Module 3 Section 3 (Depression)

Question 1

True or false: depression is one of the most common mental illnesses, affecting 10% to 15% of the population over a lifetime.

Answer 1

True

Question 2

What are the symptoms of depression?

Answer 2

People who have depression will have feelings of intense sadness, hopelessness, despair, self-disapproval, and physical and mental slowing.

Depression may also be associated with suicidal thoughts.

Question 3

What are the 3 types of depression?

Answer 3

1) Reactive (secondary) depression: this is the most common type of depression and accounts for over 60% of all cases of depression. It occurs in response to real stimuli, such as grief and illness. It may resolve spontaneously, or may respond to a variety of treatments.

2) Major depression (endogenous): major depression accounts for approximately 25% of all depressions and tends to recur throughout life. In major depression there are characteristic disturbances in sleep, hunger, and appetite. A loss of pleasure and interest in most usual activities is experienced. Additionally, a decrease in sexual drive, mental slowing, and loss of concentration can be experienced.
- According to current evidence, major depression is a genetically determined biochemical disorder, which causes an inability to cope with ordinary stress.
- Major depression usually responds to antidepressant therapy. This is the disease state most correctly called depression.

3) Depression associated with bipolar disorder: this type of depression accounts for approximately 10-15% of all depressions. A mood stabilizer is used to minimize the atypical shifts in mood associated with this disorder, and the depression is sometimes managed with antidepressants, although with variable success.

Question 4

How is major depression characterized?

Answer 4

Major depression is characterized by a depressed mood for at least two weeks and/or a loss of interest or pleasure in activities.

Major depression is associated with significant morbidity and mortality and is one of the most common causes of disability in the developed world.

Question 5

What are the 3 theories for the cause of major depression?

Answer 5

1) Amine Hypothesis: depression may be due to a reduction in the activity of one or more neurotransmitter systems in the CNS.
2) Neurotrophic Hypothesis: depression may be due to a loss of neurotrophic support characterized by a decrease in neurogenesis and synaptic connectivity.
3) Neuroendocrine Hypothesis: depression may be due to an abnormality in hormones affecting mood.

Question 6

Discuss the amine hypothesis.

Answer 6

The amine hypothesis suggests that depression is the result of a deficiency of the excitatory neurotransmitters in the CNS (norepinephrine, serotonin, and dopamine).

1) The neurotransmitters serotonin and norepinephrine are released from a presynaptic axon.
2) Serotonin reuptake transporters (SERT) and norepinephrine uptake transporters (NET) remove their respective neurotransmitters from synapses, terminating their action.
3) The enzyme monoamine oxidase A (MAO-A) inactivates the neurotransmitters, and then they cannot be repackaged into vesicles for subsequent release.

The amine hypothesis theorizes that in depression, the levels of released neurotransmitters fall below normal levels, leading to impaired neuronal function that manifests as a lack of excitation of neurons, and consequently depression.

Question 7

What makes the amine hypothesis incomplete?

Answer 7

The amine hypothesis is incomplete, as many studies have shown that the function or levels of norepinephrine, serotonin, or dopamine are not decreased in depressed patients. However, all current effective antidepressant drugs increase the amounts of these neurotransmitters.

Question 8

Research show those neurotransmitters are not decreased, however those patients are given dugs that increase the amount of those neurotransmitters. What do you think could be the cause for this discrepancy?

Answer 8

It appears that while these neurotransmitters are important in depression, they are not the only factors in the development of depression.

Question 9

Discuss the neutrophic hypothesis.

Answer 9

The neurotrophic hypothesis suggests that depression is associated with reduced neurotrophic support, which refers to the growth and inter-connectivity of neurons. Specifically, this hypothesis theorizes that a reduction in nerve growth factors are responsible for loss of neural plasticity and neurogenesis, and that antidepressants stimulate neurogenesis and synaptic connectivity in cortical areas of the brain.

1) Brain-derived neurotrophic factor (BDNF) is a protein required for neural growth and axon sprouting within the nervous system. Changes in trophic factors, such as BDNF, is thought to play a major role in the development of major depression.
2) The reduced interconnectivity between neurons, resulting from reduced levels of BDNF, leads to reduced neural activity and hence, depression.

Although much evidence supports the neurotrophic hypothesis, not all evidence does.

Question 10

How do antidepressants work to help treat the loss of neuronal plasticity and neurogenesis?

Answer 10

Antidepressants appear to reverse this process ( the process described in the neurotrophic hypothesis).

Question 11

Discuss the neutroendocrine hypothesis.

Answer 11

The neuroendocrine hypothesis suggests that major depression is associated with an abnormality in hormones which affect mood.

This theory primarily focuses on changes within and interactions between the nervous and endocrine systems.

Ex: major depression is associated with increased cortisol levels, and it is well known that endogenous elevation of cortisol is associated with mood symptoms similar to those seen in major depression.

In addition, up to 25% of depressed patients have abnormal thyroid function, and it is known that hypothyroidism is often characterized by depressive symptoms.

Sex steroids are also implicated in major depression, as estrogen deficiency in women and testosterone deficiency in men are thought to be associated with depression.

Question 12

True or false: the pathophysiology of depression can likely be explained by integrating all three theories - the amine, neurotrophic, and neuroendocrine hypotheses.

Answer 12

True

The hypotheses are not mutually exclusive, but linked. For instance, chronic stimulation of monoamine receptors appears to increase the synthesis of BDNF. In addition, evidence suggests that binding of cortisol to receptors in the brain may decrease synthesis of BDNF.

Question 13

What two (or three) neurotransmitters do you think are implicated in the mechanism of action of all current effective antidepressants?

Answer 13

Regardless of the cause of depression, all current effective antidepressants have their primary actions on the storage, metabolism, or reuptake of serotonin or norepinephrine (and in some cases dopamine).

Question 14

Describe the 3 mechanism of action for antidepressants.

Answer 14

1) Block neurotransmitter reuptake systems.
- TCAs, SSRIs, SNRIs

2) Block neurotransmitter metabolism, thereby increasing the amount of neurotransmitter released.
- MAOi

3) Directly increase the amount of neurotransmitter released
- Autoreceptor antagonists

Question 15

What do all antidepressants have in common?

Answer 15

They all have the same common end goal: to increase the amount of neurotransmitter within the synaptic cleft.

Question 16

When are maximal beneficial effects seen in antidepressants?

Answer 16

Maximal beneficial effects of antidepressants are often not seen until four to six weeks after initiation of therapy.

Question 17

What are the 3 categories of antidepressants?

Answer 17

• Tricyclic antidepressants (TCAs)
• Serotonin reuptake inhibitors (SSRIs)
• Serotonin norepinephrine reuptake inhibitors (SNRIs)

Question 18

What are Tricyclic Antidepressants (TCAs)?

Answer 18

The TCAs were the first antidepressants introduced into therapeutics, and derive their name from the fact that their chemical structures all share a three-ring nucleus.

Question 19

How do TCAs work?

Answer 19

TCAs work by inhibiting the reuptake transporters of both serotonin and norepinephrine (i.e. SERT and NET) into the presynaptic axon, causing an increased concentration of these neurotransmitters to be present in the synaptic cleft.

Question 20

What are the common adverse effects of TCAs?

Answer 20

The most common adverse effects that limit the therapeutic usefulness of TCAs are their effects on other receptor systems, which do not contribute to their efficacy, but do contribute to their toxicity:

• anticholinergic effects (dry mouth, urinary retention, constipation, and blurred vision)
• antiadrenergic (alpha) effects (hypotension when standing up)
• antihistaminic actions (sedation)
• block sodium channels (arrhythmias, seizures, fatal in overdose)
• weight gain

These drugs are effective antidepressants, however, they have a number of adverse effects, and are thus generally only used when other drugs fail to control the symptoms of depression.

Question 21

What are Selective Serotonin Reuptake Inhibitors (SSRIs)?

Answer 21

This class of antidepressants was introduced in the late 1980’s to the mid-1990’s, and is the most widely used class of drugs in the treatment of depression. The SSRI’s are relatively selective for blocking the serotonin transporter protein in the presynaptic terminal.

Question 22

Do the SSRIs or TCSa have more of an effect on the ANS?

Answer 22

The SSRIs have much less effect on the autonomic nervous system than the TCAs and therefore have less toxicity than the TCAs.

Question 23

What are some of the adverse effects of SSRIs?

Answer 23

The SSRI’s cause nausea, headache, nervousness, and insomnia more commonly than the TCAs.

In addition, there is a high incidence of sexual dysfunction with SSRIs.

Question 24

True or false: an important advantage of the SSRIs is that they are much safer than the TCAs in over-dosage.

Answer 24

True

Question 25

What kind of drug-drug interactions can SSRI therapy cause?

Answer 25

Decreased metabolism: SSRIs inhibit the CYP450 enzymes, therefore the metabolism of concurrently administered drugs is altered. This may lead to drug toxicity or loss of drug efficacy.
- Some SSRIs have minimal inhibition, while others have major interactions.

Serotonin Syndrome: this syndrome occurs due to concurrent use of multiple drugs that increase serotonin. Monoamine oxidase inhibitors are the major culprit, but TCAs and other drugs that increase serotonin can also contribute.
- Serotonin syndrome is characterized by muscle rigidity, elevated body temp, and mental status changes (i.e. confusion, agitation). The syndrome can lead to coma and death.

Question 26

What are Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)?

Answer 26

This class of drugs block transporters for both serotonin and norepinephrine, and have fairly good safety profiles.

Unlike the TCAs, these drugs do not have effects at autonomic and histaminic receptors.

Depressed patients may respond to this class of antidepressants if they do not respond to the SSRIs.

Question 27

What are some of the adverse effects of SNRIs?

Answer 27

These agents share the same adverse effects as the SSRIs. In addition, these drugs have some adverse effects attributed to norepinephrine, including an increase in blood pressure and heart rate.

Question 28

What are monoamine oxidase (MAO) inhibitors?

Answer 28

This second category of antidepressants function by blocking neurotransmitter metabolism, thereby increasing the amount of neurotransmitter released.

Question 29

What are the two MAO enzymes?

Answer 29

1) MAO-A is the enzyme primarily responsible for metabolism of norepinephrine, serotonin, and tyramine.
2) MAO-B is more selective for metabolism of dopamine. By blocking a major metabolic pathway for the monoamine neurotransmitters, the MAO inhibitors allow more amines to accumulate in presynaptic stores, resulting in more to be released when the nerve impulse reaches the presynaptic neuron.

Question 30

What are some of the adverse effects of monoamine oxidase (MAO) inhibitors?

Answer 30

Adverse effects include orthostatic hypotension, agitation, and insomnia.

Question 31

What are some drug-drug and drug-food interactions that may result from taking MAOs?

Answer 31

If MAO inhibitors are prescribed, patients must be warned that the drugs interact with many other drugs (both prescription and over-the-counter) and with tyramine-containing foods, and can cause a hypertensive crisis.

In addition, the use of a TCA, SSRI, or dextromethorphan (cough suppressant) in a patient taking a MAO inhibitor can cause serotonin syndrome. An individual must wait for the effects of an MAO inhibitor to wear off before switching to a new medication. This process usually takes several weeks.

Question 32

True or false: MAOIs are considered second line drugs and are used when therapy with other drugs has failed or are contraindicated.

Answer 32

True

Question 33

What are Autoreceptor Antagonists?

Answer 33

This newer type of antidepressant drug inhibits the activation of α2 receptors.

Question 34

What are Autoreceptor Antagonists?

Answer 34

This newer type of antidepressant drug inhibits the activation of α2 receptors (they’re located on the presynaptic neuronal membrane and are autoreceptors, meaning that activation of the receptors inhibits the release of neurotransmitter from the presynaptic neuron).
- Thus, drugs that block α2 autoreceptors remove this negative feedback loop, allowing the presynaptic neuron to release more neurotransmitter into the synaptic cleft.

Question 35

Give an example of an antidepressant that is an a2 receptor antagonist.

Answer 35

Mirtazapine is an antidepressant that is an antagonist at α2 receptors.

However, mirtazapine is also a potent antagonist at some serotonin receptors and histamine receptors, as well as a moderate antagonist for α1 and muscarinic receptors, which contributes to its adverse effects.

Question 36

Using the information provided, select which antidepressant would be the most applicable to prescribe to a patient suffering from depression.

Patient Information:

• Age: 32
• Gender: male
• Current medications: the patient is on a norepinephrine reuptake inhibitor for obesity
• Additional information: the patient has a diet rich in tyramine and has been diagnosed with hypertension.

Answer Options:

a) Isocarboxazid (MAOi)
b) Venlafaxine (SNRI)
c) Imipramine (TCA)
d) Prozac (SSRI)

Answer 36

d) Prozac (SSRI)

Prozac, a common SSRI, would be the most applicable to prescribe to this patient.

Since the patient’s diet is rich in tyramine, the drug-food interaction of MAOIs with tyrosine-rich foods would pose a safety concern.

Given the hypertensive state of the patient, the adverse effect of increased blood pressure associated with SNRIs would prevent safe use of this class of antidepressant.

Lastly, since the patient is taking a norepinephrine reuptake inhibitor to treat obesity, the use of a TCA may abolish the therapeutic effects of this drug (adverse effect is weight gain).

Question 37

What are the therapeutic uses and key adverse effect(s) of the following drug classes:

• TCAs
• SSRIs
• SNRIs
• MAOIs
• Autoreceptor antagonists

Answer 37

TCAs

• Therapeutic Use: second line therapy used when other drugs have failed
• Key Adverse Effect(s): Anticholinergic, antiadrenergic and antihistaminic effects; weight gain

SSRIs

• Therapeutic Use: Most commonly used
• Key Adverse Effect(s): Serotonin syndrome, sexual dysfunction

SNRIs

• Therapeutic Use: Prescribed if pt doesn’t respond to SSRI therapy
• Key Adverse Effect(s): Increased BP and heart rate (due to NE)

MAOIs

• Therapeutic Use: Second line therapy used when other drugs have failed
• Key Adverse Effect(s): Hypertensive crisis, serotonin syndrome

Autoreceptor antagonists

• Therapeutic Use: Prescribed if don’t respond to SSRI therapy
• Key Adverse Effect(s): Antagonistat some serotonin and histamine receptors

Question 38

What is electroconvulsive therapy?

Answer 38

ECT is considered more effective than drug therapies and beneficial effects are seen in one to two weeks, instead of the four to six weeks that drug therapies required.

Question 39

True or false: ECT has minimal adverse effects and is especially valuable for psychotic depression.

Answer 39

True

Question 40

True or false:

Answer 40

ECT appears to increase BDNF levels and neurogenesis in animal models.

Question 41

How does ECT work?

Answer 41

Patients are given a muscle relaxant to prevent movement and are put under general anesthesia. Electrodes are then placed on the head to send about a 500 to 900 milliamp current through the brain, sparking a brief seizure.

Question 42

Which one of the statements regarding the selective serotonin reuptake inhibitors is correct?

a) The SSRIS are more selective than the tricyclic antidepressants
b) The SSRIs and tricyclic antidepressants have the exact same adverse effects
c) The SSRIs are equally effective in blocking the reuptake of serotonin and norepinephrine
d) The SSRIs are rarely used clinically

Answer 42

a) The SSRIS are more selective than the tricyclic antidepressants