Chapter 23 Psychiatry
Selective Serotonin Reuptake Inhibitors (SSRIs)
MOA (Mechanism of Action)
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.
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).
Pharmacokinetics
The SSRIs typically have long half-lives (24 hours or longer), allowing for once-daily administration.
Contraindications
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.
Side Effects
Serious
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:
Non-Serious
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.
Important Notes
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.
Advanced
Drug Interactions
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).
Evidence
Depression
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:
Premenstrual Syndrome
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.
FYI
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.
MOA (Mechanism of Action)
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.
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).
Contraindications
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.
Important Notes
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.
Similarly, the affinities for blockade of receptors that mediate the side effects experienced by patients also differ markedly among agents. See Table 23-2.
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
Evidence
FYI
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.
Serotonin Noradrenaline Reuptake Inhibitors (SNRIs)
MOA (Mechanism of Action)
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.
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).
Pharmacokinetics
Compared with the SSRIs, the SNRIs have shorter elimination half-lives. Venlafaxine is available in an extended-release(ER) dosage form.
Desvenlafaxine is primarily metabolized by glucuronidation, with only minor involvement from CYP3A4.
Side Effects
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.
Important Notes
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.
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).
Evidence
Venlafaxine versus Fluoxetine for Depression
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
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
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.
Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs)
MOA (Mechanism of Action)
NaSSAs have a dual mechanism of action:
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.
Side Effects
Sedation occurs because of blockade of histamine receptors. It tends to predominate at lower doses, as increasing NA at higher doses counteracts this effect.
Important Notes
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.
Monoamine Oxidase Inhibitors (MAOIs)
Description
MAOIs are a heterogeneous group of agents that inhibit the monoamine oxidase (MAO) enzyme.
