

SNaRIs              neg        neg              neg

NaSSAs              +          +                +

Enzyme inhibitors   neg        neg              +/++
                Starting Therapy
• Drugs have similar efficacy, inter-patient variation
• TCAs, SSRIs, mirtazapine and moclobemide
  considered first line
• Treatment individualized and drug based on
- Nature severity of depression
- Other conditions
- Past response
- AE profile
- Safety in overdose : TCA very toxic
- Drug interactions
- Drug regimen and compliance

            Starting therapy
• Delay in response for 2-4 weeks, no response 4-
  6 weeks, change drug to another class
• Therapy continued for 4-12 months if response
• Tx failure: mis-diagnosis, compliance, adequate
  dose, DI, alcohol
            Switching therapy:
-   ―Wash out‖ period observed
-   Allows time for Total drug clearance
-   No drug interactions or serotonin syndrome
-   When changing drugs: withdraw first agent
    slowly, start new drug at low dose
          Serotonin Syndrome
• Toxic state excess 5HT causing mild to fatal
- confusion, agitation, hyperthermia, sweating,
  tremors, tachycardia
- TX: hospitalization, ice packs, BDZ, 5HT
  antagonist cyproheptadine
        Maintenance Therapy
- Prevent recurrence after stable remission
- Full effect may take 6-8 weeks
- Continue treatment for 4-12 months after a
  single episode of major depression
- 2 occurrences of major depression within 5 years
  or 3 prior episodes
- Tx usually 3-5 years
- Some may need lifelong therapy
    Treatment of Depression – Drug
• Patients with cardiac disease (at risk of
  dysrhythmias) – avoid TCAs
• Patients with epilepsy or prone to seizures – all
  antidepressants can lower seizure threshold –
  TCAs, mirtazapine have been shown to have
  greatest effect on seizure threshold..
• Patients with a previous history of self harm,
  suicidal tendencies, overdose – avoid TCAs.
 Treatment of Depression – Drug
• Pregnancy – TCAs and SSRIs are thought to be
  relatively safe in pregancy. Less is known about
  the other antidepressants,
• Lactation – TCAs and SSRIs appear safe.
  However reports recently suggest fluoxetine can
  cause ADRs in neonate. Therefore monitoring
  of neonate useful.
• Elderly patients – more sensitive to effects of
  drugs. If hepatic impairment – dose reduction
  necessary. Maybe more prone to Antimuscarinic
    Adherence to medications
• Patients who will be treated with medication should be
  told the following, at the initiation of treatment:
• Do not stop medications without talking with the
  prescribing clinician
• There may be a lag of two to three weeks before
  medications begin to relieve symptoms
• Early side effects, such as nervousness, headache and
  stomach upset, occur frequently during the first few days,
  but are predictably gone within a week of starting the
• It is important to continue a full course of antidepressant
  therapy (usually 6 to 12 months), even if symptoms are
  alleviated in the first month, to prevent early relapse
• Call to discuss side effects or other questions.
 Other Therapies for Depression
• Electroconvulsive therapy (ECT)
  – Most effective treatment for psychotic depression
    and severe treatment resistant depression
     • More effective and more rapid than drug therapy in these
  – Disadvantages of ECT include:
     • Frequent relapse after termination of treatment
     • Temporary cognitive impairment
     • Social stigma
               St. John’s wort
• Hypericum perforatum
• Patients with mild acute depression can be offered St.
  John‘s Wort as an alternative to psychotherapy or
  conventional pharmacotherapy, not be used in patients
  with significant major depression.
• Avoiding concurrent use with other antidepressants.
  Concomitant use with the SSRIs may lead to the
  "serotonin syndrome,‖
• St. John‘s wort also has potentially important drug
  interactions with a number of medications

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