NEUROLOGIST APROACH TO DEPRESSION

1. DR. SUMIT KAMBLE
SENIOR RESIDENT
DEPT. OF NEUROLOGY

2.  Estimated 3-4% of India's population suffers from major
mental disorders and about 7-10% of the population suffers
from minor depressive disorders.
 Ambulatory prevalence rates in general neurology clinics -
range of 15 to 20% .
 Source of considerable morbidity.
 Diagnosis of depression in the setting of disorders that
produce psychomotor retardation and changes in
vegetative function can be particularly challenging.

3. Criteria for major depressive episode: DSM 5
A. Five (or more) of the following symptoms have been
present during the same 2-wk period and represent a
change from previous functioning; at least one of the
symptoms is either (1) depressed mood; or (2) loss of
interest or pleasure-
 1) Depressed mood most of the day, nearly every day, as
indicated either by subjective report or observation made
by others.
 (2) Markedly diminished interest or pleasure in all, or
almost all, activities most of the day, nearly every day.
 (3) Significant weight loss when not dieting or significant
gain, or decrease or increase in appetite nearly every day.

4.  4) Insomnia or hypersomnia nearly every day.
 (5) Psychomotor agitation or retardation nearly every day.
 (6) Fatigue or loss of energy nearly every day.
 (7) Feelings of worthlessness or excessive or inappropriate
guilt (which may be delusional) nearly every day (not
merely self reproach or guilt about being sick).
 (8) Diminished ability to think or concentrate, or
indecisiveness, nearly every day (either by subjective
account or as observed by others).
 (9) Recurrent thoughts of death (not just fear of dying),
recurrent suicidal ideation without a specific plan, or a
suicide attempt or specific plan for committing suicide.

5.  B. Symptoms cause clinically significant distress or
impairment in social, occupational or other important
areas of functioning
 C. Symptoms are not due to the direct physiological effects
of a substance (e.g., a drug of abuse, a medication) or a
general medical condition (e.g., hypothyroidism)

6.  DSM approach creates several problems for neurologists.
 1. Although depressive syndrome is present to a milder
degree than is defined by the checklists of DSM diagnoses,
it may still create a functional problem for patient.
 2. Signs of depression are present in these patients without
their subjective awareness.
 3. Sometimes depression is experienced and observed as
progression or deepening of the neurological syndrome,
such as motor deterioration in basal ganglion disorders,
cognitive deterioration in dementia syndromes, deepening
fatigue in white matter diseases, and worsening pain in
headache or related disorders.

7.  Point prevalence- between 5% and 10% of people seen in
primary care settings.
 Women are affected twice as often as men.
 Fourth most important cause of disability worldwide
 Lifetime prevalence- 26% for women and 12% for men.
 1.5 to 3 times with a first-degree biological relative.
 84% had at least one comorbid condition, 61% had
additional psychiatric disorder and 58% comorbid medical
illness
 Follows psychosocial stressor- death of a loved one, marital
separation, or Childbirth.
Incidence

8.  Loss of interest or pleasure of some degree-nearly always
present,
 Less interested in hobbies, "not caring anymore," or not
feeling any enjoyment in activities previously considered
pleasurable.
 Family members- social withdrawal or neglect of
pleasurable avocations.
 Reduction from previous levels of sexual interest or desire.
 Appetite-reduced, and many individuals feel that they have
to force
 Some may have increased appetite, crave specific foods.
 Significant loss or gain in weight.
Clinical features

9.  Decreased energy, tiredness, and fatigue.
 Efficiency-reduced.
 Sense of worthlessness or guilt-unrealistic negative
evaluations of one's worth or guilty preoccupations or
ruminations over minor past failings.
 Report impaired ability to think, concentrate, or make
decision.
 Easily distracted or complain of memory difficulties.

10.  Thoughts of death, suicidal ideation, or suicide attempts
 Belief that others would be better off if person were dead,
to transient but recurrent thoughts of committing suicide,
to actual specific plans of how to commit suicide.
 Transient (1- to 2-minute), recurrent (once or twice a week)
thoughts.
 Appearance: neglected dress & grooming
 Facial features: turning downwards of corners of mouth,
vertical furrowing of centre of brow, shoulders bent & head
inclined forwards, direction of gaze downwards, gestural
movements decreased

11.  Sleep disturbance-insomnia
 Typically have middle insomnia (waking up during night
and having difficulty returning to sleep) or terminal
insomnia (waking too early and being unable to return to
sleep).
 Initial insomnia (difficulty falling asleep).
 Oversleeping(hypersomnia)-prolonged sleep episodes at
night or increased daytime sleep.
 Psychomotor changes-agitation or retardation.
 Speech-decreased in volume, inflection, amount, or
variety of content, or muteness.

12. A) Pharmacotherapy-
I) Antidepressants-
TCA
MAO inhibitors
SSRI, SNRI, SDRI
II) Augmentation therapies
B) Psychosocial therapies
C) ECT
TREATMENT OF DEPRESSION

13.  Characteristic three-ring nucleus
 Clinical effects
 Normalization of mood and resolution of
neurovegetative symptoms
 Biochemical effects
 Inhibit monoamine uptake at nerve terminals
 May potentiate action of drugs that cause
neurotransmitter release
 Temporal delay of weeks for clinical effects, although
biochemical effects are immediate
Tricyclic Antidepressants (TCAs)

14. Mechanism of action of TCAs
“Tertiary” TCAs  Inhibit 5-HT uptake
imipramine (weaker inhibition of NE uptake)
amitriptyline
clomipramine
“Secondary” TCAs  Inhibit NE uptake
desipramine (weaker inhibition of 5-HT uptake)
nortriptyline

15.  Dry mouth
 Constipation
 Dizziness
 Tachycardia
 Urinary retention
 Impaired sexual function
 Orthostatic hypotension
 Contraindications
 QTc greater than 450 msec
 Conditions worsened by muscarinic blockade (eg myasthenia
gravis, BPH)
 Pre-existing orthostatic hypotension
 Seizure disorder
Side effect of TCAs

16.  Irreversibly inhibit monoamine oxidase enzymes
 2 isoforms
 MAO-A (norepinephrine, serotonin, tyramine)
 MAO-B (dopamine)
 Effective for major depression, panic disorder, social
phobia
 Drug interactions and dietary restrictions limit use
Monoamine Oxidase Inhibitors (MAOIs)

17.  Irreversible, non-selective MAOIs
 phenelzine
 isocarboxazid
 tranylcypromine
 Selective MAO-B inhibitors
 deprenyl (selegiline)
 loses its specificity for MAO-B in antidepressant
doses
 Reversible monoamine oxidase inhibitors (RIMAs)
 Moclobemide – not approved
 Appears to be relatively free of food/drug
interactions
Examples of MAOIs

18.  Currently marketed medications
 fluoxetine.
 sertraline.
 paroxetine
 fluvoxamine
 citalopram
 escitalopram
 Selectively inhibit 5-HT (not NE) uptake
 Differ from TCAs by having little affinity for muscarinic,
as well as many other neuroreceptors
Selective Serotonin Uptake Inhibitors
(SSRIs)

19.  Much higher therapeutic index than TCAs or MAO-I’s
 Much better tolerated in early therapy
 Equal or almost equal in efficacy to TCAs
 Side effects
 Nausea
 Sexual dysfunction
 Delayed ejaculation/anorgasmia
 Anxiety
 Insomnia
SSRI

20.  Venlafaxine, Duloxetine:
 relatively devoid of antihistaminergic, anticholinergic,
and antiadrenergic properties
 nonselective inhibitor of both NE and 5-HT uptake.
 Adverse effects:
 GI
 Sexual dysfunction
 Hypertension (venlafaxine)
Selective Norepinephrine-Serotonin
Reuptake Inhibitors

21.  Trazodone
 mixed 5-HT agonist/antagonist
 1 antagonist
 H1 antagonist
 Nefazodone
 5 HT2 antagonist
 Vilazodone
• Combined selective serotonin reuptake inhibitor and serotonin 5-
HT1A receptor partial agonist
• Advantages: no adverse sexual effects
Other antidepressants

22.  Mirtazapine
 2 antagonist
 5HT2 and 5HT3 antagonist
 Net effect selective increase in 5HT1A function
 H1 antagonist
 Advantages: sedation, no adverse sexual effects
 Bupropion
 Inhibits uptake of DA and NE
 antismoking properties probably involves parent molecule
 Lacks sexual side effects
 Seizure risk

23. Psychotherapies:
 Interpersonal psychotherapy (IPT)
 Problem solving therapy (PST)
 CBT

24. Neurological Diseases with Associated Depression
Neurological
Diseases
AP(ambulatory
prevalence)
LR( lifetime risk.)
Stroke variable 30% during first year after
stroke
Parkinson's disease 10-20% 50%
Multiple sclerosis 14% 50%
Chronic headache 10-20% unknown
Epilepsy 10-20% unknown
Alzheimer's disease 10-20% unknown
Wilson disease variable 30%
Neoplastic 15-20% variable
Traumatic brain injury variable 60%

25. Historical features suggesting Neurological disease in patients with
Psychatric symptoms
Presence of Atypical Psychiatric features-
o Late or very early age of onset
o Acute or subacute onset
o Lack of significant psychosocial stressors
o Cognitive decline
o Intractability despite adequate therapy
o Progressive symptoms
History of present illness-
o New or Worsoning headache
o Focal neurological complants.
o Anorexia/ weight loss
o Neuroendocrine changes
o Somnolence
o incontince

26. Patients History-
o Risk factors for cerebrovascular diseases, or CNS infections
o Malignancy
o Immunocompromised
o Significant head trauma
o Seizures
o Movement disorders
o Hepatobilliary diseases
o Abdominal crisis of unknown cause
o Biological relative with similar diseases or complaints
Unexplained Diagnostic Abnormalities
o Screening laboratories
o Neuroimaging studies
o Electroencephalogram
o Cerebrospinal fluid

27. DEPRESSION IN PARKINSON’S DISEASE
 Prevalence of depression in PD is between 20–45%.
 Causes significant morbidity in terms of quality of life.
 Psychiatric symptoms may precede motor symptoms of PD
by a number of years.
 Depression relative to the course of PD is biphasic.
 More common in those people with more rapidly
progressive PD.

28. Diagnosis of depression in Parkinson’s disease-
 Symptoms that are common to both depression and
idiopathic Parkinson’s disease include motor slowing,
bradyphrenia, sleep and appetite disturbance, weight loss,
loss of interest and concentration, and reduced libido.
 Montgomery and Asberg depression rating scale (MADRS)
and Hamilton depression scale (HAM-D) scales are used
to measure depression in Parkinson’s disease.

30. Symptoms that may help in the diagnosis of depression in PD
 Pervasive low mood with diurnal variation (for at least two
weeks)
 Early morning wakening
 Pessimistic thoughts about the world, themselves, and the
future (out of context with their level of disability or their
previous attribution style)
 Suicidal ideation.

31. Differential diagnosis of depression in Parkinson’s
disease
 Adjustment disorder
 Mood disorder caused by a general medical condition
(infection, subdural haematoma)
 Drug induced mood disorder
 Dementia
 Non-motor fluctuation
 Transient mood changes in relation to DBS (dysphoria,
pseudobulbar crying)

32. Treatment of depression in Parkinson’s disease-
 Recent Cochrane library review concluded that there are
‘‘insufficient data on the effectiveness and safety of any
antidepressant therapy in Parkinson’s disease’’.
 Desipramine and citalopram are equally effective
 Nortriptyline is efficacious while paroxetine controlled
release is not
 Atomoxetine is not beneficial
 Paroxetine and venlafaxine improved depression and did
not worsen motor function.

33.  Dopaminergic agonists ropinirole and pramipexole may
improve depressive symptoms in patients with PD.
 Electroconvulsive therapy (ECT) has been used in the
treatment of depression in PD and appears to be a safe
treatment.
 Cognitive therapies
 Transcranial magnetic stimulation (TMS)

34. DEPRESSION IN MULTIPLE SCLEROSIS
 Aprox 40% have depression with a subgroup of 30% having
moderate or severe depression.
 Younger people with MS are more likely to be depressed
than older.
 Suicidal behaviour in MS-25% with MS have suicidal
ideation sometime .Around 3% of people with MS will kill
themselves.
 Additional risk factors for suicide in MS include being
male, young age of onset, previous history of depression,
social isolation, and substance abuse.

35.  Differential diagnosis of depression in MS includes
adjustment disorders, paroxysmal changes in mood (such
as pathological crying or emotional lability), and mood
changes in relation to drugs for MS.
Important clues to depression in multiple sclerosis
 Pervasive mood change
 Diurnal variation in mood
 Mood congruent psychotic symptoms
 Suicidal ideation
 Change in function not related to physical disability

36.  Risk factors for depression in MS-disability, pain,
fatigue,drugs, perception about prognosis, location of
lesion.
Treating depression in MS
 Mild to moderate forms of depression-cognitive
behavioural therapy (CBT).
 Severe forms of depression and in those with cognitive
Impairment-drug treatment(SSRIs)
 ECT in treatment of severe depression-MS symptoms
worsening in around 20%

37. DEPRESSION AND STROKE
There are three main reasons why people are at increased risk
of depression following stroke:
 They often suffer sudden, multiple loss events (loss of
physical function, employment, change in social or marital
status)
 They may lose the neurological capacity to process these
loss events
 Stroke may affect areas of the brain directly involved in
control of mood.

38.  Peak incidence of depression is between six months and
two years post-stroke.
 Prevalence varies between 10–34%
 Patients with depression post-stroke are more likely to be
younger, white and less likely to be alive three years post-
cerebrovascular accident (CVA) than those who are not
depressed post-stroke.
 Other risk factors for depression include functional and
cognitive impairment, a past history of depression, and a
lack of social support.
 Location of lession

39. Diagnostic difficulties of depression post-stroke-
 Communication difficulties, impairments of facial and
emotional expression, and disturbance in vegetative
functions can make assessment of mental state extremely
difficult.
 Abulia can sometimes be mistaken for depression
 Pathological emotionalism

40. Causes of post stroke depression- Physiological
4 hypothesized mechanisms-
 Lesion Location
 Neurotransmitter
 Inflammatory cytokines
 Gene Polymorphism

41.  Lesion Location
o Research inconsistent
o Basal Ganglia or Left Frontal Lobe lesions may play a role in
etiology of PSD
 Neurotransmitters
o During an acute brain lesion, there is a decreased monoamine
synthesis because of enzyme inhibition during ischemia
o Injury to the ascending axonal projections to the cortex from the
basal ganglia causing a decrease in norepinephrine and serotonin
production
o Neurogenesis impaired, decreased brain derived neurotrophic
factor protein

42.  Inflammatory cytokines
o Stroke induces an inflammatory response
o Role of inflammatory cytokines (immune system) resulting from
stroke leads a chemical cascade that depletes serotonin
o Serotonergic depletion in paralimbic areas of left frontal and
temporal cortex may lead to depression
 Gene Polymorphism
o Genetic vulnerability for depression
o Reduction of serotonin reuptake
o Vulnerability to stress reaction in response to stroke deficits
resulting in depression

43. Causes of post stroke depression- Psychological
 loss
 powerlessness
 grief
 fear
 anger
 shame
 identity issues
 dependence, change in roles and relationships,
 uncertainty about the future. “Will I get better? “Will I be a
burden? Can I have a meaningful life?”

44. Rating scales for depression post-stroke
 On acute hospital wards, -‘‘signs of depression’’ scale
 In rehabilitation settings, the best validated scales are
hospital anxiety and depression scale (HADS) and general
health questionnaire-12 (GHQ-12)
 In the community, HADS and GHQ-12 are recommended
 For those with communication problems, stroke aphasic
depression questionnaire-10 (SADQ-10) is recommended

45. Preventing and treating depression after stroke
 Prophylactic treatment-
 No definitive evidence to guide the specific choice of
therapy for patients with poststroke depression
 Transcranial magnetic stimulation.

46. DEPRESSION IN EPILEPSY
 Prevalence-20–30% in those with recurrent seizures and 6–
9% in those in remission are found to be depressed.
 Depression can make epilepsy worse
Risk factors-
 Uncontrolled seizures
 Temporal lobe epilepsy
 Depression in a first degree relative
 Polytherapy

47. Suicide
 In epilepsy, death by suicide is more common than in the
population as a whole (5% compared to 1.4%).
Risk factors-
 Younger (25–49 years) male patients,
 Co-existing psychopathology including personality
disorders,
 Temporal lobe epilepsy,
 Personal difficulties including social or work related
problems,
 Prolonged duration of epilepsy
 Inadequate control of seizures

48. Antiepileptic drugs and depression-may be dose-
related
 Vigabatrin
 Phenobarbital
 Levetiracetam
 Zonisamide
 Topiramate
 Tiagabine
 Clonazepam

49. Recognition of depression-
 Screen for mood disorder which can be completed
reasonably quickly
 PRIME-MD patient questionnaire or
 Centre for Epidemiologic Studies depression scale.

50. Scores of 5, 10, 15, and 20 represent cutpoints for mild, moderate, moderately severe
and severe depression

51. Management-
 All classes of antidepressant state are contraindicated or
should be used with caution in people with epilepsy.
 Tricyclic overdose carries a high risk of provoked seizure ,
but the risk with low dose is minimal.
 Tricyclic agents are best avoided and use of the selective
serotonin reuptake inhibitors (SSRIs) or serotonin–
norepinephrine reuptake inhibitors (SNRIs) are to be
preferred.
 No contraindication ECT.

52. Pharmacokinetic drug interactions between SSRIs and
antiepileptic drugs-
 Rare
 Inhibition of carbamazepine and phenytoin metabolism
by fluvoxamine.
 Combination of either carbamazepine or oxcarbazepine
and SSRIs because of the tendency for both to cause
hyponatraemia.

53. DEPRESSION IN NEURODEGENERATIVE
DISORDERS
 In presence of any neurodegenerative disease, depression
diagnosis may be difficult-
o Symptoms are masked by cognitive decline.
o Weight loss and sleep disorders can appear in neurological
diseases with or without any associated mood disturbance.
o Existence of a language disorders
o Pseudobulbar palsy
o Anhedonia, anxiety, apathy.

54. Cornell scale for depression in dementia
 Mood-related signs
 Anxiety: Anxious expression, rumination, worrying
 Sadness: Sad expression, sad voice, tearfulness
 Lack of reaction to present events
 Irritability: Annoyed, short tempered
 Behavioral disturbance
 Agitation: Restlessness, hand writing, hair pulling
 Retardation: Slow movements, slow speech, slow reactions
 Multiple physical complaints (score 0 if gastrointestinal
symptoms only)
 Loss of interest: Less involved in usual activities (score only if
change occurred acutely, i.e., in less than one months)
 Physical signs
 Appetite loss: Eating less than usual

55.  Weight loss: (score 2 if greater than 5 pounds in one month)
 Lack of energy: Fatigues easily, unable to sustain activities
 Cyclic function
 Diurnal variation of mood: Symptoms worse in the morning
 Difficulty falling asleep: Later than usual for this individual
 Multiple awakening during sleep
 Early morning awakening: Earlier than usual for this individual
 Ideational disturbance
 Suicidal: Feels like is not worthy living
 Poor self-steem: Self-blame, self-depreciation, feelings of failure
 Pessimism: Anticipation of the worst
 Mood congruent delusions: Delusions of poverty, illness or loss
Scoring system A= Unable to evaluate; 0 = Absent; 1 = Mild to
intermittent; 2 = Severe
score greater than; 12 = Probable depression

56. Alzheimer's disease
 About 80% can develop depressive symptoms to a greater or lesser
degree.
 Depressive symptoms have been described up to 30% of the patients
with mild cognitive impairment
Frontotemporal degeneration
 Depression is quite common in FTD -40%
 Patients experience mainly apathy and decreased energy, hyperphagia
and inappropriately preserved self-esteem

57. Lewy body disease
 Depression in Dementia with Lewy bodies is similar to depression in
Alzheimer’s disease.
Corticobasal degeneration
 Depression is common in CBD and it has been described in up to 70%
of these patients
Huntington's disease
 Depression is diagnosed up to 40% of cases
 Suicide rates in Huntington’s disease patients are over four times those
of the general population

58. Provisional diagnostic criteria for depression in Alzheimer's
disease
Three or more of the following criteria over the same 2-wk period,
representing a change from previous functioning:
 Depressed mood (sad, hopeless, discouraged, tearful)
 Decreased positive affect or pleasure in response to social contacts and
activities
 Social isolation or withdrawal
 Disruption in appetite
 Disruption in sleep
 Psychomotor agitation or retardation
 Irritability, Fatigue or loss of energy
 Worthlessness, hopelessness or excessive guilt
 Recurrent thoughts of death or suicidal ideation
 All criteria are met for dementia of the Alzheimer’s type
 Symptoms cause distress or disruption in functioning
 Symptoms do not occur exclusively during delirium
 Symptoms are not due to substances (medications or drugs of abuse)

59. THERAPEUTIC APPROACH AND RECOMMENDATIONS
 Treatments should be used individually considering presence of
comorbidities and associated medications.
 In most of patients- SSRIS, specially sertraline and citalopram.
 Paroxetine has been proposed specifically to fontotemporal
dementia
 Tricyclic antidepressants are poorly tolerated-tend to worse
cognition and generate orthostatic hypotension
 Cholinesterase inhibitors have shown a mild but consistent effect
on behavioral symptoms in Alzheimer’s disease.
 Mirtazapine, trazodone, duloxetine and venlafaxine- restricted
to cases of very limited or no response to initial treatment with
SSR

60. Depression and chronic pain
 Major depressive disorder (MDD) is often found in
conjunction with chronic pain- prevalence of 30–54%
 Presence of depression in a patient with chronic pain is
associated with decreased function, poorer treatment
response and increased health care cost.
 Pain-depression relationship-
 Antecedent Hypothesis
 Consequence Hypothesis.
 Common Pathogenesis.

61. Association between pain and major depression-
 1. Psychological and physical distress of persistent pain may
precipitate episode of major depression.
 2.depression may be a precursor to, and in some way
contribute to pain.
 3. Serotonergic and noradrenergic neurotransmitters have
been implicated in both conditions.

62. Management
 Pharmacological treatment-
 Tricyclic antidepressants (TCAs)-have analgesic properties
independent of their antidepressant effect.
 SNRIs- effective for both neuropathic and nociceptive pain— an
effect independent of reductions in depression or anxiety.
 TCAs and venlafaxine at analgesic doses are subtherapeutic for
major depression
 Combining TCAs with selective serotonin reuptake inhibitors
(SSRIs) has the potential to induce a serotonergic syndrome

63.  Psychological interventions
 12 sessions of standardised and adherent cognitive
behaviour therapy (CBT) or interpersonal therapy were
found to be equivalent to imipramine (200 mg) and
more effective than placebo or supportive therapy in
treating major depression.

65. References
 DEPRESSION IN NEUROLOGICAL DISORDERS: PARKINSON’S
DISEASE, MULTIPLE SCLEROSIS, AND STROKE J Neurol Neurosurg
Psychiatry 2005;76(Suppl I):i48–i52. doi: 10.1136/jnnp.2004.060426
 DEPRESSION AND ANXIETY IN EPILEPSY Neurol Neurosurg
Psychiatry 2005;76(Suppl I):i45–i47. doi: 10.1136/jnnp.2004.060467
 Bradley’s Neurology in clinical practice. Sixth edition
 Depression in Neurological Practice: Diagnosis, Treatment,
Implications Semin Neurol. 2009;29(3):220233.
 Practice guidelines for depressive disorders; American psychiatric
association;Oct 2010
 Diagnostic and statistical manual for mental diseases Fivth edition