Depression Flashcards
The monoamine theory of depression suggests that depression occurs as a result of a deficit in the monoamine neu- rotransmitters serotonin (sometimes called 5-hydroxytryptamine and abbreviated as 5-HT) and norepinephrine.
This theory arose from the findings that drugs used to treat various disease states that had the ad- verse effect of altering monoamine levels also affected mood. Further investigation revealed that by deliberately decreasing monoamine neu- rotransmitter levels, mood could be depressed, with the opposite effect occurring when monoamine levels were deliberately elevated. Thus arose the idea that depressed mood is tied to deficits in monoamine neurotransmitter signalling.
These findings ultimately led to the devel-opment of various types of drugs whose mode of action was to elevate serotonin or norepinephrine in the brain through a number of different mechanisms.
Tricyclic Anti-depressants
Tricyclic and heterocyclic anti-depressants were widely used prior to the development of SSRIs. TCAs are no longer considered first-line treatment for depression since they have more adverse effects, take longer to reach an optimal dose, and have a greater potential for lethal- ity when taken in overdose situations. They have more recently found a place in the treatment of neuropathic pain. The TCAs are thought to act primarily by blocking the reuptake of serotonin and norepineph- rine. TCAs that contain a secondary amine in their structure (e.g., nortriptyline [Aventyl, Norventyl]) primarily block the reuptake of norepinephrine, whereas those that possess a tertiary amine in their structure (e.g., amitriptyline [Elavil, Levate], imipramine [Impril]) can block the reuptake of both norepinephrine and serotonin. As shown in Figure 11.15, this block of reuptake processes results in the accumula- tion of neurotransmitter in the synapse.
Selective Serotonin Reuptake Inhibitors
The SSRIs were introduced in hopes of providing a useful tool in the treatment of depression that would display fewer adverse effects than the TCAs. As the name implies, SSRIs such as fluoxetine (Prozac), par- oxetine (Paxil), citalopram (Celexa), escitalopram (Cipralex), and flu- voxamine (Luvox) preferentially block the reuptake of serotonin from the synaptic cleft. Sertraline (Zoloft) inhibits the neuronal reuptake of serotonin but to a lesser degree also inhibits norepinephrine and do- pamine neuronal reuptake. SSRIs bind more poorly to acetylcholine muscarinic and H1 receptors than the TCAs and so tend to have fewer adverse effects in comparison. They seem to show comparable effi- cacy in treating depression without the anti-cholinergic and sedating
adverse effects that limit patient adherence to other drug regimens. However, SSRIs have other adverse effects: inappropriate stimulation of various serotonin receptors due to increased serotonin levels may lead to insomnia, low libido and failure of orgasm, and nausea or vom- iting (Rang et al., 2016) (Figure 11.13). While much less likely to cause cardiotoxicity in comparison to TCAs in overdose situations, SSRIs in high doses can cause ventricular arrhythmias that can lead to death.
Serotonin–Norepinephrine Reuptake Inhibitors
SNRIs are medications that increase both serotonin and norepinephrine levels in the brain. Venlafaxine (Effexor XR) and desvenlafaxine (Pristiq) are effective inhibitors of neuronal serotonin and norepinephrine reup- take and weak inhibitors of dopamine reuptake. Thus these neurotrans- mitters will accumulate in the synapse. Venlafaxine has the dual mech- anism of working as an SSRI at lower doses (75 mg/day), affecting the reuptake of serotonin, and as an SNRI at higher doses (150–225 mg/day), affecting the reuptake of both serotonin and norepinephrine.
Duloxetine (Cymbalta) affects norepinephrine and serotonin reuptake equally. Thus it has a greater noradrenergic effect than does venlafaxine at lower doses. This SNRI is indicated for acute and maintenance treatment of major depressive disorder, for acute treatment of GAD, for managing fibromyalgia, and for managing neuropathic pain associated with diabetic peripheral neuropathy. In fact, many SNRIs, as with the TCAs, have thera- peutic effects on neuropathic pain. The common underlying mechanism of neuropathic pain is nerve injury or dysfunction. The mechanism by which TCAs and SNRIs reduce neuropathic pain is through activation of the descending norepinephrine and serotonin pathways to the spinal cord, thereby limiting pain signals ascending to the brain.
Serotonin Modulator and Stimulator
Vortioxetine (Trintellix) is a serotonin modulator and stimulator. It affects many different serotonin receptors by inhibiting serotonin reuptake like the SSRIs, activating 5-HT1A receptors like buspirone, acting as a partial agonist at 5-HT1B receptor, and blocking 5-HT3, 5-HT1D, and 5-HT7 re- ceptors. Geriatric patients may experience an improvement of cognitive deficits independent of its anti-depressant properties. Common adverse effects include constipation, nausea, and vomiting. More serious side ef- fects are hyponatremia and, rarely, induction of hypomania or mania
Serotonin and Norepinephrine Disinhibitors
The class of drugs described as serotonin and norepinephrine disin- hibitors (SNDIs) is represented by only one drug, mirtazapine (Rem- eron). This unique drug increases norepinephrine, dopamine, and se- rotonin transmission by acting as an antagonist at central presynaptic α2-adrenergic receptors. The normal function of these receptors is to inhibit neurotransmitter release when norepinephrine binds to them. Thus any drug that prevents noradrenaline from binding to these re- ceptors will potentiate neurotransmitter release. This is why this drug is called a disinhibitor. Mirtazapine tends to have a more rapid onset of effect than do single neurotransmitter anti-depressant drugs, and this may be because it can simultaneously affect several neurotransmitter systems. Mirtazapine is a potent antagonist of 5-HT2C receptors, which may account for its anti-anxiety and anti-depressant effects, as these receptors, when activated by serotonin, typically inhibit norepineph- rine and dopamine release. In addition, this drug acts as an antago- nist at 5-HT2A and 5-HT3 receptors, activation of which are thought to mediate sexual dysfunction and nausea. Thus these effects are less likely to occur, and this is an advantage compared to other drugs used in depression. Mirtazapine is also a potent H1-receptor antagonist, which accounts for drowsiness and increased appetite resulting in weight gain being the most common adverse effects. Patients may also experience orthostatic hypotension and the occasional occurrence of anti-cholinergic adverse effects. When discontinuing use of any anti- depressant drug, but particularly SSRIs or SNRIs, patients should be weaned gradually over several weeks rather than abruptly due to the risk of discontinuation symptoms such as dizziness, agitation, anxi- ety, sleeping difficulties, nausea, excessive sweating, and fatigue. These symptoms do not indicate that an addiction has developed. Most peo- ple taking anti-depressant drugs never develop a “craving” or feel the need to increase the dose. What these symptoms do indicate is that the brain has adapted to drug-induced changes in neurotransmitter levels. These symptoms typically resolve within 4 to 6 weeks after discontinu- ation of the drug. However, if the symptoms persist beyond this time frame, there is the potential that depression is still present and that the drugs are still needed.
Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs) are a group of drugs used to treat depression that prevent the destruction of monoamines by inhib- iting the action of MAO. MAOIs illustrate the principle that drugs can have a desired and beneficial effect in the brain, while at the same time having possibly dangerous effects elsewhere in the body. To understand the action of these drugs, keep in mind the following definitions:
* Monoamines are a type of organic compound and include the neu- rotransmitters norepinephrine, epinephrine, dopamine, and sero- tonin, as well as many different food substances and drugs.
* MAO is an enzyme that degrades monoamines and is located in the nerve endings that release dopamine, serotonin, and noradrenaline.
* MAOIs inhibit the action of MAO and thereby prevent the degrada-
tion of monoamines.
The monoamine neurotransmitters, as well as any monoamine food substance or drug, are destroyed by the enzyme MAO, which is locat- ed in neurons and in the liver. Anti-depressant drugs such as phen- elzine (Nardil), tranylcypromine (Parnate), and selegiline (Eldapryl) are MAOIs that act by inhibiting the enzyme and interfering with the degradation of the monoamine neurotransmitters. This action, in turn, increases the presynaptic availability of the neurotransmitters, which leads to the neurotransmitter leaking out of the nerve endings and into the synaptic cleft. This is the mechanism by which synaptic levels of neurotransmitters are increased and by which the anti-depressant ef- fects of these drugs are thought to occur (Figure 11.16).
The use of MAO-inhibiting drugs is complicated by the fact that MAO is also present in the liver and is responsible for destroying mono- amines that enter the body via food or drugs. Of particular importance
Fig. 11.16 Monoamine oxidase inhibitors (MAOIs) prevent the break- down of monoamines and increase the availability of neurotrans- mitter in the presynaptic nerve terminal. This increased availability leads to an increase in neurotransmitter concentrations in the syn- aptic cleft.
is the monoamine tyramine, which is present in many food substances, such as aged cheeses, pickled or smoked fish, chocolate, many types of beans, and beer and wine. Tyramine, which is normally metabolized by liver and gut MAO and so never reaches a concentration in the blood high enough to cause any issues, poses a threat of hypertensive cri- sis when MAO is inhibited. The displacement of norepinephrine from neuronal storage vesicles by elevated tyramine levels and the resulting increase in norepinephrine availability are thought to cause an increase in blood pressure (pressor response). In severe cases, a hypertensive crisis can occur.
A substantial number of drugs are chemically monoamines. The dosages of these drugs are determined by the rate at which they are metabolized by MAO in the liver. In a patient taking MAOIs, the blood level of monoamine drugs can reach high levels and cause serious tox- icity. Therefore MAOIs are contraindicated with concurrent use of any other anti-depressant or sympathomimetic drugs (those that affect the sympathetic nervous system). Concurrent use with some over-the- counter products with sympathomimetic properties (e.g., oral decon- gestants) should also be avoided.
Because of the serious dangers that result from inhibition of hepatic MAO, patients taking MAOIs must be given a list of foods high in tyra- mine and drugs that must be avoided.
Other Drugs Used to Treat Depression
Bupropion is effective both as a treatment for depression and as a smoking cessation aid. It seems to act as a dopamine–norepinephrine reuptake inhibitor and also as an antagonist at nicotinic acetylcholine receptors. Since bupropion has no serotonergic action, it does not cause sexual dysfunction. Adverse effects include insomnia, tremor, anorexia, and weight loss. Bupropion is contraindicated in patients with a seizure disorder, in patients with a current or prior diagnosis of bulimia or anorexia nervosa, and in patients undergoing abrupt dis- continuation of alcohol or sedatives (including benzodiazepines), ow- ing to the increased seizure risk.
Trazodone (Trazodone) is a serotonin antagonist and reuptake in- hibitor (SARI) and is not a first choice for treatment of depression. Its anti-depressant effects are seen only at high therapeutic doses. An ad- verse effect of trazadone is sedation, which arises from its ability to act as a potent H1-receptor antagonist. However, this can prove to be useful in those patients who suffer from insomnia. Another common adverse effect is orthostatic hypotension due to α1-adrenergic receptor antago- nism. Its potent blockade of these receptors can lead to rare cases of priapism (painful, prolonged penile erection).
Ketamine is a potential new drug treatment for depression and has been called one of the most important discoveries in mood research over the last half century (Wei et al., 2020). Unlike traditional anti-depressant drugs, ketamine induces a rapid, long-lasting reversal of symptoms and appears to treat suicidal ideation (Duman, 2018). Additionally, these ef- fects occur in patients resistant to traditional depression medications.
Ketamine is a dissociative anesthetic that is used in selective medi- cal procedures. Its widespread use as an anesthetic is limited because it can induce hallucinations and delirium during emergence from an- esthesia in some patients. This property is sought after in those that use ketamine illicitly and ketamine has become a popular “club drug.”
Ketamine is known to block a type of glutamate receptor (the N- methyl-d-aspartate [NMDA] receptor). While this appears to be an im- portant mechanism in its anti-depressant effects, it is clearly not the whole story as other drugs that block these receptors do not show the same ef- fects on depression. Experimental evidence suggests that a number of ad- ditional targets, including the brain-derived neurotrophic factor (BDNF) system, likely play a role (Hashimoto, 2020; Zanos & Gould, 2018).
