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. The efficacy of these agents is a result of their actions within the CNS, whereas the side effects are largely mediated by their actions outside of the CNS.
image MAO inhibition can be either reversible or irreversible. Irreversible binding leads to a much more prolonged effect (Figure 23-5).
image The benefits and adverse effects of MAOIs will therefore be determined by their selectivity for these isoenzymes and whether the inhibition is reversible.
image Therefore MAO-A inhibitors are thought to work by increasing levels of amines such as norepinephrine and serotonin.
image Because the MAO-B enzyme has no effect on epinephrine, norepinephrine, or serotonin, at normal doses MAO-B inhibitors increase dopamine levels in the CNS without increasing levels of these other neurotransmitters. Parkinson’s disease is characterized by a relative deficiency of dopamine in the CNS; therefore MAO-B inhibitors are used to treat Parkinson’s disease.
image At higher doses, MAO-B inhibitors begin to lose selectivity, and thus begin to inhibit MAO-A as well as MAO-B. Therefore in higher doses, MAO-B inhibitors can also be used to treat depression.
image It is also believed that byproducts such as peroxide associated with dopamine degradation lead to further CNS damage in Parkinson’s disease. Therefore an additional proposed mechanism of the MAO-B inhibitors is to inhibit the production of these toxic metabolites. There is also some work suggesting that these toxic byproducts may play a role in the pathophysiology of depression, suggesting a potential disease-modifying role for MAO inhibition in this condition, as well.
image

Figure 23-5

Pharmacokinetics

image Moclobemide undergoes extensive hepatic metabolism by acetylation.
image Selegiline is also metabolized in the liver, primarily by CYP2B6 and CYP1A2. Two metabolites have stimulant properties: l-amphetamine and l-methamphetamine. Selegiline is also available in a transdermal patch.
image Rasagiline is metabolized primarily by CYP1A2.

Indications

image Depression (atypical)

MAO-B Inhibitors

image Parkinson’s disease

Contraindications

image Drug interaction: with sympathomimetics: nonselective MAOIs may potentiate the hypertensive effects of sympathomimetics, leading to a hypertensive crisis that can be fatal. Methylphenidate, dopamine, epinephrine, norepinephrine, and similar agents (methyldopa, l-dopa, l-tryptophan, l-tyrosine, phenylalanine) should be avoided.
image Foods with tyramine: See Side Effects.

Side Effects

image Sleep disturbances include insomnia and reduction in rapid eye movement (REM) sleep. The insomnia is likely a central stimulatory effect from the increased monoamines, although a mechanism has not been established. Moclobemide, a reversible and selective MAO-A inhibitor, may cause fewer problems with sleep.
image Weight gain is a common side effect of antidepressants; likely, increased monoamines play a role, but the mechanism has not been established.
image Postural hypotension: The mechanism has not been established. This can be problematic in elderly patients, leading to falls. Note that this side effect is distinct from the hypertensive crisis, described later, which occurs because of an interaction with other agents and has a very specific mechanism.
image Sexual disturbances: The mechanism has not been established, although several antidepressants that affect monoamine levels have this side effect, and enhanced serotonin is believed to mediate sexual dysfunction with these agents.

Serious

image Hypertensive crisis occurs because of a drug-drug or drug-food interaction, leading to increased levels of norepinephrine and subsequent rapid elevation in blood pressure. Before the triggering factors (tyramine-rich foods) were identified, this interaction limited the utility of these agents.

Important Notes

image MAO-A in the gut breaks down tyramine, a chemical that stimulates the release of norepinephrine. Tyramine is typically found in aged foods such as cheese, wine, beer, yogurt, and yeast. Ingestion of these foods leads to increased tyramine, and because its breakdown is inhibited, there is increased norepinephrine release, leading to hypertensive crisis.
image Little MAO-B is found in the gut; therefore an MAO-B selective inhibitor will have minimal effect on the metabolism of dietary tyramine. Although MAO-B selectivity reduces the risk of hypertensive crisis, this selectivity is lost at higher doses.
image Reversible MAOIs lead to much less accumulation of tyramine and thus are considered to have minimal risk for hypertensive crisis resulting from the wine-cheese reaction.
image A novel approach to avoiding accumulation of dietary tyramine is to bypass the GI MAO-A altogether by use of a patch.
image Linezolid, the first in a new class of antibiotics called the oxazolidinones, is also an MAOI. Concomitant use of these agents should therefore be avoided.
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

MAO-B Inhibitors versus Dopaminergics for Early Parkinson’s Disease

image A 2009 Cochrane review (two trials, N = 593 patients) compared MAO-B inhibitors with a dopamine agonist or levodopa in patients with early Parkinson’s. No difference in deaths was found between selegiline and either agent, but patients treated with selegiline were more likely to need add-on therapy during follow-up than patients receiving levodopa (OR 12.02) or a dopamine agonist (OR 2.00). Motor fluctuations were reduced by MAO-B inhibitors versus levodopa (OR 0.55) but not dopamine agonists. Withdrawals because of adverse events were less common with MAO-B inhibitors compared with dopamine agonists (OR 0.11).

FYI

image MAOIs were among the earliest antidepressants, although their discovery was accidental. The first MAOI was actually developed to treat tuberculosis (TB). The drug was ineffective for TB but had “psychoenergizing” effects and was also discovered to be an MAOI.
image Phenylethylamine is a neurotransmitter believed to play a role in mood, although its exact role in the body has not been fully characterized. It is found in some “comfort foods,” particularly chocolate, and is also sold as a supplement in some jurisdictions.

Noradrenaline and Dopamine Reuptake Inhibitors (NDRIs)

Description

Noradrenaline and dopamine reuptake inhibitors (NDRIs) are agents that inhibit the reuptake of both dopamine and norepinephrine. The NDRIs fall under a broader classification of atypical antidepressants, so named because they do not fit into any of the other antidepressant classes.

Prototype

image Bupropion

MOA (Mechanism of Action)

image Bupropion inhibits the presynaptic reuptake of both dopamine (DA) and noradrenaline (NA), leading to increased levels of both of these neurotransmitters in the synaptic cleft (Figure 23-6).
image The clinical efficacy of all antidepressants is delayed a few weeks 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 With respect to smoking cessation, dopamine is believed to be the key neurotransmitter in the reward pathway associated with addiction. It is believed that the increased levels of dopamine in the synapse help to mimic the reward associated with smoking, thus attenuating some of the withdrawal symptoms associated with abstinence.
image There is also some evidence that bupropion is a nicotinic receptor antagonist. By blocking the nicotinic receptor, bupropion prevents exogenously administered nicotine from binding to this receptor, attenuating the reward that smokers gain from nicotine.
image

Figure 23-6

Pharmacokinetics

image Bupropion is extensively metabolized, primarily through the CYP2B6 isozyme.

Indications

image Depression
image Smoking cessation

Contraindications

image Seizures: Bupropion may lower the seizure threshold, so it must be avoided in individuals with a history of seizures or who are prone to seizures:

image Patients undergoing drug or alcohol withdrawal
image Prior diagnosis of bulimia or anorexia nervosa

image MAOIs: MAOIs inhibit the breakdown of neurotransmitters such as dopamine and norepinephrine. Simultaneous inhibition of the reuptake and breakdown of these neurotransmitters can lead to complications such as hypertensive crisis.
image Thioridazine: Bupropion may inhibit the metabolism of thioridazine, increasing the risk of ventricular arrhythmia and sudden cardiac death caused by elevated thioridazine levels.

Side Effects

image Dry mouth may be caused by increased noradrenergic transmission.
image Nausea is a frequent side effect of dopaminergic agents, likely through a central effect.
image Insomnia may occur due to the stimulating effects of enhanced NA.

Rare, Serious

image Seizures: A small risk of seizures has been observed with the use of bupropion. The risk increases with higher doses.

Important Notes

image Bupropion is unique among antidepressants as an inhibitor of dopamine reuptake, leading to increased dopamine levels in the synapse. This has lead to its use as a smoking cessation therapy, the indication for which it is most commonly prescribed.
image Another unique feature of bupropion is its lack of serotonergic effects. Antidepressants are known for eliciting sexual dysfunction, and this side effect has been attributed to their serotonergic properties. In clinical trials bupropion appears to have a lower propensity for sexual side effects compared with SSRIs and other serotonergic antidepressants.
image In many jurisdictions, bupropion is marketed under two separate names, Wellbutrin and Zyban. Wellbutrin is prescribed for depression, and Zyban is used for smoking cessation. Because of the risk of overdose signs and symptoms, specifically seizures, care must be taken to ensure that patients do not take Wellbutrin and Zyban concomitantly.
image Reboxetine is an antidepressant that selectively targets noradrenaline reuptake. It has received marketing approval in Europe but not in the United States 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.

Evidence

Smoking Cessation: Antidepressants versus Placebo

image A 2007 Cochrane review (53 trials) compared antidepressants to placebo or alternative pharmacotherapies for smoking cessation or relapse prevention. The review included 31 RCTs of bupropion versus placebo or no treatment for smoking cessation, finding that bupropion doubled the odds of cessation across these studies (OR 1.94). In four trials, nortriptyline also improved the odds of quitting smoking (OR 2.34).

Smoking Cessation: versus Varenicline (Partial Nicotine Agonist)

image A 2007 Cochrane review (7 trials, N = 7267 participants) assessed the efficacy and tolerability of varenicline versus other interventions and placebo for smoking cessation. The authors included three double-blind randomized controlled trials that compared bupropion with varenicline and when the data from these studies were combined, found that more varenicline subjects were abstinent or continuously abstinent from smoking at 12 months compared with bupropion (relative risk [RR] 1.52).

FYI

image Bupropion does not fit well into other drug classes; therefore it is often inappropriately lumped together with other agents. The simplest and most accurate classification is as an atypical agent.

Lithium

Description

Lithium is a chemical element used primarily in the treatment of bipolar disorder.

Prototype

image Lithium

MOA (Mechanism of Action)

image Decades after the discovery of lithium’s utility in bipolar disorder, the mechanism behind its efficacy is still poorly understood.
image One thing that is clear is that lithium has multiple effects on second messengers (Figure 23-7):

image Fine-tuning of cyclic adenosine monophosphate (cAMP)

• Because lithium causes an increase in baseline cAMP and a decrease in stimulation of cAMP formation, lithium is able to fine-tune cAMP levels

image Depletion of inositol

• Inhibition of inositol monophosphatases, leading to a reduction in synaptic signaling through receptors that are coupled to phosphoinosital (PI) turnover

image Increasing evidence suggests that lithium may have a neuroprotective role in the CNS, although the connection between this and its efficacy in mania is unclear at present. Lithium has been reported to increase expression of the antiapoptotic protein bcl-2.
image Another neuroprotective factor thought to mediate the effects of lithium is the enzyme glycogen synthase kinase 3 (GSK-3). GSK-3 regulates numerous cellular processes such as gene transcription, synaptic plasticity, apoptosis, and circadian rhythms, among others. Lithium’s inhibition of GSK-3 is believed to have a neuroprotective effect.
image

Figure 23-7 GDP, Guanosine diphosphate; GTP, guanosine triphosphate; ATP, adenosine triphosphate; IP1, inositol monophosphate; IP2, inositol diphosphate; IP3, inositol triphosphate; DAG, diacylglycerol; PLC, phospholipase C; PIP, phosphoinositol phosphate; PIP2, phosphoinositol bisphosphate.

Pharmacokinetics

image Lithium has a narrow therapeutic index; therefore, small increases in lithium levels can lead to toxic effects. The effective plasma concentration is 0.6 to 1.25 mEq/L; moderate toxicity can occur starting at 1.5 mEq/L, and severe toxicity at 2 mEq/L.
image Lithium is almost exclusively excreted in the urine, with <1% in feces and smaller amounts excreted in sweat. Lithium is filtered freely, with 80% being reabsorbed in the nephron. In patients with normal renal function, 50% to 80% of a single dose is excreted in urine within 24 hours. Renal lithium excretion varies among individuals and is generally decreased in older patients and increased in younger patients.

Indications

image Bipolar disorder
image Treatment-refractory depression (adjunctive)

Contraindications

image In the presence of the following conditions, lithium should be used only with extreme caution, when other treatments have failed:
image Significant renal or cardiovascular disease: Lithium is cleared almost exclusively by the kidneys; therefore the risk of toxicity is high in those with compromised renal function. Lithium is also arrhythmogenic in some individuals (see later).
image Severe dehydration or sodium depletion: Lithium toxicity can arise in cases in which the body tries to conserve sodium (see Pharmacokinetics for details).

Side Effects

Serious

image Acute lithium toxicity causes nausea, vomiting, diarrhea, renal failure, neuromuscular dysfunction, ataxia, tremor, confusion, delirium, and seizures.
image Arrhythmia: Lithium inhibits K+ entry into myocytes, which leads to abnormal repolarization and abnormal T-waves. This can also lead to intracellular K+ depletion, and extracellular hyperkalemia, increasing the risk of sudden cardiac arrest from small changes in potassium levels.
image Nephrotoxicity: Nephrogenic diabetes insipidus (symptoms include polyuria and polydipsia) may occur after long-term therapy. The kidneys become insensitive to ADH. Irreversible kidney damage may also occur because of tubulo-interstitial nephropathy.
image Weight gain: The mechanism has not been established.
image Nausea, GI irritation: The mechanism has not been established.
image Memory disturbances, cognitive dulling: The mechanism has not been established.

Important Notes

image Lithium is unique among all psychotropic agents in that it lacks any sedative, euphoriant, or depressive effects in normal individuals who do not suffer from psychiatric illness.

Advanced

Drug Interactions

image A drug interaction between lithium and diuretics has a unique mechanism. In response to decreased volume secondary to diuretic use, the kidneys will try to retain Na+ in an effort to retain water. When the kidney reabsorbs Na+, it will also reabsorb Li+, as it has a hard time differentiating between these two monovalent cations.
image The clinical significance of this interaction is enhanced by the fact that lithium has a narrow therapeutic index, so only a small increase in Li+ levels can lead to toxicity. The same problem, enhanced Li+ reabsorption, can occur in patients with low Na+ levels or who are hypovolemic.

Evidence

Bipolar Disorder

image A 2007 Health Technology Assessment (United Kingdom) review (45 trials) compared various mood stabilizers in preventing relapse in bipolar disorder. The authors found that lithium, valproate, lamotrigine, and olanzapine were more efficacious than placebo as maintenance therapy for relapse prevention. Lithium and olanzapine were effective for preventing manic relapses, but not for depressive relapses.

Lithium versus Placebo for Maintenance Treatment in Mood Disorders

image A 2001 Cochrane review (nine trials, N = 825 participants) compared lithium to placebo for treatment of mood disorder. Lithium was most beneficial at preventing relapse when used in bipolar disorder (OR 0.29). No significant benefit for relapse prevention was found in unipolar disorder. Because of low event rates, no conclusions could be drawn about the impact of lithium on suicide.

FYI

image The discovery of lithium, one of the most important drugs in psychiatry, is an example of serendipity and scientific acumen. In the late 1940s an Australian scientist was administering lithium salt to guinea pigs to increase the solubility of urates. After noting that lithium made the animals lethargic, he decided to give lithium carbonate to agitated or manic psychiatric patients. Lithium appeared to have a positive effect on mania, paving the way for its use for this indication.

First-Generation Antipsychotics

Description

Antipsychotics are agents used in the treatment of psychosis. First-generation antipsychotics are also referred to as typical antipsychotics.

Prototypes and Common Drugs

Phenothiazines

image Prototype: chlorpromazine
image Others: thioridazine, fluphenazine, perphenazine, trifluoperazine, pipotiazine, pericyazine, prochlorperazine

Butyrophenones

image Prototype: Haloperidol
image Others: droperidol

Thioxanthenes

image Prototype: Flupenthixol
image Others: thiothixene, zuclopenthixol

MOA (Mechanism of Action)

image Dopamine is believed to play a key role in schizophrenia and thought disorders. Patients with schizophrenia experience hallucinations (visual, auditory, and tactile experiences in the absence of stimulation—for example, seeing something that is not there) and delusions (beliefs that are not true).
image There are several dopamine pathways in the CNS, but the following are key in both the efficacy and side effects of antipsychotic therapy:

image Mesolimbic (behavior, mood)
image Nigrostriatal (movement) Tuberoinfundibular (prolactin release) (Figure 23-8)

image All antipsychotics are antagonists at dopamine D2 receptors. It is the antagonism of D2 receptors in the mesolimbic pathway that is thought to alleviate the positive symptoms of schizophrenia. Blockade of D2 receptors in other pathways is believed to result in many of the side effects of typical antipsychotics.
image Recently, subtypes of the D2 receptor have been identified: D3, and D4. Collectively, D2, D3, and D4 receptors are often referred to as the “D2-like receptors.” These receptors all have different distributions in the brain and subtle differences in pharmacology that are still not fully understood.
image First-generation antipsychotics antagonize numerous other receptors, including adrenergic and cholinergic as well as histamine H1 receptors. Although it is still unclear to what extent, if any, antagonism of these receptors contributes to the efficacy of antipsychotics, they have a clear role in mediating many of the side effects associated with these agents.
image

Figure 23-8

Pharmacokinetics

image Most antipsychotics are highly lipophilic (and therefore easily enter the brain) and accumulate in well-perfused tissues such as brain and lung. Because of their lipophilic nature, most antipsychotics have the potential to cross the placenta and to enter breast milk.
image A number of first-generation antipsychotics have active metabolites, including haloperidol, chlorpromazine, and thioridazine. The activity of these active metabolites may complicate the correlation of plasma drug monitoring with clinical efficacy.
image Elimination half-lives are typically in the 12- to 24-hour range, so all first-generation antipsychotics permit once-daily dosing.
image The elderly as well as the very young may have an impaired ability to metabolize antipsychotics.
image Several first-generation antipsychotics are available in parenteral formulations, both standard intravenous and intramuscular formulations to achieve faster onset, and depot formulations to achieve prolonged effects (Table 23-3).

TABLE 23-3 Onset and Duration of Action of Depot and Intramuscular Formulations of First- Generation Antipsychotics

  Onset Duration
Depot
Haloperidol decanoate   3 weeks
Fluphenazine decanoate   3-4 weeks
Pipotiazine palmitate   3-6 weeks
Intramuscular (IM)
Haloperidol IM 30-45 minutes  
Chlorpromazine IM 15-30 minutes  
Fluphenazine IM <1 hour  

Indications

Common

image Psychosis (from any cause, such as schizophrenia or drug use)
image Acute agitation, delirium, acute mania (haloperidol)
image Nausea and vomiting (droperidol, chlorpromazine, prochlorperazine)

Rare

image Tourette’s syndrome (haloperidol)
image Intractable hiccups (chlorpromazine, haloperidol)

Contraindication

image Severe CNS depression: Typical antipsychotics tend to have CNS depressant effects and should be avoided in conditions of decreased level of consciousness.

Side Effects

Common

image Anticholinergic effects include dry mouth, constipation, difficulty urinating, and loss of accommodation.
image α-Antagonism: Orthostatic hypotension and ejaculatory failure may occur.
image Sedation is probably due to H1 receptor antagonism, and is more common with the phenothiazines.
image Extrapyramidal syndrome (EPS): Blockade of dopamine receptors in the basal ganglia leads to Parkinson-like symptoms such as slow movement (bradykinesia), stiffness, and tremor.
image Tardive dyskinesia: Slow-developing, often permanent dyskinesia typically appears well after initiation of therapy (months to years). This effect is characterized by repetitive, involuntary movements of the face, arms, and trunk. One theory is that D2 receptors become hypersensitive after prolonged blockade. It can be very resistant to treatment.
image Hyperprolactinemia: Dopamine inhibits prolactin secretion. Antidopaminergic drugs will therefore have the potential to increase prolactin secretion, resulting in the following:

image Amenorrhea (loss of menstrual period)
image Galactorrhea (production of breast milk in women only, not in association with pregnancy)
image Gynecomastia (feminization of men)
image Decreased libido (sex drive)

Rare but Serious

image Neuroleptic malignant syndrome (NMS) is a rare but life-threatening side effect. The mechanism is not fully understood, but it is thought to be a result of inhibition of dopamine in the hypothalamus, an area responsible for temperature regulation.

image The condition is characterized by:

• Decreased or altered level of consciousness
• Increased muscle tone (rigidity)
• Fever
• Myoglobinemia and death, which occur in about 10% of these cases
• Autonomic instability (variable heart rates and blood pressures)

image Agranulocytosis: A decreased white blood cell count can occur as a result of antipsychotics. This will result in undesired immunosuppression and requires discontinuation of the drug. This effect is observed with chlorpromazine and other phenothiazines (<0.1% of patients).
image Cardiac conduction abnormalities such as long QT (thioridazine, droperidol) are a rare but serious side effect that has led to the market withdrawal of these agents in some jurisdictions. Antipsychotics appear to affect cardiac potassium channels, and these two agents are likely to have a greater impact on these channels than other agents.

Important Notes

image There is increasing concern about the metabolic side effects associated with long-term use of antipsychotics. The risk of some of these side effects may be lower with first-generation antipsychotics compared with second generation antipsychotics (see Evidence section).
image After many years of research, the exact causes of schizophrenia remain a mystery. There are several theories as to the neurochemical origins; most involve serotonin and dopamine playing a key role. Glutamate, an excitatory neurotransmitter, has also become a major focus of research, based on the observation that N-methyl-d-aspartate (NMDA) antagonists exacerbate cognitive impairment and psychosis in patients with schizophrenia. Glutamate receptor agonists are currently in development for schizophrenia.

Advanced

Drug Interactions

image Chlorpromazine and haloperidol are metabolized through CYP2D6 and CYP3A4, fluphenazine through CYP2D6, and trifluoperazine through CYP1A2; therefore caution should be exercised when using known inducers or inhibitors of these isozymes.
image Haloperidol is an inhibitor of CYP3A4. Fluphenazine inhibits CYP2D6.

Evidence

Risk of Diabetes in First- versus Second-Generation Antipsychotics

image A 2008 systematic review (11 studies) compared diabetes risk among various antipsychotics. The majority of studies in this review were cross-sectional or retrospective cohort studies, which somewhat limits confidence in the analysis. The authors found an increased risk of diabetes in patients taking second-generation versus first-generation antipsychotics (RR 1.32). Data were insufficient to include aripiprazole, ziprasidone, and amisulpride in this analysis. Relative risks ranged from a low of 1.16 with risperidone to a high of 1.39 with clozapine. Differences in risk were statistically significant for all second-generation agents except risperidone.

FYI

image Phenothiazines are among the earliest synthetic drugs, first synthesized in the late nineteenth century as a result of the development of aniline dyes. The first phenothiazines were antihistamines, and it was their sedative effects that led to their use in agitated psychiatric patients.
image Chlorpromazine was developed in 1950 for use in anesthesia. Shortly after, it was used in psychiatry for agitation and anxiety. Initially its efficacy in these patients was attributed to its sedative properties, but it was later determined that chlorpromazine was effective in the treatment of a variety of psychoses.
image The extrapyramidal system technically refers to the basal ganglia, but the term was coined in 1912 and originally referred to movement disorders in patients with liver disease.

Second-Generation Antipsychotics

Description

Antipsychotics are used to treat disorders of thought. Second-generation antipsychotics are also called atypical antipsychotics.

Prototype and Common Drugs

image Prototype: clozapine
image Others: olanzapine, quetiapine, risperidone, paliperidone, ziprasidone, aripiprazole

MOA (Mechanism of Action) (Figure 23-9)

image Dopamine is believed to play a key role in schizophrenia and thought disorders. Patients with schizophrenia experience hallucinations (visual, auditory, and tactile experiences in the absence of stimulation—for example, seeing something that is not there) and delusions (beliefs that are not true).
image The second-generation antipsychotics are believed to antagonize several different receptors, primarily dopamine and serotonin (5-HT).
image There are several dopamine pathways in the CNS, but the following are key in both the efficacy and side effects of antipsychotic therapy:

image Mesolimbic (behavior)
image Nigrostriatal (movement)
image Tuberoinfundibular (prolactin release)

image All antipsychotic drugs are D2-receptor antagonists, and it is believed that blockade of D2 receptors in the mesolimbic pathway leads to an antipsychotic effect, addressing the positive symptoms of schizophrenia.
image Recently, subtypes of the D2 receptor have been identified: D3, and D4. Collectively, D2, D3, and D4 receptors are often referred to as the “D2-like receptors.” These receptors all have different distributions in the brain and subtle differences in pharmacology that are still not fully understood.
image The role of serotonin (specifically 5-HT2A) antagonism in the efficacy of antipsychotics is less well understood. Unlike many of the first-generation agents, the second-generation agents are potent antagonists of 5-HT2A receptors. Because second-generation agents are better at treating the negative symptoms of schizophrenia, it is believed that blockade of 5-HT2A receptors may contribute to the improvement in negative symptoms.
image It is also thought that 5-HT2A blockade might affect nigrostriatal dopamine release, leading to reduced extrapyramidal symptoms (EPS). Other theories accounting for the different propensities among antipsychotics to cause EPS include different D2 binding affinities and anticholinergic activity.
image Second-generation antipsychotics, as first-generation antipsychotics, antagonize numerous other receptors, including adrenergic and cholinergic (particularly olanzapine and clozapine) as well as histamine H1 receptors. Although it is still unclear to what extent, if any, antagonism of these receptors contributes to the efficacy of atypical antipsychotics, they have a clear role in mediating many of the side effects associated with these agents.
image

Figure 23-9

Pharmacokinetics

image The second-generation antipsychotics vary in bioavailability, elimination half-life, and metabolism.
image All are eliminated by hepatic metabolism, and all but one rely on the CYP450 system for their metabolism. Paliperidone is the active metabolite of risperidone and is not reliant on CYP450 for its metabolism.
image A long-acting intramuscular injection form of risperidone is available. It is administered every 2 weeks. Because of the delay in achieving therapeutic plasma concentrations, it is suggested that oral risperidone be given for the first 3 weeks after the initial IM injection.

Indications

image Schizophrenia
image Inappropriate behavior associated with dementia (risperidone)
image Acute mania associated with bipolar disorder (risperidone, olanzapine, quetiapine)

Contraindications

All

image History of neuroleptic malignant syndrome (see Side Effects)

Clozapine

image Myeloproliferative disorders are a contraindication because of the risk of agranulocytosis with clozapine (see later).
image Liver disease or failure is a contraindication.
image Severe renal or cardiac disease: See the discussion of cardiovascular toxicity.
image Paralytic ileus is a contraindication because of significant anticholinergic effects.
image Seizure disorders: Clozapine appears to lower the seizure threshold, thus promoting seizures.

Ziprasidone

image QT prolongation: Ziprasidone may prolong the QT interval and therefore should be avoided in patients with a history of QT prolongation (see Side Effects). Ziprasidone should also be avoided in patients with recent significant cardiac events for this reason.

Side Effects

image The side effect profile of atypical antipsychotics varies widely owing to their heterogeneous receptor binding profiles.

Serious

All Agents

image Increased mortality in elderly patients: These agents are associated with increased risk of death in elderly patients with dementia, from a variety of causes, largely cardiovascular or infectious. The mechanism is still unclear at this time.
image Endocrine:

image Weight gain occurs because of suppression of satiety and other factors. The receptor responsible has not been established, although the focus is currently on H1.
image Exacerbation of diabetes, hyperglycemia: Diabetes (type 2) may simply be secondary to weight gain, but these agents might also affect glucose transporters.
image Dyslipidemia is probably secondary to weight gain.
image Hyperprolactinemia: Dopamine inhibits prolactin release, so dopamine blockade leads to increased prolactin release.

image Neuroleptic malignant syndrome (NMS) is a rare but critically life-threatening effect seen with both first- and second-generation antipsychotics. The mechanism is not fully understood, but it is thought to be caused by inhibition of dopamine in the hypothalamus, an area responsible for temperature regulation. It is characterized by:

image Decreased or altered level of consciousness
image Fever
image Increased muscle tone (rigidity)
image Autonomic instability
image Myoglobinemia and death (in about 10% of cases)

Clozapine

image Agranulocytosis can be fatal and necessitates weekly or biweekly blood monitoring of all patients taking clozapine. The risk is about 1% in the first 3 months and then decreases to about 0.01% after 1 year. Although agranulocytosis is a risk with all antipsychotics, it is much more common with clozapine compared to other agents.
image Seizures may occur.

Quetiapine

image Cataracts: No causal link has been established.

Ziprasidone

image QT interval prolongation: As a class, the second-generation agents are considered to prolong the QT interval; however, ziprasidone is the only member of this class in which this adverse effect has lead to consistent clinically relevant events.

Nonserious Adverse Effects, Common to All Agents (to Varying Extents)

image Orthostatic hypotension is most commonly observed with clozapine. This side effect is probably caused by α1 blockade
image EPS secondary to D2 receptor blockade in the nigrostriatal region. The incidence of EPS is lower with second-generation compared with first-generation agents, and among the second-generation agents, is lowest with clozapine.
image Sedation is probably caused by H1 antagonism. Among second-generation antipsychotics, clozapine is believed to cause the most sedation.
image Anticholinergic effects are most commonly observed with clozapine. Exercise caution in patients with conditions exacerbated by cholinergic blockade, such as glaucoma (narrow angle), paralytic ileus, or enlarged prostate.

Important Notes

image Clozapine is itself considered to be atypical among atypical antipsychotics, with a unique side effect profile and a greater degree of success in treatment-resistant patients. Thus many consider clozapine to be in a class of its own.
image The second-generation antipsychotics are considered “atypical” because they do not cause EPS to the same extent as first-generation agents. It is important to note that EPS has still been observed with these agents, and the mechanistic rationale for why atypical agents are less likely to cause EPS has not been established.
image The incidence of tardive dyskinesia tends to vary with age and drug class used. The incidence in children is low with second-generation antipsychotics, in adults it is lower with second-generation than first-generation agents, and first- and second-generation agents have the same annual incidence in the elderly.
image The weight gain associated with antipsychotics can be significant and lead to long-term health issues such as type 2 diabetes and cardiovascular disease. It appears that olanzapine and clozapine may cause the greatest degree of weight gain among the second-generation agents.
image Conversely, ziprasidone may be least associated with weight gain, and in fact has been associated with weight loss in some trials. The adverse lipid effects seen with other agents in this class are also not seen with ziprasidone. However, ziprasidone is associated with QT interval prolongation, a potentially fatal adverse effect. This creates an interesting dilemma—choosing between rare short-term side effects that are potentially fatal, and more common long-term side effects that have serious, but less readily identifiable consequences.

Advanced

Drug Interactions

image Clozapine is metabolized by CYP1A2 and CYP3A4, and its metabolism is affected by notable inducers or inhibitors of these isozymes, such as the following:

image Inhibitors: erythromycin, cimetidine, azole antifungals, protease inhibitors, SSRIs
image Inducers: carbamazepine, phenytoin, rifampin, omeprazole, cigarette smoking

image Olanzapine is a weak inhibitor of CYP1A2, CYP2D6, and CYP3A4, but it has not been shown to have significant effects on other drugs. The metabolism of olanzapine has been affected by the following:

image Inhibitor: fluvoxamine

image Quetiapine is metabolized mainly by CYP3A4. Its metabolism is affected by the following:

image Inhibitor: azole antifungals, macrolide antibiotics
image Inducer: carbamazepine, phenytoin

image Risperidone is metabolized by CYP2D6 and has a major active metabolite. The metabolism of risperidone is affected by the following:

image Inhibitors: fluoxetine, paroxetine
image Inducers: carbamazepine

Evidence

Schizophrenia

image A recent (2006) systematic review of atypical antipsychotics found differences in effectiveness among agents in this class:

image Clozapine reduced the risk of suicide in high-risk schizophrenic patients compared with olanzapine.
image Risperidone had a faster onset of effect, shorter length of hospitalization and lower rates of discontinuation than olanzapine. However, maintenance use of olanzapine was associated with a lower risk and longer time to treatment than risperidone or quetiapine.

image A 2010 Cochrane review (50 studies, N = 9476 participants) compared olanzapine with other second-generation agents. Fewer participants treated with olanzapine had to be rehospitalized compared with quetiapine (NNT 11, 2 RCTs) and ziprasidone (NNT 17, 2 RCTs) but not clozapine. Olanzapine improved symptoms more than aripiprazole (2 RCTs), quetiapine (10 RCTs), risperidone (15 RCTs) and ziprasidone (4 RCTs) but not amisulpride or clozapine. Olanzapine elicited more weight gain than all others except clozapine, and more EPS than quetiapine, but less EPS than risperidone and ziprasidone.

Psychosis and Aggression Associated with Alzheimer’s Disease

image A 2006 Cochrane review (10 trials) found that although risperidone and olanzapine were useful in reducing aggression and risperidone was useful for psychosis, these agents also had serious harmful effects such as a higher incidence of stroke as well as EPS and other adverse events. There were insufficient data to assess cognitive function.

Safety in Patients with Alzheimer’s Disease or Dementia

image A 2005 systematic review (15 trials, N = 5100 patients) examined the use of atypical antipsychotics versus placebo in patients with Alzheimer’s disease or dementia. The risk of death was higher in patients taking atypicals (3.5% versus 2.3% of patients died) compared with placebo (OR 1.54).

FYI

image Clozapine is widely recognized as being the atypical antipsychotic with the greatest efficacy; however, its 50-year history has been tumultuous. From its early trials in the 1960s, clozapine was noted as being “atypical” because of its lack of disabling neurologic side effects. However, the lack of EPS was interpreted as an indication that it lacked antipsychotic efficacy as well, as at that time the two effects were considered to be connected.
image The first serious impediment to clozapine’s widespread use was the discovery of orthostatic hypotension. After this hurdle was overcome, reports of deaths from severe blood disorders began to emerge from Finland in the mid-1970s. The incidence of agranulocytosis was much higher in the Finnish population, shedding light on a rare toxicity that had previously been overlooked. The manufacturer of clozapine dropped its request for approval by the FDA, and the drug became available only through a “compassionate use” program.
image Interest in clozapine reemerged in North America in the 1980s, because of both the rising health care costs of mental illness and the success the Europeans had had using a monitoring program to minimize harm. Clozapine was approved by the FDA in 1989 and continues to be a vital drug for those refractory to other therapies.

Benzodiazepines

Description

The benzodiazepines (BZDs) are a group of agents with primarily anxiolytic, sedative, and hypnotic effects.

Prototypes and Common Drugs

image Prototype: lorazepam
image Others: alprazolam, bromazepam, chlordiazepoxide, clonazepam, diazepam, flurazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam

Antagonist

image Flumazenil

Atypical or Nonbenzodiazepines

image Prototype: zopiclone
image Others: zolpidem, eszopiclone, zaleplon

MOA (Mechanism of Action)

image γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS. GABA binds to three different types of receptors: GABAA, GABAB, and GABAC.

image Binding of GABA to GABAA receptors leads to the opening of the chloride (Cl−) channel, facilitating Cl− influx and cellular hyperpolarization (making the inside more negative).
image Hyperpolarization of a cell decreases the probability that the cell can be subsequently depolarized by other incoming excitatory signals; this will have a net inhibitory effect Figure 23-10).

image BZDs also have their own receptor directly on the Cl− channel. Binding of BZDs to this BZD receptor enhances the effects of GABA at the GABAA receptor.
image BZDs are unable to activate the GABAA receptor on their own; therefore BZDs have no pharmacologic effects on the Cl− channel when GABA is absent.
image Atypical BZDs also act as GABA enhancers but bind to a different subunit of the BZD receptor than typical BZDs.
image For example, the atypical BZDs zolpidem and zopiclone bind to the BZ1 (ω1) receptor subtype of the BZD receptor.
image

Figure 23-10

Pharmacokinetics

image The elimination half-lives of BZDs differ greatly (see Table 23-4).
image The elimination half-lives of BZDs play a key role in determining how they are used (see Important Notes for further discussion).
image Lorazepam, midazolam, and diazepam are all available for intravenous administration. Onset time is quite short (minutes) when these drugs are given intravenously.
image Patients who use alcohol regularly will have significant resistance to BZDs and require larger doses to achieve the same effect as would be achieved in an otherwise identical patient who does not use alcohol regularly.

TABLE 23-4 Elimination Half-Lives of Various Benzodiazepines

Half-life Duration Half-Life (Hours)
Short Half-Life Agents
Triazolam 2-3
Intermediate Half-Life Agents
Alprazolam 12-15
Lorazepam 10-20
Oxazepam 10-20
Temazepam 10-40
Chlordiazepoxide* 15-40
Long Half-Life Agents
Diazepam* 20-80
Flurazepam* 40-100

* These agents have active metabolites

Indications

image Sedation for:

image Anxiety states (called anxiolytics when used this way)
image Procedures
image Acute agitation

image Insomnia
image Acute seizure treatment
image Alcohol withdrawal

image BZDs are the first-line treatment for alcohol withdrawal and delirium tremens (DTs).

image Muscle relaxation

image Useful for patients with restless leg syndrome and muscle spasms

Contraindications

image Addiction to other drugs or past history of BZD addiction is a contraindication.
image Sleep apnea: Patients with central or obstructive sleep apnea have abnormal respiratory centers and may be at risk for exacerbations of sleep apnea if given sedatives of any type.

Side Effects

image Amnesia—the impaired ability to remember—may be a desired effect for medical procedures.
image Respiratory depression may be seen at higher doses and can lead to respiratory acidosis, particularly in those with chronic obstructive pulmonary disease (COPD).
image Decreased blood pressure, increased heart rate: These cardiovascular effects are seen at higher doses and are likely mediated by a decrease in vascular resistance (midazolam) or cardiac output (diazepam).
image Daytime sedation: This is a continuation of the intended therapeutic effect of BZDs. The extent of sedation is largely a function of the half-life and frequency of use.
image Disinhibition may occur.

Important Notes

image BZDs are not analgesics. They do not reduce the perception of pain.
image The ability of BZDs to cause amnesia is advantageous in the performance of uncomfortable procedures, as the patient is still able to comply with instructions but does not retain memory of the procedure afterward.
image Although the clinical effects of the BZDs resemble and overlap with those of other sedative-hypnotics, BZDs are more effective as anxiolytics.
image Because BZDs are CNS depressants (inhibitors), and seizures are states of pathologically elevated electrical activity in the brain, BZDs are ideally suited for treating seizures.
image Tolerance, dependence, and withdrawal are all of major concern with BZDs. Discontinuation of BZDs can be particularly unpleasant for the patient and, typical of drug withdrawal, is characterized by side effects that are the opposite of those intended with therapy—that is, insomnia, anxiety, tremor, and (rarely) seizures.
image Longer half-life agents are less prone to cause withdrawal than agents with a short half-life, as the longer half-life agents allow time for receptor density to return to predrug levels before the drug is completely eliminated. However, for certain indications, particularly when used as hypnotics, shorter-acting agents are preferable because of their reduced propensity for a hangover effect (i.e., grogginess).
image Balancing the need to minimize withdrawal while avoiding BZD hangover is tricky, and it is strongly recommended that short-acting hypnotics such as triazolam be used sparingly.
image Flumazenil is a BZD antagonist that is used to reverse the sedative effects of BZDs.

Advanced

image BZDs can act as either agonists or inverse agonists at the BZD binding site on the GABAA receptor.
image GABAA and GABAC receptors are found on ion channels and are therefore said to be ionotropic. GABAB receptors are G protein coupled and are said to be metabotropic.

Evidence

Generalized Anxiety Disorder

image A 2007 systematic review examined three commonly used BZDs—diazepam (12 trials), lorazepam (7 trials), and alprazolam (4 trials)—versus placebo. All included studies were DBRCTs. The authors chose withdrawal from study as their primary outcome measure, and fewer patients treated with BZD withdrew for any reason (RR 0.78) or for lack of efficacy (RR 0.29). However, more BZD-treated patients withdrew because of an adverse event compared with placebo (RR 1.54).

Older Adults with Insomnia

image A 2005 systematic review examined the risks and benefits of sedative use for insomnia in adults 60 years of age or older. The review included 20 DBRCTs, covering sleep quality, sleep time, awakenings, or latency of sleep onset. BZDs (830 participants) and non-BZDs (1099 participants) were the main interventions used, versus placebo (468 participants). Based on four studies, the authors calculated a number needed to treat (NNT) of 13 for improvement in sleep quality with sedatives. However, the number needed to harm (NNH) was six versus placebo. No difference in sleep quality was detected across three studies that compared BZDs with atypical BZDs. Sedatives increased sleep time by 25 minutes overall. Cognitive adverse effects were significantly more common with sedatives than with placebo (OR 4.78).

Benzodiazepine Withdrawal

image A 2006 Cochrane review (8 studies, 458 subjects). Although the studies could not be pooled, the authors concluded that progressive withdrawal from BZDs was preferred to abrupt withdrawal. Carbamazepine was identified as a potential adjunctive therapy to manage BZD withdrawal.

Alcohol Withdrawal

image A 2005 Cochrane review found that BZDs were significantly better for alcohol withdrawal seizures compared with placebo and had similar efficacy to other drugs, or anticonvulsants specifically. BZDs elicited similar changes in alcohol withdrawal scores compared with other drugs. The findings of the review are complicated by the heterogeneity among trials.

FYI

image The ability of BZDs and related GABA agonists to produce amnesia has led to their criminal use as date rape drugs.
image BZDs have their two nitrogen atoms at 1,4 positions. Other, atypical BZDs have their nitrogens at 1,5 positions. An example of this is clobazam, an anticonvulsant.
image Clozapine, an atypical antipsychotic, is a dibenzodiazepine. It has two benzene rings attached to the seven-membered diazepine ring.

Central Nervous System Stimulants

Description

CNS stimulants are a heterogeneous class of compounds, structurally and pharmacologically related to amphetamine.

Prototypes and Common Drugs

Amphetamines

image Prototype: amphetamine
image Others: dextroamphetamine, lisdexamfetamine, mixed amphetamine salts, methamphetamine, MDMA (3,4-methylenedioxymethamphetamine)

Nonamphetamines

image Prototype: methylphenidate
image Others: dexmethylphenidate

MOA (Mechanism of Action)

image Methylphenidate and amphetamine work by increasing neurotransmitter levels in the synapse, specifically, levels of dopamine (DA) and noradrenaline (NA). They accomplish this through a variety of mechanisms.
image The primary mechanism is via stimulating the release of catecholamine from presynaptic vesicles.
image Methylphenidate and amphetamine also inhibit the reuptake of the monamines as well as inhibiting the activity of a key enzyme that breaks them down, MAO (Figure 23-11).
image Methylphenidate and amphetamine increase dopamine levels in the prefrontal cortex, an area thought to play an important role in attention-deficit/hyperactivity disorder (ADHD). The connection between the increased dopamine and noradrenaline in the synapse and the behavioral improvements seen in ADHD is still unclear. Dopamine is thought to be the key neurotransmitter mediating the beneficial effects of these agents in ADHD.
image Increased dopamine levels in the nucleus accumbens elicits a euphoric effect and is likely most responsible for the use of these agents as drugs of abuse. Significant dopamine release in this area is typically seen only at higher doses.
image

Figure 23-11

Pharmacokinetics

image Wide variations in bioavailability of methylphenidate occur among individuals.
image The elimination half-life of methylphenidate is relatively short (approximately 2 hours); therefore it is also available in extended release (ER) forms. The main metabolite is ritalinic acid, and the methylphenidate metabolites are mostly excreted in urine.
image Once-daily formulations are considered ideal for convenience. However, after evidence suggesting that the period immediately after a dose of methylphenidate provides the most benefit, manufacturers have tried to develop formulations that release the drug in a biphasic manner. These formulations have both an immediate-release (IR) and an ER component, in a variety of proportions. The agents with a large proportion of the IR component have greater efficacy early (2 hours) after administration, whereas the agents with a larger ER proportion have greater efficacy later (12 hours).
image Prodrugs such as lisdexamfetamine have been developed in an effort to reduce the abuse potential of these agents. Lisdexamfetamine is converted to dexamphetamine after oral administration, by the actions of the enzyme trypsin, which is found in the GI tract.
image A transdermal formulation of methylphenidate is also available. The patch is worn for 9 hours and provides continual release of methylphenidate over that time.

Indications

image ADHD
image Narcolepsy

Contraindications

image Conditions in which CNS activation would create a problem: anxiety, tension, agitation, thyrotoxicosis
image Conditions in which peripheral sympathetic stimulation would create a problem: hypertension (moderate to severe), glaucoma, pheochromocytoma, symptomatic cardiovascular disease

Side Effects

image Central stimulant effects:

image Euphoria
image Insomnia
image Psychomotor stimulation
image Anxiety
image Hyperthermia

image Peripheral sympathomimetic effects: tachycardia, hypertension
image Anorexia: The reason for appetite suppression is unclear but is believed to be the result of the actions of these agents in the feeding center of the hypothalamus. This can be a particularly concerning side effect in children.

Serious

image Sudden cardiac death: Sudden deaths have been reported in adults and children who had a history of cardiac abnormalities. Stimulants therefore either are not recommended or should be used with extreme caution in these individuals.

Important Notes

image The short half-life of the IR formulations of methylphenidate means that doses are typically given early in the day in children (morning and noon), to maximize the effects of the drug while the child is in school and to hopefully minimize the insomnia and appetite suppressant side effects.

Evidence

Safety of Methylphenidate in Adults

image A 2009 systematic review (26 trials, 811 participants) examined the safety of methylphenidate versus placebo for a variety of disorders, including ADHD, in adults. The trials were of relatively short duration (1 to 12 weeks) and therefore provide no information about chronic use. No serious (life-threatening or irreversible) adverse effects were reported in any studies. Dry mouth, anorexia, changes in mood, “jitteriness,” depression or sadness, weight loss, and vertigo were the most common adverse events that occurred more frequently with methylphenidate than placebo. The five studies reporting cardiovascular changes found slight increases in blood pressure and pulse rate.

FYI

image Amphetamine was first introduced commercially in the 1930s as Benzedrine, for narcolepsy. The product was available without a prescription, and when word got out about its stimulant properties, sales soared until it reverted back to prescription-only status.
image Methylphenidate is an old drug that has seen a variety of indications over the years. First synthesized in 1944, it has been used for chronic fatigue, lethargy, and depression, among other indications.
image The behavioral effects of amphetamines in children were first noted 70 years ago. After observing positive responses in a small study of benzedrine, an amphetamine derivative, larger clinical trials demonstrated that “behavior disorders” in children responded to this agent.
image The CNS stimulants are a heterogeneous drug class, and that heterogeneity is seen in the wide variety of plant sources of agents in this class. Leaves of the shrub tree Catha edulis, native to Africa and the Middle East, contain norpseudoephedrine. Fresh leaves or stems are referred to as Khat and are an integral part of many social rituals in Middle Eastern countries such as Yemen. Ephedra sinica yields ephedra, an herb that dates back to first-century Chinese books of herbal medicine, used for asthma and upper respiratory tract infections.
image Ritalinic acid is the major metabolite of methylphenidate—hence the brand name, Ritalin.
image MDMA is also known as the street drug ecstasy.
image Dextroamphetamine is a stereoisomer of amphetamine and is considered to be approximately twice as potent as amphetamine.

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