Major depressive disorder (MDD)
is a serious mood disorder that consists of unremitting depression or periods of depression that do not alternate with periods of mania
Bipolar disorder
is a serious mood disorder characterized by cyclical periods of mania and depression. It impacts men and women equally, and is often difficult to treat
Affective disorders - depressive symptoms
- People who are depressed might have little energy, and move and talk slowly. At other times, they might pace restlessly and cry a lot.
- They may be unable to experience pleasure and lose their appetite for food and sex. Sleep may be disturbed and even some bodily functions can be depressed.
- Severely depressed people might feel extremely unworthy and have strong feelings of guilt.
Affective disorders - manic symptoms
- People who are manic might have a sense of euphoria that does not seem justified by their circumstances. The diagnosis of mania is partly a manner of degree. They might experience nonstop speech and motor activity, as well as grandiosity.
- People experiencing mania quickly change from topic to topic and often have delusions, but they lack the severe thought disorganization seen in schizophrenia.
- People can become irritable, angry or defensive if they are contradicted, go long periods without sleep, work furiously on projects that are often unrealistic, or engage in other increased, goal directed behaviours
Genetic factors of affective disorders
- The tendency to develop an affective disorder is a heritable characteristic
- Close relatives of individuals diagnosed with affective disorders are 10 times more likely to develop an affective disorder than people without diagnosed relatives
- If one monozygotic twin has depression, the likelihood that the other twin has an affective disorder is 69%. For dizygotic twins, this is only 13%
Genetic factors - gene variations
- Findings from genetic studies are mixed but suggest several chromosomes might be affected.
- A review of GWAS work implicated the RORA gene involved in the control of circadian (time of day rhythms) - links to major depressive disorder
- RORB also involved in circadian rhythms might also be implicated in rapid cycling bipolar disorder in children
- Suggests circadian rhythms might influence the development of affective disorders
Biological treatments for affective disorders
A number of biological methods can be used to treat affective disorders, suggesting that in part they have a physiological basis • Pharmacological Treatments • Electroconvulsive Therapy • Vagus Nerve Stimulation • Transcranial Magnetic Stimulation • Deep Brain Stimulation
Pharmacological treatments - antidepressants - MAO inhibitors
• In the 40s, the drug iproniazid was found to treat the
symptoms of depression
• It inhibits the activity of MAO (enzyme) which destroys excess monoamine neurotransmitter substances in terminal buttons
• Therefore, iproniazid acts as an agonist that increases levels of norepinephrine, dopamine and serotonin in synapse
• MAO inhibitors have very negative side-effects
Pharmacological treatments - antidepressants - reuptake inhibitors
- Next, tricyclic antidepressants were discovered
- They inhibit the reuptake of norepinephrine and serotonin into terminal buttons
- Like MAO inhibitors, they are agonists that increase levels of neurotransmitter in the synapse and allow for continued binding with the postsynaptic cell
- However, they inhibit the reuptake of NTs other than Ne and 5-HT which can be problematic
Pharmacological treatments - antidepressants - SSRIs
• Recently, Selective serotonin reuptake inhibitors
(SSRIs) were developed (e.g. Prozac, Celexa)
• These drugs specifically inhibit reuptake of serotonin and are used for their antidepressant properties, as well as for their ability to reduce the symptoms of obsessive compulsive disorder and social phobia
- SSRIs and SNRIs have fewer nonspecific actions,
and therefore fewer side effects, than the tricyclic antidepressants and MAO inhibitors.
Pharmacological treatments - antidepressants - SNRIs
• There are also serotonin and norepinephrine reuptake inhibitors (SNRIs) that specifically inhibit the reuptake of norepinephrine and serotonin without significantly affecting the reuptake of other neurotransmitters (e.g. duloxetine)
- SSRIs and SNRIs have fewer nonspecific actions,
and therefore fewer side effects, than the tricyclic antidepressants and MAO inhibitors.
Antidepressants and therapeutic lag
- All antidepressants increase the amount of monoamine in the synapse which binds to receptors and autoreceptors
- This occurs within minutes or hours of ingesting a drug
- So why do antidepressants take several weeks before they begin to work? (This is called the therapeutic lag)
Antidepressants and therapeutic lag explained (serotonin)
• Possibility that increased levels of 5-HT across several weeks desensitizes presynaptic autoreceptors making them less sensitive to serotonin
• Normally, autoreceptors regulate NT release (when
stimulated they stop the release of NT from terminal
buttons)
• Therefore, desensitization would mean more NT is
released over time and contribute to therapeutic effects seen after several weeks
Pharmacological treatments - ketamine
• Ketamine may be used for treatment-resistant
depression (A major depressive disorder whose
symptoms are not relieved after trials of several different treatments)
• Research suggests that it is effective but short-term treatment for depression
Pharmacological treatments - lithium
• Lithium is often used to treat bipolar disorder
• It is most effective in treating the manic phase of a bipolar affective disorder; once mania is eliminated, depression usually does not follow
Lithium does not suppress typical feelings of emotions = patients can feel and express joy and sadness in response to life events
• 70-80% of patients show a positive response to lithium within two weeks
Side effects of lithium
• Lithium can have adverse side effects such as hand
tremors, weight gain, excessive urine production, and
thirst
• Toxic doses result in nausea, diarrhea, motor
incoordination, confusion and coma
• Therefore, blood levels of lithium regularly checked so they don’t overdose
Why lithium works to treat bipolar disorder
• The exact reasons why lithium works are largely unknown
• Some suggest that it stabilizes the population of certain classes of NT receptors in the brain and prevents wide shifts in neural sensitivity
• Others suggest that it increases the production of
neuroprotective proteins that help prevent cell death
Electroconvulsive therapy
- ECT involves a brief electrical shock used to induce a seizure that can reduce depressive symptoms
- First, a patient receives an anaesthetic, given a drug which paralyses muscles, and attached to a respirator
- Next, electrodes are placed on the scalp (non-speech dominant hemisphere) and a pulse of electricity triggers a seizure
- A patient usually receives 3 treatments a week until maximal improvement is seen (6-12 treatments)
Electroconvulsive therapy compared to antidepressants
- In contrast to antidepressants, ECT is has rapid effects
- Can reduce symptoms of severe treatment resistant depression in a single treatment or over a few days
- Remission of symptoms is greater than 50%, but relapse is common
- Prolonged or excessive ECT causes brain damage and long term memory impairments
- Improved methods also lower memory impairments associated with the treatment
Vagus nerve stimulation
- Electrical stimulation of the Vagus Nerve (a cranial nerve) has been used to reduce depression symptoms
- It is an indirect form of brain stimulation –painless with no seizures
- 80% of axons in the vagus nerve are afferent, so if you stimulate the vagus nerve you will activate several regions of the brain stem
- Good for treatment-resistant depression
Transcranial magnetic stimulation
• Studies suggest that TMS can be used to provide similar benefits to that of ECT without introducing cognitive and memory impairments
• Several studies suggest that TMS to the PFC reduces
symptoms of depression without negative side effects
• However, TMS has a response rate of less than 30%, and long term relapse rates are quite high (similar to ECT)
Deep brain stimulation
- Mayberg et al. (2005) implanted electrodes just below the subgenual ACC (part of the medial PFC)
- Response to deep brain stimulation via these electrodes was fast and it increased with time.
Deep brain stimulation results
- One month after surgery, 35% showed improvement and 10% showed complete remission
- Six months after surgery, 60% showed improvement and 35% showed remission
- DBS has also been applied to the NAC (dopamine – response to pleasurable stimuli) – reduced symptoms in 50% of patients who previously had no response to antidepressants
Subgenual ACC and depression
- Mayberg et al.’s work (DBS treatment) suggests that the frontal cortex (specifically the subgenual ACC) plays a critical role in the development of depression
- The subgenual ACC might serve as a focal point in the network of brain regions involved in mood regulation
- Depressed patients show hyperactivity of subgenual ACC along with decreased activity in other regions of frontal cortex (Dorsolateral PFC, the ventrolateral PFC, the ventromedial PFC, and the orbitofrontal cortex)
- Antidepressant treatments reliably decrease activity of subgenual ACC
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