Psychiatry

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Chapter 23 Psychiatry

Selective Serotonin Reuptake Inhibitors (SSRIs)

Description

The selective serotonin reuptake inhibitors (SSRIs) inhibit the reuptake of serotonin in the synaptic cleft.

Prototype and Common Drugs

image Prototype: fluoxetine
image Others: paroxetine, fluvoxamine, sertraline, citalopram, escitalopram

MOA (Mechanism of Action)

image The monoamine hypothesis suggests that depression is caused by a deficiency of synaptic neurotransmitters such as serotonin (5-HT), norepinephrine, and dopamine. Serotonin, in particular, is associated with mood.
image Normally, 5-HT is released from presynaptic vesicles into the synaptic cleft, where it travels to postsynaptic receptors.
image Once released from these postsynaptic receptors, 5-HT is removed from the synaptic cleft by reuptake transporters located on the presynapse. Once it is taken up presynaptically, it is degraded (Figure 23-1).
image SSRIs bind to this reuptake transporter, preventing the removal of 5-HT and leading to increased 5-HT available to bind to postsynaptic receptors.
image The clinical efficacy of antidepressants is delayed a few weeks when compared with their pharmacological actions. It is therefore hypothesized that the efficacy of these agents in the treatment of depression is related to a downstream effect.
image There are a variety of theories as to what this downstream effect might be, although most involve either a change in receptor density or fundamental changes at the cellular level, including a reorganization of neurons.
image One of the examples of altered receptor density occurs with presynaptic 5-HT inhibitory autoreceptors. These autoreceptors reduce 5-HT release when bound by 5-HT. Excess 5-HT in the synapse because of SSRI therapy leads to down-regulation of this inhibitory autoreceptor and enhanced release of 5-HT into the synapse.
image

Figure 23-1

Pharmacokinetics

image The SSRIs typically have long half-lives (24 hours or longer), allowing for once-daily administration.
image Fluoxetine has an active metabolite (norfluoxetine) and has the longest half-life (>100 hours) of all SSRIs. Fluoxetine is more prone to drug interactions, and more caution must be exercised to ensure a proper washout period after fluoxetine discontinuation.

Indications

image Major depressive disorder
image Obsessive compulsive disorder
image Generalized anxiety disorder

image Including panic disorder

image Bulimia nervosa

Contraindications

image SSRIs and monoamine oxidase inhibitors (MAOIs): SSRIs increase serotonin concentrations in the synapse, whereas MAOIs inhibit the breakdown of serotonin. Concomitant use can therefore lead to excessive serotonin (see details in Side Effects). When switching from an SSRI to an MAOI, or vice versa, allow for a washout period of at least 1 to 2 weeks.
image SSRIs and thioridazine (an antipsychotic): Thioridazine elicits QT interval prolongation, and fluoxetine in particular enhances this effect by inhibiting the metabolism of thioridazine. A washout period of at least 5 weeks should elapse before someone who was on fluoxetine should be started on thioridazine, and fluoxetine should not be initiated for at least 2 weeks after discontinuation of thioridazine. The seriousness of these drug interactions has led to the withdrawal of thioridazine in many markets.
image Citalopram and pimozide: The combination of these two agents is associated with a greater risk of QT interval prolongation, although the mechanism is unknown.

Side Effects

Serious

image Serotonin syndrome (SS) is a rare but potentially life-threatening elevation in serotonin, most commonly caused by concomitant use of SSRIs and MAOIs. Symptoms include:

image Hyperthermia
image Muscle rigidity
image Myoclonus
image Rapid fluctuations in vital signs (because of autonomic instability)
image Rapid fluctuations in mental status (confusion, irritability, extreme agitation, delirium, coma)

image Suicide: No causal link has been established. A common theory is that the patient may experience an increase in energy or ideation before experiencing the antidepressant effects, prompting suicidal acts instead of thoughts.

Non-Serious

image Sexual dysfunction may be both mechanical, as serotonin inhibits functions such as erections, ejaculation, lubrication, and orgasm, and central, as serotonin has an inhibitory effect on dopamine, a neurotransmitter believed to play an important role in arousal. Note: sexual dysfunction can also accompany depression.
image Gastrointestinal (GI) distress: Serotonin receptors are also found in the gut, and serotonin appears to have an effect on GI motility (cramping, diarrhea, nausea) that becomes intolerable in some patients. Nausea and vomiting are also likely mediated by activation of serotonin receptors in the CNS.
image Agitation, insomnia: These effects are likely via stimulation of central serotonin receptors. The intensity of this side effect can vary among the SSRI. In some cases, these side effects can be somewhat beneficial in patients who have fatigue or apathy and hypersomnia.

Important Notes

image As with other antidepressants, when an SSRI is being discontinued, the dose should be tapered gradually in order to avoid discontinuation symptoms, including dizziness, nausea, headache, and others. The incidence and severity appears to vary between SSRI, and longer half-life agents such as fluoxetine appear to be less likely to induce a discontinuation syndrome.
image The use of SSRIs and other antidepressants in children is currently under review. The focus of concern is the propensity to elicit behavioral and emotional changes, including an increased risk of self-harm and suicide. All antidepressants thus carry safety warnings for use in pediatrics.
image Although they all increase serotonin levels, the SSRIs are a heterogeneous class and should not be considered interchangeable. For example, citalopram is considered to be the most serotonin-selective of the SSRIs, although it does have affinity for H1 receptors. Fluoxetine and sertraline have the highest affinity for dopamine D2 receptors, whereas paroxetine has the most potent anticholinergic effects. The clinical consequences of this pharmacologic heterogeneity have yet to be fully characterized.
image SS and neuroleptic malignant syndrome (NMS), two rare but very serious complications of SSRIs or MAOIs and antipsychotics, respectively, share some common features including fever, increased muscle tone (more hyperreflexia with SS), and autonomic instability.

Advanced

Drug Interactions

image The SSRIs inhibit multiple CYP450 isozymes. Fluoxetine and paroxetine inhibit the CYP2D6 isoenzyme, and this can lead to clinically important drug interactions with drugs such as tricyclic antidepressants (TCAs), carbamazepine, or vinblastine. There is also a very serious interaction with thioridazine (see Contraindications).
image Other isozymes inhibited include:

image CYP1A2 by fluvoxamine
image CYP2C9, CYP2C19, and CYP3A4 by fluvoxamine and fluoxetine

Evidence

Depression

image A 2005 Cochrane review (132 trials, N = 14,391 participants) compared fluoxetine with other antidepressants. The review found that among SSRIs, sertraline and paroxetine were more efficacious than fluoxetine in improving depression rating scores. Findings related to side effects were as follows:

image Sweating was more common with fluoxetine than with paroxetine.
image Nausea was more common with fluoxetine than with fluvoxamine.
image Weight loss was greater with fluoxetine than with SSRIs as a class.

image The same review found fluoxetine to be less efficacious than venlafaxine or mirtazapine; fluoxetine caused less dry mouth, dizziness, sweating, and nausea compared with venlafaxine.
image A 2007 Cochrane review (20 trials, N = 2000 patients) compared SSRIs with the TCA amitriptyline. The review found SSRIs and amitriptyline were equally efficacious but also found SSRIs to be more tolerable than amitriptyline.

Premenstrual Syndrome

image A 2007 Cochrane review (31 trials, N = 844 participants) found that SSRIs were highly effective in the treatment of premenstrual symptoms, both physical and behavioral, compared with placebo. There were 2.5 times as many withdrawals because of adverse events among SSRI-treated subjects as among placebo-treated subjects.

Depression in Elderly People or Seniors

image A 2006 Cochrane review (32 trials) compared various antidepressants to one another in depressed older adults. There were no statistically significant differences in efficacy between SSRIs and TCAs. There were fewer withdrawals because of side effects in the SSRI arms compared with TCAs.

FYI

image The SSRIs were the first class of antidepressants that were discovered using “rational drug design.” The strategy was based on the observation that TCAs inhibited noradrenaline (NA) or 5-HT reuptake to various extents. Scientists then discovered some nontricyclic compounds that were also reuptake inhibitors, acting on either NA or 5-HT to varying degrees. This led to the approval of the first such agent, zimeldine, which was withdrawn from the market after a few years.

Tricyclic Antidepressants (TCAs)

Description

TCAs are a class of antidepressants with a common chemical (tricyclic) structure and mode of action.

Prototype and Common Drugs

image Prototype: amitriptyline
image Others: desipramine, imipramine, nortriptyline, clomipramine, trimipramine, doxepin, maprotiline

MOA (Mechanism of Action)

image The monoamine hypothesis suggests that depression is caused by a deficiency of synaptic neurotransmitters such as serotonin (5-HT), NA, and dopamine. Serotonin, in particular, is associated with mood.
image Normally, 5-HT and NA are released from presynaptic vesicles into the synaptic cleft, where they travel to postsynaptic receptors.
image Once released from these postsynaptic receptors, 5-HT and NA are removed from the synaptic cleft by reuptake transporters located on the presynapse.
image The TCAs inhibit the reuptake of serotonin (5-HT) and NA into the presynaptic cell body, increasing the amount of 5-HT and NA available to bind to postsynaptic receptors (Figure 23-2).
image TCAs antagonize other receptors: muscarinic, histamine (H1), adrenergic (α1) receptors. This accounts for their extensive list of side effects.
image The clinical efficacy of antidepressants is delayed when compared with their pharmacologic actions. It is therefore hypothesized that the efficacy of these agents in the treatment of depression is related to a downstream effect.
image A variety of theories exist regarding what this downstream effect might be, although most involve either a change in receptor density or fundamental changes at the cellular level, including a reorganization of neurons.
image

Figure 23-2

Pharmacokinetics

image Nortriptyline is a metabolite of amitriptyline.
image Desipramine is a metabolite of imipramine.
image TCAs are metabolized by CYP450 enzymes and are therefore prone to drug interactions with inhibitors or inducers of these enzymes.

Indications

image Depression
image Chronic pain (as an adjunct)

Contraindications

image Avoid concomitant use of TCAs and MAOIs: TCAs increase serotonin concentrations in the synapse, whereas MAOIs inhibit the breakdown of serotonin. Concomitant use can therefore lead to excessive serotonin. When switching from a TCA to an MAOI, or vice versa, allow for a washout period of at least 2 weeks.

Side Effects

image Anticholinergic:

image Dry mouth
image Confusion
image Urinary retention
image Constipation
image Blurred vision
image Increased intraocular pressure (IOP)

image Sedation: via blockade of histamine (H1) receptors
image Serious: Cardiovascular toxicities are typically only seen when high doses are administered (see “Important Notes”). In high doses TCAs impair cardiac conduction, leading to a widening of the QRS complex and heart block, often accompanied by hypotension
image Orthostatic hypotension: related to blockade of α1 receptors

Important Notes

image The TCAs are grouped as a class based on their chemical structure. Although as a class they are considered to be 5-HT or noradrenaline reuptake inhibitors, the degree of reuptake inhibition differs markedly among agents. See Table 23-1.
image Similarly, the affinities for blockade of receptors that mediate the side effects experienced by patients also differ markedly among agents. See Table 23-2.
image Because of their prominent antimuscarinic effects, TCAs should be used with caution in conditions that would be exacerbated by cholinergic antagonism: urinary retention, benign prostatic hyperplasia (BPH), glaucoma (closed angle), and increased IOP.
image TCAs are potentially fatal in overdose situations and have one of the highest mortality rates associated with overdose. Cardiac arrhythmias, hypotension, and central nervous system (CNS) involvement are the most common events associated with TCA overdose. TCAs undergo slow absorption; therefore a patient may arrive on his or her own at an emergency department with a fatal dose of TCAs that has not yet been absorbed. This propensity of TCAs to be fatal in overdose is particularly concerning, given the general FDA warning about increased risk of suicidality with antidepressant use.

TABLE 23-1 Extent of Serotonin and Noradrenaline Reuptake Inhibition among TCAs

Agent Serotonin (5HT) Noradrenaline(NA)
Clomipramine +++ +
Amitriptyline ++ ±
Imipramine + +
Trimipramine 0 +
Doxepin + ++
Nortriptyline ± ++
Desipramine 0 +++

+ symbols indicate extent of reuptake inhibition, with +++ exhibiting the greatest reuptake inhibition + exhibiting the least. 0 indicates no inhibition of the reuptake transporter for that neurotransmitter.

TABLE 23-2 Extent of Antagonism of Muscarinic, Histamine (H1), and α-1 Adrenergic Receptors among TCAs

image

Advanced

Drug Interactions

image Most TCAs exhibit some degree of CP450 enzyme inhibition. The most prominent inhibitors are amitriptyline, imipramine, clomipramine, and doxepin, mainly at CYP2C19.

Evidence

Depression

image A 2007 Cochrane review (20 trials, N = 2000 patients) of amitriptyline versus other antidepressants found it to be at least as efficacious as SSRIs but also found it to have more side effects.
image Similar results were seen in comparisons of amitriptyline versus other TCAs or heterocyclic drugs. Amitriptyline was as efficacious as these agents but had more side effects.

FYI

image TCAs have been around for 50 years. Imipramine was the first TCA synthesized, and it was based on the tricyclic structure of the antipsychotic chlorpromazine. A study in 1958 found imipramine lacked efficacy in psychosis, but, surprisingly, a subgroup of patients with depression improved on imipramine. TCAs became the drugs of choice for treating depression for the next 30 years.
image Nomenclature note: TCAs with an amine (N-) group on the middle ring end with -amine, whereas agents with an oxygen (O-) on the middle ring have -ox- in their name.

Serotonin Noradrenaline Reuptake Inhibitors (SNRIs)

Description

The SNRIs are reuptake inhibitors that increase the concentration of both serotonin (5-HT) and noradrenaline (NA) in the synaptic cleft.

Prototype and Common Drugs

image Prototype: venlafaxine
image Others: desvenlafaxine, duloxetine, milnacipran

MOA (Mechanism of Action)

image The monoamine hypothesis suggests that depression is caused by a deficiency of synaptic neurotransmitters such as serotonin (5-HT), NA, and dopamine. Serotonin, in particular, is associated with mood.
image Normally, 5-HT and NA are released from presynaptic vesicles into the synaptic cleft, where they travel to postsynaptic receptors.
image Once released from these postsynaptic receptors, 5-HT and NA are removed from the synaptic cleft by reuptake transporters located on the presynapse. Once they are taken up presynaptically, they are degraded (Figure 23-3).
image SNRIs bind to these reuptake transporters, preventing the removal of 5-HT and NA and leading to increased availability to bind to postsynaptic receptors.
image Venlafaxine has much higher affinity for the serotonin reuptake transporter, and at low doses acts more like an SSRI. It is not until higher doses are used that it also blocks noradrenaline reuptake.
image Conversely, milnacipran blocks serotonin and noradrenaline reuptake equally, whereas the other agents in this class fall somewhere between these two.
image The clinical efficacy of antidepressants is delayed when compared with their pharmacologic actions. It is therefore hypothesized that the efficacy of these agents in the treatment of depression is related to a downstream effect.
image A variety of theories exist regarding what this downstream effect might be, although most involve either a change in receptor density or fundamental changes at the cellular level, including a reorganization of neurons.
image

Figure 23-3

Pharmacokinetics

image Compared with the SSRIs, the SNRIs have shorter elimination half-lives. Venlafaxine is available in an extended-release(ER) dosage form.
image Venlafaxine has an active metabolite: O-desmethylvenlafaxine. The parent and its metabolites have lower clearance in patients with hepatic cirrhosis and severe renal disease, requiring a dose reduction.
image Desvenlafaxine is primarily metabolized by glucuronidation, with only minor involvement from CYP3A4.
image Milnacipran undergoes limited metabolism.

Indications

image Depression
image Generalized anxiety disorder (GAD)
image Social anxiety disorder
image Panic disorder

Contraindications

image SNRIs and MAOIs: MAOIs inhibit the breakdown of serotonin. Concomitant use can therefore lead to excessive serotonin. When switching from an SNRI to an MAOI, or vice versa, allow for a washout period of at least 1 to 2 weeks.

Side Effects

image Gastrointestinal (GI) distress, attributed to inhibition of serotonin reuptake, appears to be most common with venlafaxine. Stimulation of serotonin receptors in the brain likely mediates nausea. Serotonin receptors are also found in the gut, and serotonin appears to have an effect on GI motility that becomes intolerable in some patients, leading to cramping and diarrhea.
image Dizziness may occur although the mechanism is unknown.
image Somnolence may be secondary to sleep disturbances, although the mechanism is unknown.
image Insomnia may occur due to stimulation of 5-HT receptors in the CNS. Both the length and quality of sleep may be impaired.
image Sexual dysfunction, attributed to inhibition of serotonin reuptake, appears to be most common with venlafaxine. It may be both mechanical, as serotonin inhibits functions such as erections, ejaculation, lubrication, and orgasm, and central, as serotonin has an inhibitory effect on dopamine, a neurotransmitter believed to play an important role in arousal.
image Sweating: The mechanism for this effect has not been established.
image Dry mouth is likely caused by NA.
image Sustained hypertension is dose related. The elevation in blood pressure is likely caused by the pressor effects of increased NA. Patients should have blood pressure monitored.

Important Notes

image When an SNRI is being discontinued, the dose should be tapered gradually in order to avoid discontinuation symptoms, including aggression, agitation, convulsions, dysphoric mood, electric shock sensations, and others. These symptoms have been particularly evident with venlafaxine.
image The theory behind the development of the SNRIs was to try and increase the levels of two neurotransmitters (serotonin, noradrenaline) simultaneously, while avoiding many of the bothersome side effects of the TCAs, which also act as reuptake inhibitors of these two neurotransmitters. There is evidence to suggest that dual reuptake inhibition is more efficacious than selective inhibition (see Evidence section).
image Reboxetine was the first noradrenaline selective reuptake inhibitor, approved in Europe for treatment of depression. It was rejected by the U.S. Food and Drug Administration (FDA) because of concerns over poor efficacy.
image All antidepressants carry an FDA warning about increased suicidality, particularly in younger (<25 years of age) patients. The mechanism has not been established and there is not enough data to determine whether a lower risk exists for some antidepressants compared with others. These concerns must also be balanced against the potential for increased risk of completed suicides in untreated depression.

Advanced

Pharmacogenetics

image Venlafaxine is extensively metabolized by CYP450, especially CYP2D6. CYP2D6 is subject to genetic polymorphisms; therefore metabolism varies among patients.

Drug Interactions

image Duloxetine and (to a lesser extent) venlafaxine are inhibitors of CYP2D6.

Evidence

Venlafaxine versus Fluoxetine for Depression

image A 2005 Cochrane review (10 trials, N = 1831 participants) compared fluoxetine with venlafaxine. The authors found venlafaxine to be significantly better than fluoxetine (an SSRI) for improving depression rating scores. Some side effects were more common with venlafaxine than with fluoxetine, including dry mouth, dizziness, sweating, and nausea.

Venlafaxine for Generalized Anxiety Disorder

image A 2003 Cochrane review (8 trials, N = 2058 participants) examined the efficacy of various antidepressants for generalized anxiety disorder (GAD). Based on two trials, the authors found venlafaxine to be statistically better than placebo for treatment response, assessed by Clinical Global Impression (CGI) scores.

Milnacipran for Depression

image A 2009 Cochrane review (16 trials, N = 2277 participants) compared milnacipran with other antidepressants for depression. Milnacipran was associated with fewer withdrawals because of adverse events (a measure of tolerability) compared with the TCAs (odds ratio [OR] 0.55), and weak evidence suggested fewer adverse events of sleepiness or drowsiness, dry mouth, or constipation versus these agents.

FYI

image The next frontier in antidepressant drug design is the development of triple rather than dual reuptake inhibitors. The third neurotransmitter of interest is dopamine. These drugs are already in clinical trials.
image Serotonin (5-HT3) antagonists are used to treat nausea and vomiting, and to treat irritable bowel syndrome.

Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs)

Description

Noradrenergic and specific serotonergic antidepressants (NaSSAs) are antidepressants that increase the concentration of noradrenaline and serotonin in the synaptic cleft.

Prototype

image Mirtazapine

MOA (Mechanism of Action)

image NaSSAs have a dual mechanism of action:

image Inhibition of α2 autoreceptors and heteroreceptors

• An autoreceptor is a receptor that when bound by ligand reduces release of that ligand into the synapse. The α2 receptor is a classic example of an autoreceptor, as when it is bound by noradrenaline (NA) it inhibits NA release.
• A heteroreceptor is like an autoreceptor, although when bound it can mediate the release of other neurotransmitters in addition to its own ligand.
• Thus inhibition of these autoreceptors and heteroreceptors prevents the negative feedback of NA on 5-HT and NA neurotransmission (Figure 23-4). Thus neurotransmission is sustained.

image Antagonism of serotonin (5-HT2) and 5-HT3 postsynaptic receptors

• This leads to enhanced 5-HT1 neurotransmission.
• Blockade of 5-HT3 receptors may lead to reduced incidence of gastrointestinal side effects.

image Mirtazapine has a low affinity for muscarinic and dopaminergic receptors. However, it has high affinity for histamine (H1) receptors. These receptors all mediate many of the side effects of antidepressants, although dopamine receptors play a role in mood disorders.
image

Figure 23-4

Pharmacokinetics

image Clearance is reduced in patients with liver disease (by 30%) or kidney disease (by 30% to 50%) and in the elderly. Dose reductions should therefore be considered in these populations.

Side Effects

image Sedation occurs because of blockade of histamine receptors. It tends to predominate at lower doses, as increasing NA at higher doses counteracts this effect.
image Increased appetite may be due to H1 antagonism, although the mechanism is unclear. Weight gain may be due to H1 antagonism, although the mechanism is unclear.

Serious, Rare

image Severe neutropenia is rare.

Important Notes

image With its distinct mechanism, mirtazapine is seen as an alternative for patients intolerant to SSRIs. It has the advantage of lower incidence of sexual dysfunction, but it also has greater propensity for weight gain compared with SSRIs.
image Because of its sedative and appetite-stimulating effects, mirtazapine may theoretically be a more useful antidepressant in the elderly, as these patients often have depression accompanied by insomnia and weight loss.
image Although they are not thought of as being in the same class, the “atypical” antidepressants trazodone and nefazodone have some similarities to mirtazapine in their mechanisms of action. Both block 5-HT2 postsynaptic receptors and promote serotonin neurotransmission, although trazodone and nefazodone enhance serotonin by inhibiting its reuptake.
image Nefazodone is also believed to inhibit the reuptake of noradrenaline. Nefazodone was withdrawn from North American markets in the early 2000s for hepatotoxicity, and trazodone, once a very popular antidepressant, has been supplanted by newer agents such as the SSRIs.
image All antidepressants carry an FDA warning about increased suicidality, particularly in younger (<25 years of age) patients. The mechanism has not been established and there is not enough data to determine whether a lower risk exists for some antidepressants compared with others. These concerns must also be balanced against the potential for increased risk of completed suicides in untreated depression.

Evidence

Versus Fluoxetine for Depression

image A 2005 systematic review compared SSRIs with newer-generation antidepressants and included three studies of mirtazapine. Mirtazapine had a better response rate than fluoxetine in two small studies (265 patients), and there were no differences between the two agents with respect to tolerability.

FYI

image Mirtazapine is derived from mianserin, an antidepressant that has been available for many years in Europe.

Monoamine Oxidase Inhibitors (MAOIs)

Description

MAOIs are a heterogeneous group of agents that inhibit the monoamine oxidase (MAO) enzyme.

Prototypes and Common Drugs

Selective (MAO-B)

image Prototype: selegiline
image Others: rasagiline

Selective (MAO-A), Reversible

image Prototype: moclobemide

Nonselective, Irreversible

image Prototype: phenelzine
image Others: tranylcypromine

MOA (Mechanism of Action)

image MAO degrades catecholamines, serotonin, and other endogenous amines in the CNS as well as in the periphery.
image There are two key isoenzymes:

image MAO-A degrades epinephrine, norepinephrine, and serotonin.
image MAO-B degrades phenylethylamine.
image Both degrade dopamine.

image The purpose of MAO inhibition is therefore to increase levels of these substances within the body, specifically the CNS.

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