This presentation provides all the relevant information about mental depression and anti-depressants. It will be useful to students of medicine, pharmacology, pharmacy, and pharmaceutical industry.

1. Mental Depression &
Anti-depressants
Dr Ashok Kumar Batham, Chief Consultant
Dr Batham Pharma Consultants

2. DEPRESSIVE DISORDERS
• Disruptive mood dysregulation disorder,
• Major depressive disorder (including major depressive episode),
• Persistent depressive disorder (dysthymia),
• Premenstrual dysphoric disorder,
• Substance/medication- induced depressive disorder,
• Depressive disorder due to another medical condition,
• Other specified depressive disorder, and
• Unspecified depressive disorder.
DSM-5

3. DEPRESSION
• According to a WHO Report there are 350 million
patients of depression in the world.
• Described as the most common disorder and the cause
of disability.
• 2 times more common in women than men.
• Life time incidence – 11% in developing countries and
15% in developed countries.

5. DEPRESSION
Prevalence rates of depression:
• North America 4-4.5%
• Latin America 5-5.5%
• Europe 4.5-5.5%
• Asia Pacific 4-4.5%
• North Africa & MEA 6-7.5%
• ROW 5.5-6%

6. DEPRESSION
• Depressed mood, feeling run-down
• Reduced interest or pleasure in activities previously
enjoyed, loss of sexual desire
• Unintentional weight loss or weight gain (without
dieting) due to low or high appetite
• Insomnia or hypersomnia

7. DEPRESSION
• Psychomotor agitation, for example, restlessness, pacing
up and down
• Psychomotor retardation
• Feelings of worthlessness or guilt
• Impaired ability to think, concentrate, or make decisions
• Recurrent thoughts of death or suicide, or attempt at
suicide

9. CAUSES OF DEPRESSION
• Genetics
• Biological - changes in neurotransmitter levels
• Environmental
• Psychosocial

11. RISK FACTORS FOR DEPRESSION
• Life events: These include bereavement, divorce, work
issues, relationships with friends and family, financial
problems, medical concerns, or acute stress.
• Personality: Those with less successful coping strategies, or
previous life trauma are more suceptible.
• Genetic factors: Having a first-degree relatives with
depression increases the risk.
• Childhood trauma

12. RISK FACTORS FOR DEPRESSION
• Prescription drugs: Corticosteroids, Beta-blockers, Interferon etc.
• Abuse of recreational drugs: Abuse of alcohol, amphetamines
• Head injury.
• History of an episode of major depression.
• Chronic pain syndromes & other chronic conditions – DM,
COPD, CVD, Cancere, TB, Arthritides.

14. DEPRESSION DSM-5 DIAGNOSTIC CRITERIA
Five or more symptoms during the same 2-week period
&
at least one of the symptoms should be either
(1)depressed mood or
(2)loss of interest or pleasure.

15. DEPRESSION DSM-5 DIAGNOSTIC CRITERIA (SYMPTOMS)
FIVE OR MORE SYMPTOMS DURING THE SAME 2-WEEK PERIOD, most of the day
or every day (NOT ATTRIBUTABLE TO ANOTHER DISEASE OR SUBSTANCE ABUSE)
1. Depressed mood
2. Markedly diminished interest or pleasure in all, or almost all,
activities
3. Significant weight loss when not dieting or weight gain, or
decrease or increase in appetite nearly every day

16. DEPRESSION DSM-5 DIAGNOSTIC CRITERIA (SYMPTOMS)
4. Slowing down of thought and a reduction of physical
movement.
5. Fatigue or loss of energy
6. Feelings of worthlessness or excessive or inappropriate guilt
7. Diminished ability to think or concentrate, or indecisiveness
8. Recurrent thoughts of death, recurrent suicidal ideation
without a specific plan, or a suicide attempt or a specific plan
for committing suicide.

17. SYMPTOMS ASSOCIATED WITH DEPRESSION
• Major depressive disorder is associated with high
mortality, much of which is accounted for by suicide.
• Irritability,
• Brooding, and
• Obsessive rumination, and
• Complaints of anxiety, phobias, pain, excessive worry
over physical health.

18. DEPRESSION & SADNESS ?
• Sadness is a normal emotional reaction to a specific situation, event, or a
person - loss of a job, the end of a relationship, or the death of a loved
one. However, in depression no such trigger is required.
• In sadness – one feels down in the dumps for a day or two, but retains
the ability to enjoy things like favourite TV show, food, sleep, motivation to
work, or company of friends. In depression, even activities enjoyed
earlier are no longer interesting or pleasurable
• In sadness, the person feels regretful or remorse for something he did but
in depression the person has self-diminishing and negative thought
patterns
• In sadness thoughts of self-harm and suicide don’t arise but in severe
depression there are thoughts of self-harm, suicide, or death.

19. Really Sad,
Depressed
and Floored

20. TREATMENT OF DEPRESSION
• Psychotherapy – Cognitive Behavioral Therapy
• Drug therapy using antidepressant drugs
• Electroconvulsive therapy

22. ANTIDEPRESSANTS

24. EVOLUTION OF TREATMENT OF DEPRESSION
•Psychoanalysis (Sigmund Freud) -1800s.
•ECT -1930s
•MAO-Is – 1950s (From an anti-TB drug Iproniazid)
•TCAs -1950 1960s
•SSRIs -1970 1980s

25. MONOAMINERGIC THEORY OF DEPRESSION
& ITS TREATMENT
• Endogenous depression is caused by synaptic deficiency of
neurotransmitters – NE, 5HT and DA in brain associated with up-
regulation of post-synaptic receptors
• Depletion of monoamines by reserpine leads to Depression
• TCAs and SSRIs block neuronal reuptake mechanisms, thereby
building up monoamine levels and allaying depression
• MAO-Is lead to build-up of monoamines and alleviate
depression
• Lithium controls manic episodes by reducing brain NE levels

26. FUNCTIONS OF NEUROTRANSMITTER -
SEROTONIN
• “Feel good hormone”
• Contributes to feeling of well-being and good mood
• Appetite control
• Social behavior
• Obsessions
• Compulsions and
• Regulation of sleep-wake cycle and internal clock.
• Abnormality in Serotonin neurotransmission leads to obsession and
compulsion

27. FUNCTIONS OF NEUROTRANSMITTER –
NOREPINEPHRINE
• Regulation of emotions
• Increases alertness and focus
• Helps retrieval of memory
• Prepares the brain for action
• Abnormality in NE neurotransmission leads to lethargy and
apathy

28. FUNCTIONS OF NEUROTRANSMITTER -
DOPAMINE
• Reward-motivated behaviour - creates feelings of pleasure and reward,
which motivates to repeat a specific behaviour,
• Attention,
• Enthusiasm,
• Memory,
• Imagery,
• Control of muscle tone and motor movement, and
• Nausea.
• Abnormality in Dopamine neurotransmission leads to reduced ability to
feel pleasure, decreased attention, cognitive slowing, apathy, reduced
imagery

29. HISTORY
• In 1951, Irving Selikoff and Edward H. Robitzek (de), working out of Sea
View Hospital on Staten Island, NY, began clinical trials on two new anti-
tuberculosis agents developed by Hoffman-LaRoche, isoniazid and
iproniazid.
• 1952-53 - A Cincinnati psychiatrist Max Lurie and Harry Salzer reported
that isoniazid improved depression in two thirds of their patients and
coined the term antidepressant. MoA was understood to be weak MAO-
Inhibition.
• 1953 - Selikoff and Robitzek also experimented with another anti-
tuberculosis drug, iproniazid; it showed a greater psychostimulant effect,
due to MAO-Inhibition. Turned out to have more pronounced toxicity
(withdrawn in 1961 due to lethal hepatotoxicity)

30. HISTORY
• Rational drug design led to identification of antihistamine-
derived compounds to selectively target Serotonin reuptake.
The first such compound to be patented was zimelidine in 1971,
while the first to be released for clinical was indalpine.
• Fluoxetine was developed at Eli Lilly and Company in the early
1970s by Bryan Molloy, Klaus Schmiegel, David T. Wong and
others.
• Fluoxetine approved for commercial use by the US FDA in 1988,
and became the first blockbuster SSRI.
• Novel antidepressants, such as SNRIs and NRIs with various
selective effects developed.

31. HISTORY
• Roland Kuhn in conjunction with Geigy Pharmaceutical
Company discovered the tricyclic compound "G 22355", later
named imipramine.
• Imipramine had a beneficial effect in patients with depression
who showed mental and motor retardation.
• Kuhn described his new compound as a "thymoleptic" "taking
hold of the emotions," in contrast with neuroleptics, "taking hold
of the nerves" in 1955–56.

33. NON-SELECTIVE AMINE REUPTAKE INHIBITORS -
TRICYCLIC ANTIDEPRESSANTS (TCAs)
•Imipramine (hydrochloride and pamoate)
•Desipramine
•Clomipramine
•Trimipramine

34. NON-SELECTIVE AMINE REUPTAKE INHIBITORS -
TRICYCLIC ANTIDEPRESSANTS (TCAs)
•Amitriptyline
•Nortriptyline
•Protriptyline
•Amitriptylinoxide
•Doxepin
•Dosulepin

35. NON-SELECTIVE AMINE REUPTAKE INHIBITORS -
TRICYCLIC ANTIDEPRESSANTS (TCAs)
•Lofepramin
•Melitracen
•Noxiptiline
•Opipramol
•Pipofezine
•Dibenzepin
•Dimetacrine
•Nitroxazepine

36. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS (SSRIs)
• Fluoxetine
• Citalopram
• Escitalopram
• Paroxetine
• Fluvoxamine
• Sertraline

37. SEROTONIN NOREPINEPHRINE
REUPTAKE INHIBITORS (SNRIs)
• Venlafaxine
• Desvenlafaxine
• Duloxetine
• Milnacipran
• Levomilnacipran
• Nefazodone

38. TETRACYCLIC ANTIDEPRESSANTS
• Amoxapin
• Maprotiline
• Mianserin
• Mirtazapin
• Septipiline

39. SEROTONIN MODULATORS AND
STIMULATORS (SMS)
• Vilazodone
• Vortioxetine

40. SEROTONIN ANTAGONISTS
•Trazodone (5-HT1A)
•Nefazodone (5-HT1A)
•Mirtazapine (5-HT2 and 5-HT3)

41. BLOCKADE OF PRE-SYNAPTIC ALPHA2
RECEPTORS
•Mirtazapine

42. DOWN-REGULATION OF PRE-SYNAPTIC
ALPHA2 RECEPTORS
•Tricyclic antidepressants (TCAs)
•MAO-Inhibitors

43. NOREPINEPHRINE REUPTAKE
INHIBITORS (NRI)
•Reboxetine
•Viloxazine
•Teniloxazine - also inhibits 5-HT2A receptors

44. NOREPINEPHRINE–DOPAMINE REUPTAKE
INHIBITORS (NDRI)
• Bupropion
• Methylphenidate

45. MONO-AMINE OXIDASE INHIBITORS
(MAO-INHIBITORS)

46. NON-SELECTIVE MAO-INHIBITORS
• Phenelzine
• Isocarboxazid
• Tranylcypromine

47. REVERSIBLE INHIBITORS OF MAO-A
(RIMA)
• Moclobemide
• Metralindole
• Pirlindole
• Toloxatone
• Bifemelane – RIMA. and weak NRI

48. ATYPICAL ANTIPSYCHOTICS
• Quetiapine – for depressive episodes in bipolar
disorder
• Amisulpride – for dysthymia
• Lurasidone – for depressive episodes in bipolar
disorder

49. OTHERS
• Agomelatine -
5HT2C receptor antagonist and MT1 and MT2 receptor agoni
st
• Ketamine – non-competitive NMDA receptor antagonist,
used in depression off-label
• Tandospirone – 5-HT1A receptor partial agonist
• Tianeptine – weak and atypical μ-opioid receptor agonist
• Minocycline – Microglia inhibitor

50. OTC ANTIDEPRESSANTS
• Hypericum perforatum [St. John's Wort (SJW)]
• Tryptophan – precursor in serotonin biosynthesis
• 5-Hydroxytryptophan (5-HTP) – precursor in serotonin biosynthesis
• Ademetionine [S-Adenosyl-L-methionine (SAMe)] – cofactor in monoamine
neurotransmitter biosynthesis
• Rubidium chloride [RbCl] (Rubinorm) – unknown/unclear mechanism of action

51. APPROVED ADJUNCTS TO ANTIDEPRESSANTS-
ANTI-PSYCHOTICS
• Aripiprazole
• Brexpiprazole
• Lurasidone
• Olanzapine
• Quetiapine
• Risperidone – (used off-label)

52. OFF-LABEL ADJUNCTS TO
ANTIDEPRESSANTS
• Tri-iodothyronine (T3)
• Tetra-iodothyronine (T4)
• Lithium
• Buspirone
• Pindolol

53. APPROVED COMBINATIONS
OF ANTIDEPRESSANTS
• Amitriptyline-Perphenazine
• Flupentixol-Melitracen
• Olanzapine-Fluoxetine
• Tranylcypromine-Trifluoperazine

54. USES OF ANTIDEPRESSANTS
• Major depressive disorder
• Dysthymia
• Bipolar disorder
• Generalized anxiety disorder
• Social anxiety disorder
• Obsessive–compulsive disorder
(OCD)
• Fibromyalgia
• Neuropathic pain
• Migraine
• Eating disorders - Bulimia
nervosa, Binge eating
• Agitation
• Childhood enuresis
(bedwetting)
• Sleep disorders

55. EFFICACY OF ANTIDEPRESSANTS
• Strong evidence supports use of antidepressants in
chronic and severe depression.
• Conflicting results studies analysing the efficacy of
Antidepressants Vs Placebo in acute mild to moderate
depression.
• A metaanalysis of 21 clinical trials, published in Lancet,
found antidepressants to be more effective than placebo
in major depressive disorder in adults.

56. LIMITATIONS OF ANTIDEPRESSANTS
•In clinical studies, approximately 1/3rd of patients
achieved full remission, 1/3rd experienced partial
response and 1/3rd turned out as non-responders.
•30% - 50% of individuals treated with a given
antidepressant do not show a response.

57. AUGMENTATION & COMBINATION OF
ANTIDEPRESSANTS
American Psychiatric Association guidelines suggest
 Adding a drug from another class with a different MoA,
and
 Augmentation therapy with drugs like, Lithium, thyroxine,
dopamine agonists, sex steroids, NRIs, glucocorticoid-
specific agents, or the newer anticonvulsants and
psychostimulants.

58. LONG TERM USE
• High relapse rate after conclusion of treatment.
• A meta-analysis of 31 placebo-controlled antidepressant trials of
1-year treatment, in 2003, found that 18% of responders
relapsed during therapy and 41% patients switched-over to
Placebo relapsed.
• Therefore, pharmacotherapy for acute episode followed by
psychotherapy.

59. GENERAL ADVERSE EFFECTS

60. SEROTONIN SYNDROME
• Serious ADR reported with high doses, and in
combination with other drugs
• Rarely fatal
• Characterized by mania, restlessness, agitation,
emotional lability, insomnia and confusion

61. HYPERTENSIVE CRISIS-CHEESE REACTION WITH MAO-
INHIBITORS
• MAOIs. Can cause a serious, pronounced, and sometimes fatal
interactions with:
 Certain drugs (sympathomimetics),
 OTC medications for common cold containing nasal decongestants,
 Foods containing very high levels of tyramine (mature cheese, cured
meats, or yeast extracts).
• Characterized by a potentially lethal hypertensive crisis.
• At lower doses an increased BP causing headache, giddiness, confusion,
agitation

62. RISK OF SUICIDE
• Use of antidepressants is correlated with an increased risk of suicidal
behaviour and thinking (suicidality) in those aged under 25.
• US FDA - the heightened risk of suicidality is within the first one to
two months of treatment.
• NICE places the excess risk in the "early stages of treatment".
• No effect or possibly a mild protective effect in patients aged 25 to
64 years (OR=0.79).
• Protective effect against suicidality among those aged 65 and over
(OR=0.37).

63. ANTI-DEPRESSANT-INDUCED MANIA
• Patients with bipolar disorder run the risk of getting
antidepressant-induced mania.
• Can occur in 20–40% of patients of bipolar disorder.
• Most often SSRIs can exacerbate or trigger symptoms of
hypomania and mania.
• Since many cases of bipolar depression are very similar to
unipolar depression, therefore, bipolar patient can be
misdiagnosed and exposed to the risk of precipitation of mania.

64. EMOTIONAL BLUNTING
•Emotional blunting - both positive and negative
can occur.
•This may necessitate a dose reduction or change
of medication.
•The mechanism of this effect is unknown.

65. EFFECTS ON BODY WEIGHT
• Body weight changes depend on the predominant effect
of antidepressant on neurotransmitters.
• Mirtazapine and paroxetine produce weight gain
and/or increased appetite.
• Fluoxetine, Bupropion and Venlafaxine cause weight loss
due to decreased appetite.

66. ATROPINE-LIKE EFFECTS OF TCA
• Dryness of mouth
• Loss of sweating – interference with heat-regulating mechanisms
• Difficulty in near-vision due to interference with accommodation of
lense
• Tachycardia, palpitations
• Constipation
• Difficulty in micturition, particularly in presence of obstructive uropathy,
eg BPH
• Mental confusion, delirium

67. SEXUAL SIDE EFFECTS
• Common with SSRIs, and include loss of sexual drive, failure to reach orgasm, and erectile
dysfunction.
• In a study of 1022 outpatients, overall sexual dysfunction with all antidepressants averaged
59.1%.
• MoA relating to effects of serotonin on 5-HT2 and 5-HT3 receptors; decreased
dopamine; decreased norepinephrine; blockade of cholinergic and α1-adrenergic
receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels.
• Moclobemide, a RIMA does not cause sexual dysfunction, and can actually lead to an
improvement in all aspects of sexual function.
• Mirtazapine is reported to have fewer sexual side-effects, most likely because it
antagonizes 5-HT2 and 5-HT3 receptors and may, in some cases, reverse sexual
dysfunction induced by SSRIs by the same mechanism.
• Bupropion, a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido
as a result of SSRI treatment.

68. SAFETY IN PREGNANCY
• Increased risk of spontaneous abortion of about 1.7-fold, preterm birth and
low birth weight with SSRIs.
• A study found a 27% increased risk of major malformations in SSRI
exposed pregnancies.
• Fluoxetine-exposure during pregnancies caused a 12% increase in the risk
of major malformations in a study.
• A systematic review and meta-analysis in 2013 could not show statistically
significant increased risk of major birth defects in antidepressant-exposed
pregnancies compared to non-exposed pregnancies.
• The FDA advises for the risk of birth defects with the use of paroxetine
• MAO-Is should be avoided.

69. DISCONTINUATION SYNDROME
• Antidepressant discontinuation symptoms were first reported
with imipramine in the late 1950s, and similar reports appeared
for monoamine oxidase inhibitors (MAOIs), SSRIs, and SNRIs.
• By the year 2001, at least 21 different antidepressants,
representing all the major classes, were reported to cause
discontinuation syndromes mostly in case reports.
• Incidence is difficult to determine and controversial.

72. DISRUPTIVE MOOD DYSREGULATION DISORDER
(DSM-5)
• Severe recurrent temper outbursts manifested verbally (e.g., verbal rages) and/or
behaviorally (e.g., physical aggression toward people or property) that are grossly out of
proportion in intensity or duration to the situation or provocation.
• The temper outbursts are inconsistent with developmental level.
• The temper outbursts occur, on average, three or more times per week.
• The mood between temper outbursts in persistently irritable or angry most of the day,
nearly every day, and is observable by others (e.g., parents, teachers, peers).
• Criteria A–D have been present for 12 or more months. Throughout that time, the
individual has not had a period lasting 3 or more consecutive months without all of the
symptoms in Criteria A–D.
• Criteria A and D are present in at least two of the three settings (i.e., at home, at school,
with peers) and are severe in at least one of these.

73. DISRUPTIVE MOOD DYSREGULATION DISORDER
(DSM-5)
• The mood between temper outbursts in persistently irritable or angry most of the
day, nearly every day, and is observable by others (e.g., parents, teachers, peers).
• Criteria A–D have been present for 12 or more months. Throughout that time, the
individual has not had a period lasting 3 or more consecutive months without all
of the symptoms in Criteria A–D.
• Criteria A and D are present in at least two of the three settings (i.e., at home, at
school, with peers) and are severe in at least one of these.

74. PERSISTENT DEPRESSIVE DISORDER (DYSTHYMIA)
DSM-5
A. Depressed mood for most of the day, for more days
than not, as indicated by either subjective account or
observation by others, for at least 2 years.
(In children and adolescents, mood can be irritable and
duration must be at least 1 year)

75. PERSISTENT DEPRESSIVE DISORDER (DYSTHYMIA)
DSM-5
B. Presence, while depressed, of two (or more) of the following:
1. Poor appetite or overeating.
2. Insomnia or hypersomnia.
3. Low energy or fatigue.
4. Low self-esteem.
5. Poor concentration or difficulty making decisions.
6. Feelings of hopelessness.

76. PERSISTENT DEPRESSIVE DISORDER (DYSTHYMIA)
DSM-5
C. During the 2-year period (1 year for children or adolescents) of the
disturbance, the individual has never been without the symptoms in
Criteria A and B for more than 2 months at a time.
D. Criteria for a major depressive disorder may be continuously present
for 2 years.
E. There has never been a manic episode or a hypomanic episode, and
criteria have never been met for cyclothymic disorder.

77. PERSISTENT DEPRESSIVE DISORDER (DYSTHYMIA)
DSM-5
F. The disturbance is not better explained by a persistent schizoaffective
disorder, schizophrenia, delusional disorder, or other specified or
unspecified schizophrenia spectrum and other psychotic disorder.
G. The symptoms are not attributable to the physiological effects of a
substance (e.g., a drug of abuse, a medication) or another medical
condition (e.g., hypothyroidism).
H. The symptoms cause clinically significant distress or impairment in
social, occupational, or other important areas of functioning.

79. PREMENSTRUAL DYSPHORIC DISORDER
DSM-5
Criterion A at least 5 of the following 11 symptoms (including at least 1 of the
first 4 listed) must be present in the final week before the onset of menses,
start to improve within a few days after the onset of menses, and become
minimal or absent in the week postmenses.
1. Marked lability (e.g., mood swings)
2. Marked irritability or anger
3. Markedly depressed mood
4. Marked anxiety and tension
5. Decreased interest in usual activities

80. PREMENSTRUAL DYSPHORIC DISORDER
DSM-5
6. Difficulty in concentration
7. Lethargy and marked lack of energy
8. Marked change in appetite (e.g., overeating or specific food
cravings)
9. Hypersomnia or insomnia
10.Feeling overwhelmed or out of control
11. Physical symptoms (e.g., breast tenderness or swelling, joint or
muscle pain, a sensation of ‘bloating’ and weight gain)[

82. PREMENSTRUAL DYSPHORIC DISORDER
DSM-5
Criterion B; One (or more) of the following symptoms must be
present:
• Marked affective lability (e.g., mood swings; feeling suddenly sad
or tearful, or increased sensitivity to rejection).
• Marked irritability or anger or increased interpersonal conflicts.
• Marked depressed mood, feelings of hopelessness, or self-
deprecating thoughts.
• Marked anxiety, tension, and/or feelings of being keyed up or on
edge.

83. PREMENSTRUAL DYSPHORIC DISORDER
DSM-5
Criterion C: One (or more) of the following symptoms must be present additionally,
to reach a total of five symptoms when combined with symptoms from Criterion B
above.
• Decreased interest in usual activities (e.g., work, school, friends, hobbies).
• Subjective difficulty in concentration.
• Lethargy, easy fatigability, or marked lack of energy.
• Marked change in appetite; overeating; or specific food cravings.
• Hypersomnia or insomnia.
• A sense of being overwhelmed or out of control.
• Physical symptoms such as breast tenderness or swelling, joint or muscle pain, a
sensation of "bloating," or weight gain.

84. PREMENSTRUAL DYSPHORIC DISORDER
DSM-5
Criterion D: The symptoms are associated with clinically significant
distress or interference with work, school, usual social activities, or
relationships with others (e.g., avoidance of social activities; decreased
productivity and efficiency at work, school, or home).
Criterion E: The disturbance is not merely an exacerbation of the
symptoms of another disorder, such as major depressive disorder, panic
disorder, persistent depressive disorder (dysthymia), or a personality
disorder (although it may co-occur with any of these disorders).

85. PREMENSTRUAL DYSPHORIC DISORDER
DSM-5
• Criterion F: Criterion A should be confirmed by prospective daily
ratings during at least two symptomatic cycles.
• Criterion G: The symptoms are not attributable to the
physiological effects of a substance (e.g., a drug of abuse, a
medication, other treatment) or another medical condition (e.g.,
hyperthyroidism).

91. ABNORMALITIES OF
NEUROTRANSMITTERS ARE ASSOCIATED
WITH DIFFERENT SYMPTOMS
• • NOREPINEPHRINE •
• SEROTONIN
• – Obsessive compulsive symptoms
• – Decreased ability – Lethargy
• to experience pleasure
• – Decreased motivation
• – Apathy DOPAMINE
• – Decreased attention
• – Cognitive slowing
• – Decreased alertness
• Stahl. Essential Psychopharmacology. 1996 Foote. In: Bloom. Psychopharmacology. 1995

92. ANTIDEPRESSANTS
• Tricyclic antidepressants (TCAs)
• Monoamino oxidase inhibitors (IMAO, RIMA)
• Selective serotonin re-uptake inhibitors (SSRI)
• Antidepressants acting on different receptors
(sometimes called SSRI 3rd, 4th or even 5th generation,
NaSSA, SNRI, NDRI)

93. TCA
• Action: Blockade of
– reuptake of NE & 5-HT (sometimes DA)
– Muscarinic, Histamine, Alpha Adrenergic
• Clomipramine most SRI, Doxepine most anticholinergic
• Start & Stop slowly
• Monitor plasma levels

94. TCA - INDICATIONS
• Depression
• Panic Disorder (low dose IMI)
• GAD (Doxepine)
• OCD (Clomipramine)
• Anorexia, Bulimia
• Enuresis (IMI),
• ADHD
• Narcolepsy, sleep walking, sleep terrors

95. TCA – ADVERSE EFFECTS
Important side effects in 15-20%, (increases with age) - most are transient and
occur during first few weeks of treatment
• Anticholinergic - dry mouth, urinary retention, constipation, dizziness, blurred
vision hallucinations, excitement, confusion
• Alpha 1 blockade: Orthostasis
• Anti-histamine: Sedation, Weight Gain, Sexual SE
• Cardiac arrhythmias, QT prolongation, depression of ST
• Overdosage: Serious, often fatal. Delirium, Seizure, BP & Temperature
dysregulation

96. TCA - SEROTONERGIC SIDE EFFECTS
• Sexual dysfunction
• GI upset
• Sleep disturbance
• Suppression of dopamine neurotransmission, which may result in:
• Decreased ability to experience pleasure
• Apathy and decreased motivation
• Decreased attention
• Cognitive dysfunction

97. TCA - NORADRENERGIC SIDE EFFECTS
• Tremor
• Tachycardia

98. TCA - DOPAMINERGIC SIDE EFFECTS
• Psychomotor activation
• Aggravation of psychosis

99. TCA INTERACTIONS
• P450 2D6
•Cimetidine, Quinidine, SSRI, antipsychotics, antiarrhythmics cause
Increased TCA levels
• Smoking, Lithium, Chloral Hydrate: Reduced TCA levels
• Additive effects with CNS depressants: Benzodiazepines, opioids,
hypnotics,

100. MONOAMINE OXIDASE INHIBITORS (MAOIs)
• Isocarboxazide
• Nialamide
• Fenelzine
• Tranylcypromine
• Moclobemide (RIMA)
• Selegiline(IMAOB)

101. MAO INHIBITORS (MAOI)
• Monoamine oxidases (MAO) responsible for metabolism of amines –
serotonin, dopamine and noradrenaline.
• Inhibition of MAO - increases the levels of amine neurotransmitters in
neurons
• MAO exists in two forms, A and B which are encoded by separate genes.
• 5-HT and NA - metabolized by MAO A
• DA is metabolised by both forms of MAO
• Non isoform-selective MAO inhibitors have been widely prescribed for
depression (e.g. tranylcypromine, isocarboxazide, phenelzine, pargyline).

102. RIMAs - REVERSIBLE INHIBITORS OF
MONOAMINE OXIDASE
Moclobemide
• Benzamide derivative which inhibits the deamination of serotonin, noradrenaline
(and dopamine).
• Preferentially inhibits MAO-A; at a 300 mg dose, the inhibition of MAO-A is
approximately 80%, while that of MAO- B is approximately 20 to 30%.
• MAO-A inhibition is short-lasting (maximum 24 hours) and reversible.

103. MAO-I SIDE EFFECTS
• Tyramine (Increased BP) metabolized GI MAO
• Hypertensive Crisis:
• headache, N, V, stiff neck, photophobia, diaphoresis, palpitations
• Serotonin Syndrome:
• autonomic instability, hyperthermia, myoclonus, confusion, delilrium, coma
• No longer first line, but very effective
• SE: orthostasis, sedation, sexual dysfunction, increased wt

104. MAO-INHIBITORS (MAOIS) -
INTERACTIONS
Must:
LOW TYRAMINE DIET: no cheese, smoked/aged meats, wine, beans, liver
Avoid:
• OTC decongestants
• Diet pills (ephedrine)
• DA agonists (Bupropion)
• SSRIs, Venlafaxine, most TCAs
• L-Tryptophan
• Antihypertensives & Diuretics
• Narcotics

105. REUPTAKE INHIBITORS
• SSRI (serotonine)
– citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline,
• escitalopram
• SNRI (serotonine and noradrenaline)
• – venlafaxine, milnaciprane
• NARI (noradrenaline)
• – reboxetine
• NaSSA
– mirtazapine, trazadone, nefazodone (antagonists of the 5-HT
• and alpha adrenergic receptors)
• DNRI
– bupropione

106. SSRIs
Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Citalopram,
Escitalopram
– Clomipramine (TCA) also SRI
– Sertraline: weak DA uptake inh – Paroxetine: weak
anticholinergic
• 5-HT potency: parox>fluvox>sertr>fluox
• Similar efficacy to TCA, better safety

107. SSRIs
• Best selling class of antidepressants fluoxetine (Prozac), paroxetine (Paxil),
sertraline (Zoloft), citalopram, fluvoxamine, clomipramine
• Mechanism of action: Inhibit the reuptake of serotonin, with almost no effect on
noradrenaline and dopamine.
• Efficacy: similar to tricyclics, but may be better tolerated for long- term treatment
and with fewer side effects
• Therapeutic uses: major depression, bulimia, secondary depression, aggression,
obsessive-compulsive disorder, panic disorder, premenstrual depression, chronic
fatigue syndrome, posttraumatic stress syndrome

108. SSRIs SIDE EFFECTS
Generally safe &well tolerated
CNS
• Nervousness, jitteriness
• Insomnia / sedation, fatigue
• Headache,, Tremors
GI
• Nausea / Vomiting 11-16%, Diarrhoea, Constipation, anorexia, dry mouth
• Caution in Hepatic Disease
Sexual 5-HT2 (25-50%)
• delayed orgasm, reduced libido, reduced erection/lubrication
Induction of Mania
Pregnancy: Fluoxetine OK, others no data

109. SSRIS INTERACTIONS
• • Absolute contraind. MAOI, L-Tryptophan – Wait 2 wks (more with fluoxetine) if
switching
• • p450system:
• • Fluvoxamine: 1A2 (Incraesed TCA, clozapine, theoph, tylenol, propranolol levels) &
3A4 (arrithmias with Increased astemizole & terfenadine, cisapride (
• • Fluoxetine 2D6, 3A4, 2C19
• • Paroxetine 2D6
•

110. SSRIs DOSAGE
• Fluoxetine 10-80 mg/d
• Paroxetine 10-50 mg/d
• Sertraline 25-200 mg/d
• Fluvoxamine 50-300 mg/d
• Citalopram 20-50 mg/d
Initial response 2-4 weeks, if no improvement after 3-4 weeks Increase the dose

111. MAJOR ADVANTAGES OVER THE TCAs
AND MAOI
• • lessseveresideeffectsandlesslikelytolead to discontinuation of therapy
• • titration of dosing not necessary
• • increased compliance, especially during long- term exposure
• • well tolerated
• • extremely safe in terms of overdosing
• • effectivefortricyclicnonresponderstowhen tricyclics are contraindicated

112. VENLAFAXINE (SNRI)
• • XR & Regular (t1/2=5 hrs) available
• • Potent 5-HT, NE uptake inh.
• • Prot. Binding (27%), low p450 problems
• • SE SRI-like: N/V, dizziness, sedation
• • Dosage:
• – 37.5 bid, optimal dose 175-225
• – XR 37.5 qd 5-7 d., 75 qd, 150 qd after wk 3 – Monitor Blood Pressure
•

113. BUPROPION (DNRI)
• DA Agonist
• • Structure similar to amphetamine – decrease sleep & appetite, Tx ADHD
• • Liver metab, kidney excreted
• • t1/2: 8-12 hrs (bid, tid)
• • Indications: Depression & ADHD
• • RiskofSeizures@450-600mg/d – Single dose <150, >4hrs apart
• – Max dose 400 mg/d
•

114. BUPROPION: SE
• • N, V, sleep, restlessness, irritability, agitation,
• – No sexual SE
• • Do not use with MAOI
• • Delirium, psychosis, dyskinesias combined w DA agonists (amantadine, L-dopa,
bromocriptine)
• • RiskofSeizures
• • Contraind. Hx HI, brain tumor, Sz threshold
•

115. TRAZODONE
• A weak 5-HT reuptake inhibitor and blocks alpha 2, 5- HT2A receptors;causes
sedation but this can be advantageous
• • Blocks 5-HT 2 & 1 receptors
• • Weakinhibitor5-HTreuptake
• • Helpful for sleep
• • GIabsorbed,t1/23-9hrs
• • Dose: 150 mg/day divided doses, max 400
• • SE:
• • Sedation, occasional orthostasis
• • Rare: Priapism (1 in 6,000) (alpha-1 block)

116. NEFAZADONE
• • Similar to Trazodone
• • less sedating, no priapism
• • 5-HT2 antagonist: little sexual SE
• • Mild inhibition 5-HT, NE reuptake
• • t1/218-24hrs:
• • Metabolite of p450 3A4:
• – interaction: alprazolam, ketokonazole, terfenadine, astemizole, cisapride
•

117. MIRTAZAPINE
• • Presynaptic alpha 2 blockade
• – (blocks feedback that reduces the release of NE, 5-HT)
• • Postsynap 5-HT2 block: Reduced sexual SE
• • Postsynap 5-HT3 block: Reduced N,V,HA
• • 5-HT to 5-HT1antidepressant effect
• • SE: Sedation, Constipation, Wt gain
•

118. MIANSERIN
• blocks alpha 2 adrenergic, 5-HT2A and Histamine H1
• receptors;
• causes sedation but this can be advantageous
• blood monitoring for mianserin required as can cause agranulocytosis.

119. BUSPIRONE
• A partial agonist at the 5-HT1A receptor
• few side effects but the most common are dizziness, headache, drowsiness and
nausea (<10%).
• Usually prescribed for short-term relief of excessive anxiety in generalised anxiety
disorder