Psychology: Chapter 14: Antidepressants and Mood Stabilizers

I. INTRODUCTION
* There are two types of 1st generation antidepressants: (1) monoamineoxidase inhibitors (MAOIs) and (2)tricyclic
antidepressants. The 2nd generation antidepressants make up a diverse group that inc the selective serotonin reuptake
inhibitors (SSRIs), the Norepinephrine reuptake inhibitors, the dopamine reuptake inhibitors, and a variety of others.
In addition the element lithium is used in the treatment of bipolar disorder as well as drugs that were originally dev as
anticonvulsants.

- Define monoamine oxidase inhibitors (MAOIs)

- Define tricyclic antidepressants (TCAs)
- What were the first drugs that were successfully used to treat depression?
- What are 1st-generation antidepressants
- What are 2nd generation antidepressants
- Define Selective serotonin reuptake inhibitors (SSRIs)
- Define Inhibitors of Norepinephrine reuptake (NARIs or SNRIs)
- Define Dopamine Reuptake
- Other drugs that selectively block or stimulate specific serotonin and Norepinephrine
receptors
- What was the first MAOI used?
- What is the reason for the name given to the tricyclic antidepressants?
- What are some examples of both 1st and 2nd generation antidepressants?
- Define and explain the element lithium
- What drugs are now more likely used to treat bipolar disorder?
- Define and explain Anticonvulsant drugs
II. THE NATURE OF DEPRESSION AND MANIA
* Depression has symptoms such as los of appetite, loss of energy, sleeping problems, intense feelings of guilt or
worthlessness and thoughts of suicide. Depression can come in cycles or be constant. If depression comes in cycles in
which states of depression alter with states of highs (mania), states of extreme over activeness and hyperactivity where
a person actions are not typical of their character and are impulsive, risky, illegal, dangerous, or irrational, this is
considered bipolar disorder.

- For people who suffer from depression:

o There may be no cause in their enviro
o The depression either does not go away or keeps coming back for no apparent reason
o They show loss of appetite, or unsatisfied appetite, loss of interest in pleasurable
activities, loss of energy, sleep problems, extreme feelings of worthlessness and
hopelessness and guilt, and thoughts of suicide and death.
- Box 14-1 DSM-IV Criteria for a major depressive episode
- It can occur in persons who do not actually feel depressed
- Often older people show many signs of depression
- Define anhedonia
- Clinical depression or depressive illness
- Depression is classified as an affective disorder or mood disorder
- Traditionally mild depression was labeled “neurotic depression” but serious depression
accompanied by physical symptoms was considered a psychosis.
- Today the DSM-IV does not separate the two and doesn’t consider depression psychotic
- Depression is often called the common cold of mental disorders? Why?
- In western cultures depression is more frequent in every generation since WWII
 - Women are 2x as likely to suffer from depression compared to men, but there is no gender
difference in bipolar disorder
- Only about 20% of people who suffer with depression seek or receive help from a professional
- Issues caused by depression such as missed work, accidents at work, disability, etc are est. to
cost the U.S. about $26 billion annually
- The over all mortality rate for depressed people is higher and the probability of suicide is 20x
more likely
- Depression is a chronic illness
- 88% of those who suffer from depression and receive drug therapy improve w/in 6 months, but
less than 1/3 will remain well
- Depression typically comes in cycles that may alternate with normal periods
- If depression cycles alternate with periods of mania instead of normal times, the person
suffers from Manic depressive disorder now called bipolar disorder
- Mood is related to the functioning of the monoamines (MAs) in particular, serotonin (5-HT)
and Norepinephrine (NE), although dopamine (DA) may also play a role.
- Define Monoamine theory and explain its original form and contemporary form
- All three of the MAs are involved in some aspect of mood, and they interact with each other in
complex ways
- Decreased activity in the serotonin system makes an individual vulnerable to depression
- What do all treatments of depression have in common
- Increases in serotonin transmission due to treatments may be caused by an dmay in turn
cause changes in activity of other transmitters systems even some that do not use MAs
- Increase in serotonin transmission is necessary but not sufficient in the treatment of
depression
- Activity at specific serotonin synapses may in fact be only one link in a long and complex
chain of neurological deficiencies that cause depression and mania
- 3 brain systems that use MA transmitters have been implicated in some aspect of mood all
have centers in the midbrain and upper brain stem and send projections forward to the
various parts of the limbic system and the fore brain through the medial forebrain bundle: (a)
NE fibers that arise in the locus coeruleus in the midbrain
- (b) Serotonergic fibers that originate in areas of the Raphe system and
- (c) Dopaminergic fibers of the meso limbic system that originate in the ventral tegmental area
III. IN THE BODY
 Antidepressants are absorbed orally and reach peak blood levels in about 4 hrs. Most tricyclics have very long
½ lives; 2nd generation antidepressants ½ lives are usually shorter.
 All agents that act as antidepressants have the effect of increasing transmission at sesrotonergic synapses.
There is a delay of about 2 wks in the start of the therapeutic effects. This could be due to serotonin receptor
down-regulation or habituation of a serotonin autoreceptor.

A. Absorption
- TCAs reach maximal bl concentrations in 1 – 3 hrs although some may take as long as 8 hrs
- The absorption of SSRIs is slower usually 4 – 8 hrs are needed to reach maximum concentrations
- Antidepressants generally have high levels of protein binding (e.g. over 95% with fluoxetine)
- Explain protein binding and its effects on absorption, excretion, distribution, and potency of meds
- A significant portion of a dose is destroyed in the digestive system and liver before it reaches the
bloodstream (this first pass metabolism is inhibited by alcohol, thus increasing the amount absorbed
greatly by the same dose)
- Overdoses of TCAs are much more serious when in conjunction with alcohol
- SSRIs are an exception they appear to have little interaction with alcohol, and have actually been
suggested as a treatment for alcoholism
- Orally admin lithium is rapidly absorbed, peak levels in the bl occur between ½ hr to 2 hrs
- However lithium is much slower in getting inside the cells this is the reason for the drug’s delayed
therapeutic effects
- Lithium has a low therapeutic index of about 3, so it is important to maintain bl levels avoiding them
being to high
- B/c lithium is rapidly absorbed it peaks in the bl at high levels and these peaks often exceed the
therapeutic index
- It is also excreted rapidly, thus a need for several repeated admin throughout the day
- Both the above issues are handled using a slow-release capsule calling for only 2 admin a day

B. Distribution
- Antidepressants readily cross the placental and bl-brain barriers
- They tend to be concentrated in the lungs, kidneys, liver, brain, and some in breast milk
- Lithium enters and leaves the brain slowly, reaching a peak after more than 24hrs
- It seems to be concentrated in some parts of the brain
- There is NO protein binding with lithium
- It easily crosses the placental barrier and finds its way into breast milk and should not be used by
nursing mothers

C. Excretion
- MAOIs have a short ½ life of 2 – 4 hrs, may be taken once a day due to an irreversible effect on MAO
and their effects persist long after they are eliminated from the body
- Newer MAOIs have a reversible effect and two or three daily doses are required
- TCAs have a ½ life of about 24hrs and in most reach a steady state level after about 5 days, with only a
single daily dose
- 2nd generation antidepressants have shorter ½ lives than the tricyclics and often require more frequent
dosing
- Newer SSRIs generally have a short to medium ½ life (15-20hrs) and do not have active metabolites,
with these drugs a steady state bl level can be achieved in a few days with single daily dosing.
- One exception is fluoxetine, has an extremely long half-life and an active metabolite that blacks the
enzyme responsible for its destruction
- Fluoxetine has a ½ life of 6 days and its active metabolite, norfluxetine has a ½ life of 16 days it may
take as long as 75 days for the drug and its metabolite to reach a steady state level in the body
- It can also take this long for the drug and its metabolite to be eliminated from the body
- There is considerable variability between individuals in the pharmacokinetics of antidepressants (e.g.
a fixed daily dose of a tricyclic can be 36x higher in one person than in another)
- This difference among individuals basically depends on genetics and possession or lack of certain
enzymes, this can be influenced by ethnicity
- Lithium is excreted unchanged in the urine and has a ½ life of between 12 and 21 hrs
- The excretion rate varies considerably among individuals and increases with age to as long as 36 hrs
- Blood levels must be carefully monitored

D. Neurophysiology
a. Antidepressants
 Antidepressants generally work by increasing the activity of one or
more of the MA systems of the brain
 These drugs are usually classified by how they do this, increase
activity of the MA systems
 Explain the neurophysiology of MAOIs and there properties
 Explain the neurophysiology of SSRIs and there properties and side
effects
 Explain the neurophysiology of TCAs and there properties and side
effects, know specific drugs
 Explain the neurophysiology of 2nd generation antidepressants and
there properties
 Explain why therapeutic effects are possibly delayed for 2 -3 wks
with antidepressants
b. Mood Stabilizers
 No one knows how lithium works
  It appears to stabilize the neurochemical mechanisms that control
mood and to keep them from swinging radically between extremes
 Lithium is know to do several things in the brain, tell and explain
them.
 The anticonvulsant mood stabilizers valproic acid and
carbamazepine and lamotrigine have diff neurological effects, define
and explain these
 Clearly membrane stabilization or inhibition is important in the
effectiveness of drugs in treating bipolar disorder, but we don’t
know why
IV. THE EFFECTS
 The MAOIs also block the destruction of toxic substances found in some foods. People taking MAOIs should
not eat foods like pickled herring and some types of cheese, they can cause a buildup of tyramine and this is
less of a problem with the newer, reversible MAO-A inhibitors. Lithium also causes unwanted side effects such
as thirst, tremor, and nausea.
 Clinical trials show that there is a high rate of placebo effect for antidepressants, but antidepressants are more
effective than a placebo. SSRIs are the only antidepressants that have shown to be effective in children.
 Increases in violence and suicide have been reported with SSRIs after they have been taken for several weeks
this is sometimes associated with restlessness and akathesia, especially in children and young people

A. On the Body
- Tricyclics’ anticholinergic effects block the parasympathetic nervous system, which uses Ach as a
transmitter
- These effects are characterized by symptoms such as: dry mouth, constipation, dizziness, irregular
heartbeat, blurred vision, ringing in ears, retention of urine, excessive sweating (10%)
- Side effects are usually worse during the 1st 2 wks or sudden increase in dose, also worse in elderly
(who r also more likely to exhibit symptoms of confusion and delirium, incidence can b as high as 50%
in patients over 70
- Extrapyramididal symptoms or Parkinsonian symptoms, similar to the side effect of antipsychotics are
unusual with tricyclics but have been reported
- The SSRIs may cause nausea, headache, nervousness, and insomnia, all of which, apart from the
insomnia, tend to disappear
- A more serious danger is serotonin syndrome
- Define and explain serotonin syndrome
- Patients taking the tricyclics often report an increase in appetite especially for sweets, thus an increase
in body weight
- Major weight gain is one reason people stop taking these drugs,
- MAOIs and lithium also cause weight gain but the opposite is reported with SSRIs
- MAOIs alone do not have very marked effects apart from a lowering of blood pressure and postural
hypotension
- Define postural hypotension
- Explain the complication with how MAOIs interact or interfere with other drugs
- MAOs also destroy the MAs and are responsible for the digestion of some substances in food
- Define Tyramine and explain its relation to MAOIs
- Explain the seriousness of not watching your diet while taking MAOIs
- Explain why selective MAO-A inhibitors are much safer
- About 90% of patients on lithium report unwanted side effects inc: hand tremors, increased thirst,
nausea, vomiting, diarrhea, swelling, weight gain and after extended treatment may experience fatigue
and muscle weakness
- Long term use of lithium can cause kidney damage
- Anticonvulsant drugs can cause frequent urination, nausea, vomiting, and in higher doses tremors,
weight gain, hair loss, dizziness
- The anticonvulsant Lamotrigine causes a rash in 10% of patients

B. On sleep
 - Tricyclics cause sleepiness, even a single dose can cause drowsiness and is somex prescribed to treat
insomnia, but they do not increase total sleeping time and high doses cause nightmares
- Antidepressants usually reduce REM sleep time, however
- Bupropion increases REM
- Reduction of REM may be associated with a drugs antidepressant effects, b/c sleep increases
depression while REM deprivation can actually decrease symptoms of depression
- Fluoxetine increases vividness of dreams

C. On Behavior and Performance in Humans

a. Subjective Effects
 Antidepressants do not produce euphoric or even pleasant effects
 At low doses effects are similar to those of antipsychotics: tiredness,
apathy, and weakness
 Higher doses produce impaired comprehension and a confusion that
is unpleasant
 Amitriptyline causes feelings of calmness and relaxation
 Lithium has few if any subjective effects
 Some do report feeling mentally slow and difficulty with
concentration
b. Effects on Performance
 Acute doses of the tricyclic antidepressants imipramine and
amitriptyline can have detrimental effects on vigilance task and can
cause cognitive, memory, and psychomotor impairment that seems
to be related to sedation.
 So it would be a bad idea for these people to. . . .
 Some studies have shown improvement in cognitive func over
chronic treatment, proving tolerance but other studies have not had
these results
 There is no evidence that SSRIs cause any impairment
 Extensive systematic studies of mental abilities after acute and
chronic lithium admin indicate a small but significant slowing of
mental processes, they appear to be few effects on performance of
task or reaction time but difficulty in slowing of info and processing
and memory.
 The anticonvulsant drugs also cause a slowing of cognitive func and
learning and can be sedating.
c. Effects on Personality
 Define cosmetic psychopharmacology
 SSRIs are useful in treating people with diagnosed personality
disorders, and with compulsive behaviors
 Issues with personality Explain

D. On Behavior of Non-Humans
a. Conditioned Behavior
 Tricyclic antidepressants are more effective than methamphetamine
in increasing operant response rates
 Appear to increase high rates where amphetamine tends to decrease
 Tend to decrease avoidance behavior at doses that have no effect on
escape behavior
 Are similar to anti-anxiety and antipsychotic meds
 NDo not increase punishment suppressed behavior, decrease it
making it similar to psychomotor stimulants and anmphetamine
V. EFFECTIVENESS IN TREATING DEPRESSION
- Numerous clinical trials have shown that many of these drugs are more effective than a
placebo, although there is often a strong placebo effect seen in these studies
 - A study found that the % of responders in the placebo group has been increasing steadily over
the last 20 yrs
- There is considerable differences :
o In effectiveness of diff drugs as well
o In the way that diff types of depression respond to dif antidepressants
o In the severity of diff side effects in diff individuals
o WHY R THERE SO MANY DIFF KINDS OF ANTIDEPRESSANTS?
o Advancement are focused on fewer side effects NOT on greater therapeutic effect
o TCAs are not effective for children and adolescents but SSRIs are
VI. DISCRIMINATIVE STIMULUS PROPERTIES
- Neither MAOIs or TCAs have discrimtory properties
- SSRIs and NARIs do have discriminate stimulus properties at therapeutic doses
- These properties do not seem to arise from the antidepressants properties of the drug
VII. TOLERANCE
* Tolerance dev to many of the effects of antidepressants, withdrawal symptoms are sometimes seen with sudden
stopping of use, especially if using a high dose.

- Therapeutic effectiveness may show tolerance in some of these drugs after a few months
but clinical significance is not known
- Tolerance to the side effects typically develop within several weeks and tolerance never
dev to tiredness
VIII. WITHDRAWAL
- Explain withdrawal symptoms from suddenly stopping tricyclics
- Explain w/drawal from SSRIs
IX. SELF-ADMINISTRATION
* Antidepressants do not appear to be reinforcing in non humands and are never abused or taken for recreational
purposes.

X. COMPLIANCE
- Research has shown that SSRIs are far superior to any other antidepressant drugs in terms of
patients being compliant and continuing use with chronic drug treatments.
XI. HARMFUL EFFECTS
* The tricyclics have been known to cause sexual side effects, both sexes report having difficulty achieving orgasm.
Lithium has been shown to cause cardiac malformations in the fetus during early pregnancy.

A. Reproduction
- Tricyclics can interfere with male sexual arousal and sexual function as well as some MAOIs and
some SSRIs this side effect and it level of intensity varies considerably from person to person
- In one study 96% of the male patients on these drugs reported having difficulting achieving orgasm.
- There is little evidence to conclude that antidepressants can cause damage to the fetus during
pregnancy however some animal studies have presented some risk therefore use of these drugs should
be discontinued until after pregnancy
- Lithium is known to cause cardiac malformations in a fetus during early stages of pregnancy
- Both antidepressants and lithium can be found in breast milk so nursing mothers should refrain from
using these drugs.

B. Violence and Suicide

- Prozac induced violence and/or suicide became an issue a while back of hot discussion. However
large-scale drug trials have actually shown that prozac (fluoxetine) reduces the incidence of suicide
and violence
- Such drugs are prescribed to very agitated, depressed, and suicidal people. Suicide and/or violence
after being treated with antidepressant drugs may NOT be a drug induced effect
- However after being taken for 3 to 4 wks, fluoxetine may induce an activating effect with racing
thoughts, nervousness, and tremor
- Sometimes this dev to the point of being labeled Akathesia, this is not prevalent
- Define Akathesia
- In 2005 the FDA enforced the drug companies to put a warning on antidepressants stating that it
could increase suicidal thoughts in children.

C. Overdose
- SSRIs in combination with other antidepressants or psychomotor stimulants can cause serotonin
syndrome
- Tricyclics are the 3rd most common cause of drug –related deaths, exceeded only by alcohol drug
combinations and heroin. The toxicity of the tricyclics is due primarily to their effect on the
contractility of the heart muscle.
- There is considerable variability in the death rates attributed to drugs with in the same class.
- Among the tricyclics Clomiprimine is relatively safe, but many deaths have been attributed to
amitriptyline
- Tranylcypromine an MAOI, is responsible for the high rates of deaths, but the rate of isocarboxazide is
low
- The SSRIs are considerable safer, NO overdose deaths have been attributed to fluoxetine