15. Drug Therapy of Depression and Anxiety Disorders

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Drug Therapy of Depression and Anxiety Disorders: Introduction

Depression and anxiety disorders are the most common mental illnesses, each affecting in excess of 10-15% of the population at some time in their lives. Both anxiety and depressive disorders are amenable to pharmacological treatments that have been developed since the 1950s. With the discovery of more selective and safer drugs, the use of antidepressants and anxiolytics has moved from the domain of psychiatry to other medical specialties, including primary care. The relative safety of the majority of commonly used antidepressants and anxiolytics notwithstanding, their optimal use requires a clear understanding of their mechanisms of action, pharmacokinetics, potential drug interactions, and the differential diagnosis of psychiatric illnesses.

A confluence of symptoms of depression and anxiety may affect an individual patient; some of the drugs discussed here are effective in treating both disorders, suggesting common underlying mechanisms of pathophysiology and response to pharmacotherapy. In large measure, our current understanding of pathophysiological mechanisms underlying depression and anxiety has been inferred from the mechanisms of action of psychopharmacological compounds (Chapter 14). While depression and anxiety disorders comprise a wide range of symptoms, including changes in mood, behavior, somatic function, and cognition, some progress has been made in developing animal models that respond with some sensitivity and selectivity to antidepressant or anxiolytic drugs (Cryan and Holmes, 2005; Miller et al., 2010). Recent work has focused on identifying endophenotypes associated with psychiatric diseases, with the goals of understanding their underlying pathophysiology and targeting them pharmacologically (Cannon and Keller, 2006). Although animal models are useful for investigating pharmacological mechanisms of action and providing initial evidence of efficacy, the development of antidepressant and anxiolytic drugs depends on clinical trials. However, it is not uncommon for psychopharmacological agents to fail to show efficacy in clinical trials; in large measure this is due to significant placebo effects and the lack of objective and firm end points. In spite of these limitations, the last half century has seen notable advances in the discovery and development of drugs for treating depression and anxiety.Characterization of Depressive and Anxiety Disorder

Symptoms of Depression

Depression, in general, is classified as major depression (i.e., unipolar depression) or bipolar depression (i.e., manic depressive illness); bipolar depression and its treatment are discussed in Chapter 16. Lifetime risk of unipolar depression is ~15%. Females are affected twice as frequently as males (Kessler et al., 1994). Depressive episodes are characterized by depressed or sad mood, pessimistic worry, diminished interest in normal activities, mental slowing and poor concentration, insomnia or increased sleep, significant weight loss or gain due to altered eating and activity patterns, psychomotor agitation or retardation, feelings of guilt and worthlessness, decreased energy and libido, and suicidal ideation, occurring most days for a period of at least 2 weeks. In some cases, the primary complaint of patients involves somatic pain or other physical symptoms and can present a diagnostic challenge for primary care physicians. Depressive symptoms also can occur secondary to other illnesses such as

hypothyroidism, Parkinson's disease, and inflammatory conditions. Further, depression often complicates the management of other medical conditions (e.g., severe trauma, cancer, diabetes, and cardiovascular disease, especially myocardial infarction) (Andrews and Nemeroff, 1994).

Depression is underdiagnosed and undertreated (Suominen et al., 1998). This is of particular concern due to the inherent risk of suicide associated with depression. Approximately 10-15% of those with severe depression attempt suicide at some time (Chen and Dilsaver, 1996). Thus, it is important that symptoms of depression be recognized and treated in a timely manner. Furthermore, the response to treatment must be assessed and decisions made regarding continued treatment with the initial drug, dose adjustment, adjunctive therapy, or alternative medication.

Symptoms of Anxiety

Anxiety disorders encompass a constellation of symptoms, and include generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobias, and acute stress (Atack, 2003). In general, symptoms of anxiety that lead to pharmacological treatment are those that interfere significantly with normal function. Symptoms of anxiety also are often associated with depression and other medical conditions.

Anxiety is a normal human emotion that serves an adaptive function from a psychobiological perspective. However, in the psychiatric setting, feelings of fear or dread that are unfocused (e.g., generalized anxiety disorder) or out of scale with the perceived threat (e.g., specific phobias) often require treatment. Drug treatment includes acute drug administration to manage episodes of anxiety, and chronic or repeated treatment to manage unrelieved and continuing anxiety disorders.Antidepressant Drugs

Mechanisms of Action

Many different antidepressants have established track records of efficacy for treating major depression (Millan, 2006). However, they all suffer some limitations in efficacy, since at least 20% of all depressed patients are refractory to multiple different antidepressants at adequate doses (Rush et al., 2006). The most commonly used medications, often referred to as second-generation antidepressants, are the selective serotonin reuptake inhibitors (SSRIs) and the serotonin-norepinephrine reuptake inhibitors (SNRIs), which have greater efficacy and safety compared to most older drugs (i.e., first-generation antidepressants). Relatively selective norepinephrine reuptake inhibitors also have been developed as antidepressants (e.g., maprotiline, reboxetine).

In monoamine systems, reuptake of the transmitter is the main mechanism by which neurotransmission is terminated; thus, inhibition of reuptake can enhance neuro-transmission, presumably by slowing clearance of the transmitter from the synapse and prolonging the dwell-time of the transmitter in the synapse. Enhancing neurotransmission may subsequently lead to adaptive changes (described later). Reuptake inhibitors inhibit either SERT, the neuronal serotonin (5-hydroxytryptamine;

5-HT) transporter; NET, the neuronal norepinephrine (NE) transporter; or both (Figure 15–1). Similarly, the first-generation drugs, which include monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), also enhance monoaminergic neurotransmission: the MAOIs by inhibiting monoamine metabolism and thereby enhancing neurotransmitter storage in secretory granules, the TCAs by inhibiting 5-HT and norepinephrine reuptake. While efficacious, these first-generation agents exhibit side effects and drug and food interactions that limit their use relative to the newer drugs. Table 15–1 summarizes the actions of the most widely used antidepressants.

Figure 15–1.

Sites of action of antidepressants. Schematics representing noradrenergic (top) and serotonergic (bottom) nerve terminals. SSRIs, SNRIs, and TCAs increase noradrenergic or serotonergic neurotransmission by blocking the norepinephrine or serotonergic transporter at presynaptic terminals (NET, SERT). MAOIs inhibit the catabolism of norepinephrine and serotonin. Some antidepressants such as trazodone and related drugs have direct effects on serotonergic receptors that contribute to their clinical effects. Chronic treatment with a number of antidepressants desensitizes presynaptic autoreceptors and heteroreceptors, producing long-lasting changes in monoaminergic neurotransmission. Post-receptor effects of antidepressant treatment,

including modulation of GPCR signaling and activation of protein kinases and ion channels, are involved in the mediation of the long-term effects of antidepressant drugs. Note that NE and 5-HT also affect each other's neurons.

Table 15–1 Antidepressants: Chemical Structures, Dose and Dosage Forms, and Side Effects

NONPROPRIETARY NAME (TRADE NAME)

DOSE AND

DOSAGE FORMS

AMINE EFFECTS

SIDE EFFECTS

Norepinephrine Reuptake Inhibitors:

Tertiary Amine Tricyclics

Usuala Dose (mg/day)

Dosage Form

Agitation

Seizures

Sedation

Hypotension

Anticholinergic Effects

GI Effects

Weight Gain

Sexual Effects

Cardiac Effects

Amitriptyline (ELAVIL and others)

100–200

O, I NE, 5-HT

0 2+ 3+ 3+ 3+ 0/+ 2+ 2+ 3+

Clomipramine (ANAFRANIL)

100–200

O NE, 5-HT

0 3+ 2+ 2+ 3+ + 2+ 3+ 3+

Doxepin (ADAPIN, SINEQUAN)

100–200

O NE, 5-HT

0 2+ 3+ 2+ 2+ 0-+ 2+ 2+ 3+

Imipramine (TOFRANIL and others)

100–200

O, I NE, 5-HT

0/+ 2+ 2+ 2+ 2+ 0/+ 2+ 2+ 3+

(+)-Trimipramine (SURMONTIL)

75–200

O NE, 5-HT

0 2+ 3+ 2+ 3+ 0/+ 2+ 2+ 3+

Norepinephrine Reuptake Inhibitors:

Secondary Amine Tricyclics

Amoxapine (ASENDIN)

200–300

O NE, DA

0 2+ + 2+ + 0/+ + 2+ 2+

Desipramine (NORPRAMIN)

100–200

O NE + + 0/+ + + 0/+ + 2+ 2+

Maprotiline (LUDIOMIL)

100–150

O NE 0/+ 3+ 2+ 2+ 2+ 0/+ + 2+ 2+

Nortriptyline (PAMELOR)

75–150

O NE 0 + + + + 0/+ + 2+ 2+

Protriptyline (VIVACTIL)

15–40

O NE 2+ 2+ 0/+ + 2+ 0/+ + 2+ 3+

Selective Serotonin Reuptake Inhibitors

(±)-Citalopram (CELEXA)

20–40

O 5-HT 0/+ 0 0/+ 0 0 3+ 0 3+ 0

(+)- Escitalopram (LEXAPRO)

10–20

O 5-HT 0/+ 0 0/+ 0 0 3+ 0 3+ 0

(±)-Fluoxetine (PROZAC)

20–40

O 5-HT + 0/+ 0/+ 0 0 3+ 0/+ 3+ 0/+

Fluvoxamine (LUVOX)

100–200

O 5-HT 0 0 0/+ 0 0 3+ 0 3+ 0

(–)-Paroxetine (PAXIL)

20–40

O 5-HT + 0 0/+ 0 0/+ 3+ 0 3+ 0

(+)-Sertraline (ZOLOFT)

100–150

O 5-HT + 0 0/+ 0 0 3+ 0 3+ 0

(±)-Venlafaxine (EFFEXOR)

75–225

O 5-HT, NE

0/+ 0 0 0 0 3+ 0 3+ 0/+

Atypical Antidepressants

(–)-Atomoxetine (STRATTERA)

40–80 (children: mg/kg)

O NE 0 0 0 0 0 0/+ 0 0 0

Bupropion (WELLBUTRIN)

200–300

O DA, ?NE

3+ 4+ 0 0 0 2+ 0 0 0

(+)-Duloxetine (CYMBALTA)

80–100

O NE, 5-HT

+ 0 0/+ 0/+ 0 0/+ 0/+ 0/+ 0/+

(±)-Mirtazapine (REMERON)

15–45

O 5-HT, NE

0 0 4+ 0/+ 0 0/+ 0/+ 0 0

Nefazodone (SERZONE)

200–400

O 5-HT 0 0 3+ 0 0 2+ 0/+ 0/+ 0/+

Trazodone (DESYREL)

150–200

O 5-HT 0 0 3+ 0 0 2+ + + 0/+

Monoamine Oxidase Inhibitors

Phenelzine (NARDIL)

30–60

O NE, 5-HT, DA

0/+ 0 + + 0 0/+ + 3+ 0

Tranylcypromine (PARNATE)

20–30

O NE, 5-HT, DA

2+ 0 0 + 0 0/+ + 2+ 0

(–)-Selegiline (ELDEPRYL)

10 O DA, ?NE, ?5-HT

0 0 0 0 0 0 0 + 0

Note: Most of the drugs are hydrochloride salts, but SURMONTIL and LUVOX are maleates; CELEXA is a hydrobromide, and REMERON is a free-base. Selegiline is approved for early Parkinson disease, but may have antidepressant effects, especially at daily doses 20 mg, and is under investigation for administration by transdermal patch. aBoth higher and lower doses are sometimes used, depending on an individual patient's needs and response to the drug; see the literature and FDA-approved dosage recommendations.

O, oral tablet or capsule; I, injectable; NE, norepinephrine; 5-HT, serotonin, DA, dopamine; 0, negligible; 0/+, minimal; +, mild; 2+, moderate; 3+, moderately severe; 4+, severe. Other significant side effects for individual drugs are described in the text. All drugs commonly used to treat depression share, at some level, primary effects on serotonergic or noradrenergic neurotransmitter systems (Shelton and Lester, 2006). In general, antidepressants enhance serotonergic or noradrenergic transmission, although the nature of this effect may change with chronic treatment (Shelton, 2000). The dependence of many current treatments on serotonergic or noradrenergic mechanisms is highlighted by clinical studies employing monoamine depletion strategies. For example, tryptophan depletion that acutely reduces 5-HT neurotransmission results in a relatively brisk relapse (within 5-10 hours) of the symptoms of depression in patients who had shown remission on an SSRI but not a NE reuptake inhibitor (Delgado et al., 1991). Conversely, catecholamine depletion by blocking the rate-limiting enzyme for the synthesis of NE and dopamine (DA) results in a relapse of symptoms in patients who

had recently remitted on an NE reuptake inhibitor, but not an SSRI (Miller et al., 1996). Sites of interaction of antidepressant drugs with noradrenergic and serotonergic neurons are depicted in Figure 15–1.

Long-term effects of antidepressant drugs evoke adaptive or regulatory mechanisms that enhance the effectiveness of therapy. These responses include increased adrenergic or serotonergic receptor density or sensitivity, increased receptor-G protein coupling and cyclic nucleotide signaling, induction of neurotrophic factors, and increased neurogenesis in the hippocampus (Schmidt and Duman, 2007). Persistent antidepressant effects depend on the continued inhibition of 5-HT or NE transporters, or enhanced serotonergic or noradrenergic neurotransmission achieved by an alternative pharmacological mechanism. For example, chronic treatment with some antidepressants that interact directly with monoamine transporters (e.g., SSRIs, SNRIs, or NE reuptake inhibitors) reduces the expression and activity of 5-HT or NE transporters in the brain, which results in enhanced serotonergic or noradrenergic neurotransmission (Benmansour et al., 1999; Zhao et al., 2008). Compelling evidence suggests that sustained signaling via NE or 5-HT increases the expression of specific downstream gene products, particularly brain-derived neurotrophic factor (BDNF), which appears to be related to the ultimate mechanism of action of these drugs (Sen et al., 2008). Unfortunately, neither earlier theories of monoaminergic receptor down-regulation and altered signaling nor current theories of neurogenesis and modulation of neurotrophic factors has yet led to new antidepressant treatments. Glutamate, neurokinin, corticotropin releasing hormone receptors and cyclic nucleotide phosphodiesterases may be potential targets for the development of novel antidepressant drugs (O'Donnell and Zhang, 2004; Rakofsky et al., 2009; Witkin et al., 2007; Zarate et al., 2006).

Clinical Considerations with Antidepressant Drugs

Following initiation of antidepressant drug treatment there is generally a "therapeutic lag" lasting 3-4 weeks before a measurable therapeutic response becomes evident. This is the reason that electroconvulsive therapy may be the treatment of choice for agitated, depressed patients with a high risk of suicide. Some patients may respond to antidepressant treatment sooner than 3-4 weeks; others may require > 8 weeks for an adequate response. Some symptoms respond more rapidly and are predictive of a more global response (Katz et al., 2004). Approximately two-thirds of depressed patients will show a 50% decrease in depressive symptoms over the course of an 8-week antidepressant trial; one-third will experience a complete remission with a single antidepressant (Rush et al., 2006). In general, if a patient does not respond to a given antidepressant after an 8-week trial on an adequate dose, then switching to another antidepressant with a different mechanism of action is a reasonable next step (e.g., SSRI to SNRI). If a partial response has been observed, other drugs may be added to the primary SSRI or SNRI medications; these additive medications include the antidepressant drug bupropion, thyroid hormone (triiodothyronine), or an atypical antipsychotics (aripiprazole or olanzapine) (Shelton, 2007). After the successful initial treatment phase, a 6-12 month maintenance treatment phase is typical, after which the drug is gradually withdrawn. If a patient has experienced two separate episodes of major depression or is chronically depressed (i.e., > 2 years), lifelong treatment with an antidepressant is advisable. Certain psychotherapies such as cognitive behavioral therapy or behavioral activation therapy are suitable options for many patients and may reduce the risk for relapse (DeRubeis et al., 2008). Finally, in addition to

electroconvulsive therapy, other non-pharmacological interventions have been developed; these include transmagnetic stimulation of the brain and deep brain stimulation (Rakofsky et al., 2009).

The challenge of management of the depressive episode through the "therapeutic lag" is compounded by the early emergence of side effects. Most of the adverse reactions are well tolerated. A significant aspect of effective management of depression is informing the patient about the time course of both the therapeutic and side effects of medications and encouraging persistence with treatment.

Another important issue in the use of antidepressants is a phenomenon known as the "switch" from a depressed episode to a manic or hypomanic episode (Goldberg and Truman, 2003), a significant challenge in managing bipolar illness. For this reason, antidepressants are not recommended as monotherapy for bipolar illness. However, patients with bipolar illness may present with major depressive episodes early in the course of their illness. SSRIs and bupropion may be somewhat less likely to induce the switch from depression to mania than antidepressants from other pharmacological classes.

A controversial issue regarding the use of all antidepressants is their relationship to suicide (Mann et al., 2006). Data establishing a clear link between antidepressant treatment and suicide are lacking. In general, for reasons of safety, suicidal patients are not enrolled in clinical trials designed to seek approval for marketing a new medication. Thus, the FDA uses "suicidality" (i.e., suicidal ideation or suicide attempts and self-injurious behavior) as a proxy for risk of suicide. The FDA has issued a "black box" warning regarding the use of SSRIs and a number of other antidepressants in children and adolescents, particularly during the early phase of treatment, due to the possibility of an association between antidepressant treatment and suicide. However, there is strong epidemiological evidence that the rate of suicide has been decreasing since the time that SSRIs were first prescribed and then gained widespread usage; these data, however, cannot demonstrate a causal relationship. An analysis of health records of over 65,000 patients undergoing different types of pharmacological treatment for depression found no suggestion of increases in suicide or suicide attempts (Simon et al., 2006). Relevant to this point is the observation that an increase in suicide occurred for children and adolescents after regulatory authorities in the U.S. and Europe issued public health warnings about a possible association between antidepressants and suicidal ideation and acts, perhaps due to a reduction in the use of antidepressants in these patient populations after the announcement (Gibbons et al., 2007). Most clinicians agree that for seriously depressed patients, the risk of not being on an effective antidepressant drug outweighs the risk of being treated with one. Of course, clinical common sense also demands that special attention be paid to potentially suicidal patients regardless of their medication status. In addition, patients and family members should be warned to look for the exacerbation of symptoms such as insomnia, agitation, anxiety, or either the onset or worsening of suicidal thoughts and behaviors, particularly early in the course of therapy.Monoamine Oxidase Inhibitors

The first class of drugs with relatively specific antidepressant effects were the MAOIs (Hollister, 1981). Iproniazid, which was developed initially for the treatment of tuberculosis, was found to have mood-elevating effects in patients with tuberculosis.

Subsequently, iproniazid was shown to inhibit MAO, leading to the development of additional MAOIs including phenelzine, isocarboxazid, and tranylcypromine. As irreversible inhibitors of both MAO-A and MAO-B, these drugs have pronounced effects on the body's ability to metabolize endogenous monoamines (e.g., 5-HT, NE, and DA) and exogenous monoamines (e.g., tyramine). The protection of exogenous monoamines leads to significant drug and food interactions. More recently, reversible and selective inhibitors of MAO-A and MAO-B have been developed (Livingston and Livingston, 1996), and these have fewer side effects and fewer interactions with food and other drugs. The MAO-B selective inhibitor selegiline is used in the treatment of Parkinson disease; selective inhibitors of MAO-A, such as moclobemide, are effective antidepressants but are not approved for use in the U.S.Tricyclic Antidepressant and Selective Reuptake Inhibitors

The initial development of the TCAs resulted from psychopharmacological characterization of a series of structural analogs that had been developed as potential antihistamines, sedatives, analgesics, and antiparkinson drugs (Hollister, 1981). One of the compounds, imipramine, which has a phenothiazine-like structure, modified behavior in animal models. Unlike the phenothiazines, imipramine had limited efficacy in schizophrenic patients, but improved symptoms of depression. Imipramine and related TCAs became the mainstay of drug treatment of depression until the later development of the SSRIs.

TCAs with a tertiary-amine side chain, including amitriptyline, doxepin, and imipramine, inhibit both norepinephrine and serotonin uptake, while clomipramine is somewhat selective for inhibition of serotonin uptake. Chemical modification of the TCA structure led to the earliest SSRI zimelidine which, while effective, was withdrawn from the market due to serious adverse effects. Fluoxetine and fluvoxamine were the first widely used SSRIs. At the same time, selective inhibitors of norepinephrine reuptake entered clinical development; while not approved for use in the U.S. for the treatment of depression, one norepinephrine reuptake inhibitor, atomoxetine, is used for the treatment of attention deficit hyperactivity disorder. Subsequent drug development efforts focused on serotonin and norepinephrine reuptake inhibitors (SNRIs), resulting in venlafaxine and duloxetine, which lack the complex receptor pharmacology exhibited by the TCAs.


A number of SSRIs were introduced from 1984-1997, including fluoxetine, paroxetine, sertraline, citalopram, escitalopram, and fluvoxamine; the FDA has approved fluvoxamine for treatment of obsessive-compulsive disorder and social anxiety disorder, but not depression. Citalopram is labeled for use in premenstrual dysphoric disorder. All of the SSRIs show a clear improvement in safety margin compared to the TCAs and are much safer in overdose, and in clinical practice have affected a broad range of psychiatric, behavioral, and medical conditions, for which they are used, on and off label.

The SSRIs are effective in treating major depression. In typical studies, only about two-thirds of SSRI-treated patients, compared to about one-third of placebo-treated patients, exhibit a 50% reduction of depressive symptoms during a 6-8 week trial. SSRI

treatment results in ~ 35% of patients enjoying a remission, as defined by a Hamilton Depression Rating Score < 7, indicative of a complete resolution of symptoms, compared to 25% of patients who experience a remission with placebo treatment (Rush et al., 2006).

In addition to use as an antidepressant, SSRIs also are anxiolytics with demonstrated efficacy in the treatment of generalized anxiety, panic, social anxiety, and obsessive-compulsive disorders. Sertraline and paroxetine also have been approved for the treatment of posttraumatic stress disorder (PTSD), although treatment of this condition remains highly challenging. SSRIs also are used for treatment of premenstrual dysphoric syndrome and for preventing vasovagal symptoms in post-menopausal women (although the SNRI venlafaxine is the most extensively studied drug for this problem).

Mechanism of Action

SERT mediates the reuptake of serotonin into the presynaptic terminal; neuronal uptake is the primary process by which neurotransmission via 5-HT is terminated (Figure 15–1). Thus, treatment with an SSRI initially blocks reuptake and results in enhanced and prolonged serotonergic neurotransmission. SSRIs used clinically are relatively selective, that is, 10-fold or more, for inhibition of SERT relative to NET (Table 15–2). Increased synaptic availability of serotonin stimulates a large number of postsynaptic 5-HT receptor subtypes, as well as somatodendritic and presynaptic terminal receptors that regulate serotoninergic neuron activity and serotonin release.

Table 15–2 Potencies of Antidepressants at the Human Transporters for Norepinephrine (NET), Serotonin (SERT), and Dopamine (DAT)

DRUG NET SERT DAT SELECTIVITY

NE Selective NET vs SERT

Oxaprotiline 5 4000 4350 800

Maprotiline 11.1 5900 1000 532

Viloxazine 156 17,000 100,000 109

Nomifensine 15.6 1000 55.6 64

Desipramine 0.8 17.5 3200 22

Protriptyline 1.4 19.6 2130 14

Atomoxetine 3.5 43 1270 12

Reboxetine 7.1 58.8 11,500 8.3

Nortriptyline 4.4 18.5 1140 4.2

Amoxapine 16.1 58.5 4350 3.6

Doxepin 29.4 66.7 12,200 2.3

5-HT Selective SERT vs NET

S-Citalopram 7840 1.1 >10,000 7127

R, S-Citalopram 5100 1.4 28,000 3643

Sertraline 417 0.3 25 1390

Fluvoxamine 1300 2.2 9100 591

Paroxetine 40 0.1 500 400

Fluoxetine 244 0.8 3600 305

Clomipramine 37 0.3 2200 123

Venlafaxine 1060 9.1 9100 116

Nor1-citalopram

780 7.4 — 105

Nor2-citalopram

1500 24 — 63

Zimelidine 9100 152 12,000 60

Trazodone 8300 160 7140 52

Imipramine 37 1.4 8300 26

Norfluoxetine 410 25 1100 16

Amitriptyline 34.5 4.3 3200 8.0

Duloxetine 11.2 1.6 — 7.0

Dothiepin 45.5 8.3 5300 5.5

Norsertraline 420 76 440 5.5

Milnacipran 200 123 — 1.6

DA Selective DAT vs NET

Bupropion 52,600 9100 526 1000

Values shown are experimentally determined constants (Ki values, nM) for inhibiting the function of human NET, SERT, and DAT expressed in cell lines. Drugs shown include clinically used antidepressants, important metabolites, and experimental drugs not used clinically. Selectivity is defined as ratio of the relevant Ki values (SERT/NET, NET/SERT, NET/DAT). Bupropion is selective for the DAT relative to the NET and SERT. Source: Data are adapted from Frazer (1997), Owens et al. (1997), and Leonard and Richelson (2000). SSRI treatment causes stimulation of 5-HT1A and 5-HT7 autoreceptors on cell bodies in the raphe nucleus and of 5-HT1D autoreceptors on serotonergic terminals, and this reduces serotonin synthesis and release toward pre-drug levels. With repeated treatment with SSRIs, there is a gradual down-regulation and desensitization of these autoreceptor mechanisms. In addition, down-regulation of postsynaptic 5-HT2A receptors may contribute to antidepressant efficacy directly or by influencing the function of noradrenergic and other neurons via serotonergic heteroreceptors. Other postsynaptic 5-HT receptors likely remain responsive to increased synaptic concentrations of 5-HT and contribute to the therapeutic effects of the SSRIs.

Later-developing effects of SSRI treatment also may be important in mediating ultimate therapeutic responses. These include sustained increases in cyclic AMP signaling and phosphorylation of the nuclear transcription factor CREB, as well as increases in the expression of trophic factors such as BDNF. In addition, SSRI treatment increases neurogenesis from progenitor cells in the dentate nucleus of the hippocampus and

subventricular zone (Santarelli et al., 2003). In animals models, some behavioral effects of SSRIs depend on increased neurogenesis (probably via increased expression of BDNF and its receptor TrkB), suggesting a role for this mechanism in the antidepressant effects. Recent evidence indicates the presence of neural progenitor cells in the human hippocampus, providing some support for the relevance of this mechanism to the clinical situation (Manganas et al., 2007). Further, repeated treatment with SSRIs reduces the expression of SERT, resulting in reduced clearance of released 5-HT and increased serotonergic neurotransmission. These changes in transporter expression parallel behavioral changes observed in animal models, suggesting some role for this regulatory mechanism in the late-developing effects of SsRIs (Zhao et al., 2009). These persistent behavioral changes depend on increased serotonergic neurotransmission, similar to what has been demonstrated clinically using depletion strategies (Delgado et al., 1991).Serotonin-Norepinephrine Reuptake Inhibitors

Many older TCAs block both SERT and NET, but at a high side effect burden. Four medications with a non-tricyclic structure that inhibit the reuptake of both 5-HT and norepinephrine have been approved for use in the U.S. for treatment of depression, anxiety disorders, and pain: venlafaxine and its demethylated metabolite, desvenlafaxine; duloxetine; and milnacipran (approved only for fibromyalgia pain in the U.S.). Off-label uses include stress urinary incontinence (duloxetine), autism, binge eating disorders, hot flashes, pain syndromes, premenstrual dysphoric disorders, and post-traumatic stress disorders (venlafaxine)

The rationale behind the development of these newer agents was that targeting both SERT and NET, analogous to the effects of some TCAs, might improve overall treatment response. Meta-analyses provide some support for this hypothesis (Entsuah et al., 2001). Specifically, the remission rate for venlafaxine appears slightly better than for SSRIs in head-to-head trials. However, many of the studies included in the meta-analyses used a daily venlafaxine dose of 150 mg, which would have modest effects on noradrenergic neurotransmission. Duloxetine, in addition to being approved for use in the treatment of depression and anxiety, also is used for treatment of fibromyalgia and neuropathic pain associated with peripheral neuropathy.

Mechanism of Action

SNRIs inhibit both SERT and NET (Table 15–2). Depending on the drug, the dose, and the potency at each site, SNRIs cause enhanced serotonergic and/or noradrenergic neurotransmission. Similar to the action of SSRIs, the initial inhibition of SERT induces activation of 5-HT1A and 5-HT1D autoreceptors. This action decreases serotonergic neurotransmission by a negative feedback mechanism until these serotonergic autoreceptors are desensitized. Then, the enhanced serotonin concentration in the synapse can interact with postsynaptic 5-HT receptors.Serotonin Receptor Antagonists

Several antagonists of the 5-HT2 family of receptors are effective antidepressants, although most agents of this class affect other receptor classes as well. The class includes two pairs of close structural analogues, trazodone and nefazodone, as well as

mirtazapine (REMERON, others) and mianserin (not marketed in the U.S.).

The efficacy of trazodone may be somewhat more limited than the SSRIs; however, low doses of trazodone (50-100 mg) have been used widely both alone and concurrently with SSRIs or SNRIs to treat insomnia. When used to treat depression, trazodone typically is started at 150 mg/day in divided doses with 50 mg increments every 3-4 days. The maximally recommended dose is 400 mg/day for outpatients and 600 mg/day for inpatients.

Both mianserin and mirtazapine are quite sedating and are treatments of choice for some depressed patients with insomnia. The recommended initial dosing of mirtazapine is 15 mg/day with a maximal recommended dose of 45 mg/day. Since the t1/2 is 16-30 hours, the recommended interval for dose changes is no less than 2 weeks.

Mechanism of Action

The most potent pharmacological effects of trazodone are blockade of the 5-HT2 and 1 adrenergic receptors. Trazodone also inhibits the serotonin transporter, but is markedly less potent for this action relative to its blockade of 5-HT2A receptors. Similarly, the most potent pharmacological action of nefazodone also is the blockade of the 5-HT2 family of receptors.

Both mirtazapine and mianserin potently block histamine H1 receptors. They also have some affinity for 2 adrenergic receptors, which is claimed to be related to their therapeutic efficacy, but this point is questionable. Their affinities for 5-HT2A, 5-HT2C, and 5-HT3 receptors are high, though less so than for histamine H1 receptors. Both of these drugs have been shown in double-blind, placebo-controlled studies to increase the antidepressant response when combined with SSRIs compared to the action of the SSRIs alone. The exact monoamine receptor accounting for the effects of mirtazapine and mianserin is not clear, although the data from clinical trials suggest that olanzapine, aripiprazole, and quetiapine enhance the therapeutic effects of SSRIs or SNRIs, an important hint that their unique capacity to block the 5-HT2A receptor is the most potent shared pharmacological action amongst these antidepressant and antipsychotic drugs.Bupropion

Bupropion (WELLBUTRIN, others) is discussed separately because it appears to act via multiple mechanisms. It enhances both noradrenergic and dopaminergic neurotransmission via reuptake inhibition (Table 15–2); in addition, its mechanism of action may involve the presynaptic release of NE and DA (Foley et al., 2006). Bupropion is indicated for the treatment of depression, prevention of seasonal depressive disorder, and as a smoking cessation treatment (under the ZYBAN brand). Bupropion has effects on sleep EEG that are opposite those of most antidepressant drugs. Bupropion may improve symptoms of attention deficit hyperactivity disorder (ADHD) and has been used off-label for neuropathic pain and weight loss. Clinically, bupropion is widely used in combination with SSRIs to obtain a greater antidepressant response; however, there are very limited clinical data providing strong support for this practice.

Mechanism of Action

Bupropion appears to inhibit NET. It also blocks the DAT but its effects on this transporter are not particularly potent in animal studies. In addition, it has effects on VMAT2, the vesicular monoamine transporter (see Figure 8–6). The hydroxybupropion metabolite may contribute to the therapeutic effects of bupropion: this metabolite appears to have a similar pharmacology and is present in substantial levels.Atypical Antipsychotics

In addition to their use in schizophrenia, bipolar depression, and major depression with psychotic disorders, atypical antipsychotics have gained further, off-label use for major depression without psychotic features (Jarema, 2007). In fact, both aripiprazole (ABILIFY) added to SSRIs and SNRIs and a combination of olanzapine and the SSRI fluoxetine (SYMBYAX) have been approved by the FDA for treatment-resistant major depression (i.e., following an inadequate response to at least two different antidepressants).

The initial recommended dose of aripiprazole is 2-5 mg/day with a recommended maximal dose of 15 mg/day following increments of no more than 5 mg/day every week. The olanzapine-fluoxetine combination is available in fixed-dose combinations of either 6 or 12 mg of olanzapine and 25 or 50 mg of fluoxetine. Quetiapine (SEROQUEL) may have either primary antidepressant actions on its own or adjunctive benefit for treatment-resistant depression; it is used off-label for insomnia. Quetiapine also is currently under review by the FDA for additional indications in major depression and generalized anxiety disorder.

Mechanism of Action

The mechanism of action and adverse effects of the atypical antipsychotics are described in detail in Chapter 16. The side effects seen with atypical antipsychotics in patients with schizophrenia may not exactly translate to patients with major depression, due to a predisposition toward metabolic syndrome in patients with schizophrenia. The major risks of these agents are weight gain and metabolic syndrome, a greater problem for quetiapine and olanzapine than for aripiprazole.Tricyclic Antidepressants

Due to their potential to cause serious side effects, the TCAs generally are not used as first-line drugs for the treatment of depression. Nevertheless, these drugs have established value for the treatment of major depression (Hollister, 1981). TCAs and first-generation antipsychotics are synergistic for the treatment of psychotic depression. Tertiary amine TCAs (e.g., doxepin, amitriptyline) have been used for many years in relatively low doses for treating insomnia. In addition, because of the role of norepinephrine and serotonin in pain transmission, these drugs are commonly used to treat a variety of pain conditions.

Mechanism of Action

The inspiration for the development of both SSRIs and SNRIs derived from the appreciation that a salient pharmacological action of TCAs is antagonism of serotonin

and norepinephrine transporters (Table 15–2). The antidepressant action of TCAs was discovered during clinical trials in schizophrenic patients; imipramine had little effect on psychotic symptoms but had beneficial effects on depressive symptoms (Hollister, 1981). In addition to inhibiting NET somewhat selectively (desipramine, nortriptyline, protriptyline, amoxapine) or both SERT and NET (imipramine, amitriptyline), these drugs also block other receptors (H1, 5-HT2, 1, and muscarinic). Given the superior activity of clomipramine over SSRIs, some combination of these additional pharmacological actions may contribute to the therapeutic effects of TCAs. One TCA, amoxapine, also is a dopaminergic receptor antagonist; its use, unlike that of other TCAs, poses some risk for the development of extrapyramidal side effects such as tardivedyskinesia.Monoamine Oxidase Inhibitors

MAOIs have efficacy equivalent to that of the TCAs but are rarely used because of their toxicity and major drug and food interactions (Hollister, 1981). The MAOIs approved for treatment of depression include tranylcypromine (PARNATE, others), phenelzine (NARDIL), and isocarboxazid (MARPLAN). Selegiline (EMSAM) is available as a transdermal patch and approved for use in the treatment of depression; transdermal delivery may reduce the risk for diet-associated hypertensive reactions (described later).

Mechanism of Action

The MAOIs nonselectively and irreversibly inhibit both MAO-A and MAO-B, which are located in the mitochondria and metabolize (inactivate) monoamines, including 5-HT and NE (Chapter 8). Selegiline inhibits MAO-B at lower doses, with effects on MAO-A at higher doses. Selegiline also is a reversible inhibitor of monoamine oxidase, which may reduce the potential for serious adverse drug and food interactions. While both MAO-A and MAO-B are involved in metabolizing 5-HT, only MAO-B is found in serotonergic neurons (Chapter 13).

Pharmacokinetics

The metabolism of most antidepressants is mediated by hepatic CYPs (see Table 15–3). Some antidepressants inhibit the clearance of other drugs by the CYP system, as discussed in the following section, and this possibility of drug interactions should be a significant factor in considering the choice of agents.

Table 15–3 Disposition of Antidepressants

DRUG ELIMINATION t1/2, (h) PARENT DRUG (Active Metabolite)

TYPICAL CP (ng/mL)

PREDOMINANT CYP INVOLVED IN METABOLISM

Tricyclic Antidepressants

Amitriptyline 16 (30) 100–250

Amoxapine 8 (30) 200–500

Clomipramine 32 (70) 150–500

Desipramine 30 125–300

Doxepin 18 (30) 150–250 2D6, 2C19, 3A3/4,

Imipramine 12 (30) 175–300 1A2

Maprotiline 48 200–400

Nortriptyline 31 60–150

Protriptyline 80 100–250

Trimipramine 16 (30) 100–300


R,S-Citalopram

36 75–150 3A4, 2C19

S-Citalopram 30 40–80 3A4, 2C19

Fluoxetine 53 (240) 100–500 2D6, 2C9

Fluvoxamine 18 100–200 2D6, 1A2, 3A4, 2C9

Paroxetine 17 30–100 2D6

Sertraline 23 (66) 25–50 2D6

Serotonin-Norepinephrine Reuptake Inhibitors

Duloxetine 11 — 2D6

Venlafaxine 5 (11) — 2D6, 3A4

Other Antidepressants

Atomoxetine 5–20 (child: 3) — 2D6, 3A3/4

Bupropion 11 75–100 2B6

Mirtazapine 16 — 2D6

Nefazodone 2–4 — 3A3/4

Reboxetine 12 — —

Trazodone 6 800–1600 2D6

Values shown are elimination t1/2 values for a number of clinically used antidepressant drugs; numbers in parentheses are t1/2 values of active metabolites. Fluoxetine (2D6), fluvoxamine (1A2, 2C8, 3A3/4), paroxetine (2D6), and nefazodone (3A3/4) are potent inhibitors of CYPs; sertraline (2D6), citalopram (2C19), and venlafaxine are less potent inhibitors. Plasma concentrations are those observed at typical clinical doses. Information was obtained from manufacturers' summaries and Appendix II, which the reader should consult for important details. Selective Serotonin Reuptake Inhibitors

All of the SSRIs are orally active and possess elimination half-lives consistent with once-daily dosing (Hiemke and Hartter, 2000). In the case of fluoxetine, the combined action of the parent and the desmethyl metabolite norfluoxetine allows for a once weekly formulation (PROZAC WEEKLY). CYP2D6 is involved in the metabolism of most SSRIs and the SSRIs are at least moderately potent inhibitors of this isoenzyme (Table 15–3). This creates a significant potential for drug interaction for post-menopausal women taking the breast cancer drug and estrogen antagonist, tamoxifen (Chapter 62); the parent molecule is converted to a more active metabolite by CYP2D6,

and SSRIs may inhibit this activation and diminish the therapeutic activity of tamoxifen. Since venlafaxine and desvenlafaxine are weak inhibitors of CYP2D6, these antidepressants are not contraindicated in this clinical situation. However, care should be used in combining SSRIs with drugs that are metabolized by CYPs 1A2, 2D6, 2C9, and 3A4 (e.g., warfarin, tricyclic antidepressants, paclitaxel).


Both immediate release and extended-release (tablet or capsule) preparations of venlafaxine (EFFEXOR XR, others) produces steady state-levels of drug in plasma within 3 days. The elimination half-lives for the parent venlafaxine and its active and major metabolite desmethyl venlafaxine are 5 and 11 hours, respectively. Desmethylvenlafaxine is eliminated by hepatic metabolism and by renal excretion. Venlafaxine dose reductions are suggested for patients with renal or hepatic impairment. Duloxetine has a t1/2 of 12 hours. Duloxetine is not recommended for those with end-stage renal disease or hepatic insufficiency.

Serotonin Receptor Antagonists

Mirtazapine has an elimination t1/2 of 16-30 hours. Thus, dose changes are suggested no more often than 1-2 weeks. Clearance of mirtazapine is decreased in the elderly and in patients with moderate to severe renal or hepatic impairment. Pharmacokinetics and adverse effects of mirtazapine may have an enantiomer-selective component (Brockmöller et al., 2007). Steady-state trazodone is observed within 3 days following either a twice or three times daily dosing regimen. Nefazodone has a t1/2 of only 2-4 hours; its major metabolite hydroxynefazodone has a t1/2 of 1.5-4 hours.

Bupropion

The terminal phase of bupropion elimination has a t1/2 of 21 hours. The elimination of bupropion involves both hepatic and renal routes. Patients with severe hepatic cirrhosis should receive a maximum dose of 150 mg every other day while consideration for a decreased dose should also be made in cases of renal impairment.


The TCAs, or their active metabolites, have plasma exposure half-lives of 8-80 hours; this makes once-daily dosing possible for most of the compounds (Rudorfer and Potter, 1999). Steady-state concentrations occur within several days to several weeks of beginning treatment. TCAs are largely eliminated by hepatic CYPs (see Table 15–3). Determination of plasma levels may be useful in identifying patients who appear to have toxic effects and may have excessively high levels of the drug, or those in whom lack of absorption or noncompliance is suspected. Dosage adjustments of TCAs are typically made according to patient's clinical response, not based on plasma levels. Nonetheless, monitoring the plasma exposure has an important relationship to treatment response: there is a relatively narrow therapeutic window, as discussed below.

About 7% of patients metabolize TCAs slowly due to a variant CYP2D6 isoenzyme, causing a 30-fold difference in plasma concentrations among different patients given the

same TCA dose. To avoid toxicity in "slow metabolizers," plasma levels should be monitored and doses adjusted downward.


MAOIs are metabolized by acetylation, although the end products are incompletely characterized. A significant portion of the population (50% of the Caucasian population and an even higher percentage among Asians) are "slow acetylators" and will exhibit elevated plasma levels. The nonselective MAOIs used in the treatment of depression are irreversible (sometimes called "suicide") inhibitors; thus, it takes up to 2 weeks for MAO activity to recover, even though the parent drug is excreted within 24 hours (Livingston and Livingston, 1996). Recovery of normal enzyme function is dependent on synthesis and transport of new MAO to monoaminergic nerve terminals. Despite this irreversible enzyme inhibition, MAOIs require daily dosing.

Adverse Effects


The SSRIs, unlike the TCAs, do not cause major cardiovascular side effects. The SSRIs are generally free of antimuscarinic side effects (dry mouth, urinary retention, confusion), do not block histamine or adrenergic receptors, and are not sedating (Table 15–4). The favorable side effect profile of the SSRIs may lead to better patient compliance compared to that for the TCAs.

Table 15–4 Potencies of Selected Antidepressants at Muscarinic, Histamine H1, and Alpha1 Adrenergic Receptors

RECEPTOR TYPE

DRUG MUSCARINIC CHOLINERGIC

HISTAMINE H1

1 ADRENERGIC

Amytriptyline 18 1.1 27

Amoxapine 1000 25 50

Atomoxetine 1000 1000 1000

Bupropion 40,000 6700 4550

R,S-Citalopram

1800 380 1550

S-Citalopram 1240 1970 3870

Clomipramine 37 31.2 39

Desipramine 196 110 130

Doxepin 83.3 0.24 24

Duloxetine 3000 2300 8300

Fluoxetine 2000 6250 5900

Fluvoxamine 24,000 >100,000 7700

Imipramine 91 11.0 91

Maprotiline 560 2.0 91

Mirtazapine 670 0.1 500

Nefazodone 11,000 21 25.6

Nortriptyline 149 10 58.8

Paroxetine 108 22,000 >100,000

Protriptyline 25 25 130

Reboxetine 6700 312 11,900

Sertraline 625 24,000 370

Trazodone >100,000 345 35.7

Trimipramine 59 0.3 23.8

Venlafaxine >100,000 >100,000 >100,000

Values are experimentally determined potencies (Ki values, nM) for binding to receptors that contribute to common side effects of clinically used antidepressant drugs: muscarinic cholinergic receptors (e.g., dry mouth, urinary retention, confusion), histamine H1 receptors (sedation), and 1 adrenergic receptors (orthostatic hypotension, sedation).

Source: Data adapted from Leonard and Richelson (2000). SSRIs are not free from side effects, however. Excessive stimulation of brain 5-HT2 receptors may result in insomnia, increased anxiety, irritability, and decreased libido, effectively worsening prominent depressive symptoms. Excess activity at spinal 5-HT2 receptors causes sexual side effects including erectile dysfunction, anorgasmia, and ejaculatory delay; these effects may be more prominent with paroxetine (Vaswani et al., 2003). Stimulation of 5-HT3 receptors in the CNS and periphery contributes to GI effects, which are usually limited to nausea but may include diarrhea and emesis. Some patients experience an increase in anxiety, especially with the initial dosing of SSRIs. With continued treatment, some patients also report a dullness of intellectual abilities and concentration. In addition a phenomenon of a residual "flat affect" can occur in an otherwise successful treatment with SSRIs. A number of these side effects may be difficult to distinguish from symptoms of depression.

In general, there is not a strong relationship between SSRI serum concentrations and therapeutic efficacy. This finding is not surprising given that most antidepressant studies have been conducted at doses/plasma exposures which saturate the brain SERT, consistent with the flat dose or exposure/efficacy relationships observed. Thus, dosage adjustments are based more on evaluation of clinical response and management of side effects than on measurements of plasma drug concentrations.

Sudden withdrawal of antidepressants can precipitate a withdrawal syndrome. For SSRIs or SNRIs, the symptoms of withdrawal may include dizziness, headache, nervousness, nausea, and insomnia. This withdrawal syndrome appears most intense for paroxetine and venlafaxine compared to other antidepressants due to their relatively short half-lives and, in the case of paroxetine, lack of active metabolites. On the other

hand, the active metabolite of fluoxetine, norfluoxetine, has such a long t1/2 (1-2 weeks) that few patients experience any withdrawal symptoms when discontinuing fluoxetine.

Unlike the other SSRIs, paroxetine is associated with an increased risk of congenital cardiac malformations. Epidemiological data suggest that paroxetine might increase the risk of congenital cardiac malformations when administered in the first trimester of pregnancy. Venlafaxine also is associated with an increased risk of perinatal complications. Therefore, these drugs should not be used in pregnant women; careful consideration should be given to using these mediations in women of reproductive potential, and these subjects should be advised to avoid pregnancy while they are taking the drugs.


The SNRIs have desirable safety advantages over the TCAs (Table 15–4). SNRIs have a side effect profile similar to that of the SSRIs, including nausea, constipation, insomnia, headaches, and sexual dysfunction. The immediate release formulation of venlafaxine can induce sustained diastolic hypertension (systolic blood pressure > 90 mm Hg at consecutive weekly visits) in 10-15% of patients at higher doses; this risk is reduced with the extended-release form. This effect of venlafaxine may not be associated simply with inhibition of NET, since duloxetine does not share this side effect.


The main side effects of mirtazapine, seen in >10% of the patients in clinical trials, are somnolence, increased appetite, and weight gain. A rare side effect of mirtazapine is agranulocytosis. In the 2 patients having this side effect during the pre-marketing phase in nearly 2800 patients, bone marrow function recovered when mirtazapine treatment was discontinued. Trazodone use is associated with priapism in rare instances; this should be considered a medical emergency and surgical intervention may be required. Nefazodone was voluntarily withdrawn from the market in Europe and the U.S. after rare cases of liver failure were associated with its use. Generic nefazodone is still available in the U.S.

Bupropion

At doses higher than that recommended for depression (450 mg/day), the risk of seizures increases significantly. The use of extended release formulations often blunts the maximum concentration observed after dosing and minimizes the chance of reaching drug levels associated with an increased risk of seizures.


TCAs are potent antagonists at histamine H1 receptors; H1 receptor antagonism contributes to the sedative effects of TCAs (Table 15–4). Antagonism of muscarinic acetylcholine receptors contributes to cognitive dulling as well as a range of adverse effects mediated by the parasympathetic nervous system (blurred vision, dry mouth, tachycardia, constipation, difficulty urinating). Some tolerance does occur for these anticholinergic effects, which are mitigated by titration strategies to reach therapeutic

doses over a reasonable period of time. Antagonism of 1 adrenergic receptors contributes to orthostatic hypotension and sedation. Weight gain is another side effect of this class of antidepressants.

TCAs also have quinidine-like effects on cardiac conduction that can be life threatening with overdose and limit the use of TCAs in patients with coronary heart disease. This is the primary reason that no more than a one-week supply should be provided to a new patient; even during maintenance treatment, only a very limited supply should be available to the patient at any given time. Like other antidepressant drugs, TCAs also lower the seizure threshold.


Hypertensive crisis resulting from food or drug interactions is one of the life-threatening toxicities associated with use of the MAOIs. Foods containing tyramine are a contributing factor. MAO-A within the intestinal wall and MAO-A and MAO-B in the liver normally degrade dietary tyramine. However, when MAO-A is inhibited, the ingestion of certain aged cheeses, red wines, sauerkraut, fava beans, and a variety of other tyramine-containing foods leads to accumulation of tyramine in adrenergic nerve endings and neurotransmitter vesicles and induces norepinephrine and epinephrine release. The released catecholamines stimulate postsynaptic receptors in the periphery, increasing blood pressure to dangerous levels. These episodes can be reversed by antihypertensive medications. Even when the patient is highly vigilant, dietary indiscretions or use of prescription or over-the-counter medications that contain sympathomimetic compounds may occur, resulting in a potentially life-threatening elevation of blood pressure. In comparison to tranylcypromine and isocarboxazid, the selegiline transdermal patch is better tolerated and safer. Another serious, life-threatening issue with chronic administration of MAOIs is hepatotoxicity.

MAO-A inhibitors are efficacious in treating depression. However, MAO-B inhibitors such as selegiline (with oral formulations) are effective in treating depression only when given at doses that block both MAO-A and MAO-B. Thus, these data emphasize the importance of enhancing the synaptic availability of 5-HT and NE as important mediating events for many antidepressant drugs. While not available in the U.S., reversible inhibitors of MAO-A (RIMAs, such as moclobemide) have been developed. Since these drugs are selective for MAO-A, significant MAO-B activity remains. Further, since the inhibition of MAO-A by RIMAs is reversible and competitive, as concentrations of tyramine rise, enzyme inhibition is surmounted. Thus, RIMAs produce antidepressant effects with reduced risk of tyramine-induced hypertensive crisis.

Drug Interactions


Most antidepressants, including the SSRIs, exhibit drug-drug interactions based on their routes of metabolism CYPs. Paroxetine and, to a lesser degree, fluoxetine are potent inhibitors of CYP2D6 (Hiemke and Hartter, 2000). The other SSRIs, outside of fluvoxamine, are at least moderate inhibitors of CYP2D6. This inhibition can result in

disproportionate increases in plasma concentrations of drugs metabolized by CYP2D6 when doses of these drugs are increased. Fluvoxamine directly inhibits CYP1A2 and CYP2C19; fluoxetine and fluvoxamine also inhibit CYP3A4. A prominent interaction is the increase in TCA exposure that may be observed during co-administration of TCAs and SSRIs.

Another important drug-drug interaction with SSRIs occurs via a pharmacodynamic mechanism. MAOIs enhance the effects of SSRIs due to inhibition of serotonin metabolism. Administration of these drugs together can produce synergistic increases in extracellular brain serotonin, leading to the serotonin syndrome. Symptoms of the serotonin syndrome include hyperthermia, muscle rigidity, myoclonus, tremors, autonomic instability, confusion, irritability, and agitation; this can progress toward coma and death. Other drugs that may induce the serotonin syndrome include substituted amphetamines such as methylenedioxymethamphetamine (Ecstasy), which directly releases serotonin from nerve terminals. The primary treatment is stopping all serotonergic drugs, administering nonselective serotonin antagonists, and supportive measures.

Since currently available MAOIs bind irreversibly to MAO and block the enzymatic metabolism of monoaminergic neurotransmitters, SSRIs should not be started until at least 14 days following discontinuation of treatment with an MAOI; this allows for synthesis of new MAO. For all SSRIs but fluoxetine, at least 14 days should pass prior to beginning treatment with an MAOI following the end of treatment with an SSRI. Since the active metabolite norfluoxetine has a t1/2 of 1-2 weeks, at least 5 weeks should pass between stopping fluoxetine and beginning an MAOI.


While 14 days are suggested to elapse from ending MAOI therapy and starting venlafaxine treatment, an interval of only 7 days after stopping venlafaxine is considered safe before beginning an MAOI. Duloxetine has a similar interval to initiation following MAOI therapy, but requires only a 5-day waiting period to begin MAOI treatment after ending duloxetine. Failure to observe these required waiting periods can result in the serotonin syndrome, as noted above for SSRIs.


Trazodone dosing may need to be lowered when given together with drugs that inhibit CYP3A4. Mirtazapine is metabolized by CYPs 2D6, 1A2, and 3A4, but does not potently inhibit any of these isoenzymes. Trazodone and nefazodone are weak inhibitors of serotonin uptake and should not be administered with MAOIs due to concerns about the serotonin syndrome. However, it is unclear whether these drugs appreciably block brain SERT at doses used in the treatment of depression.

Bupropion

The major route of metabolism for bupropion is CYP2B6. While there does not appear to be any evidence for metabolism by CYP2D6 and this drug is frequently administered with SSRIs, the potential for interactions with drugs metabolized by CYP2D6 should be

kept in mind until the safety of the combination is firmly established.


Drugs that inhibit CYP2D6, such as SSRIs, may increase plasma exposures of TCAs. Other drugs that may act similarly are phenothiazine antipsychotic agents, type 1C anti-arrhythmic drugs, and other drugs with antimuscarinic, antihistaminic, and adrenergic antagonistic effects. TCAs can potentiate the actions of sympathomimetic amines and should not be used concurrently with MAOIs or within 14 days of stopping MAOIs.


A large number of drug-drug interactions lead to contraindications for simultaneous use with MAOIs. CNS depressants including meperidine and other narcotics, alcohol, and anesthetic agents should not be used with MAOIs. Meperidine and other opioid agonists in combination with MAOIs also induce the serotonin syndrome. As discussed earlier, SSRIs and SNRIs are contraindicated in patients on MAOIs, and vice versa, to avoid the serotonin syndrome. In general, other antidepressants such as TCAs and bupropion also should be avoided in patients taking an MAOI.Anxiolytic Drugs

A variety of agents and drug classes provide anxiolytic effects. The primary treatments for anxiety-related disorders include the SSRIs, SNRIs, benzodiazepines, the azipirone buspirone, and beta adrenergic antagonists (Atack, 2003). Historically, TCAs, particularly clomipramine, and MAOIs have been used for the treatment of some anxiety-related disorders, but their use has been supplanted by drugs with lower toxicity. Specific issues relating to mechanism of action, adverse effects, pharmacokinetics, and drug interactions are discussed earlier and in Chapters 16 and 17.

The SSRIs and the SNRI venlafaxine (discussed earlier) are well tolerated with a reasonable side effect profile; in addition to their documented antidepressant activity, they also have have anxiolytic activity with chronic treatment. The benzodiazepines are effective anxiolytics as both acute and chronic treatment. There is concern regarding their use because of their potential for dependence and abuse as well as negative effects on cognition and memory. Buspirone, like the SSRIs, is effective following chronic treatment. In acts, at least in part, via the serotonergic system, where it is a partial agonist at 5-HT1A receptors. Buspirone also has antagonistic effects at dopamine D2 receptors, but the relationship between this effect and its clinical actions is uncertain. adrenergic antagonists, particularly those with higher lipophilicity (e.g., propranolol and nadolol) are occasionally used for performance anxiety such as fear of public speaking; their use is limited due to significant side effects such as hypotension.

The antihistamine hydroxyzine and various sedative-hypnotic agents have been used as anxiolytics, but are generally not recommended because of their side effect profiles. Hydroxyzine, which produces short-term sedation, has been used in patients that cannot use other types of anxiolytics (e.g., those with a history of drug or alcohol abuse where benzodiazepines would be avoided). Chloral hydrate has been used for situational anxiety, but there is a narrow dose range where anxiolytic effects are observed in the absence of significant sedation, and, therefore, the use of chloral hydrate is not

recommended.

Clinical Considerations with Anxiolytic Drugs

The choice of pharmacological treatment for anxiety is dictated by the specific anxiety-related disorders and the clinical need for acute anxiolytic effects (Millan, 2003). Among the commonly used anxiolytics, only the benzodiazepines and adrenergic antagonists are effective acutely; the use of adrenergic antagonists is generally limited to treatment of situational anxiety. Chronic treatment with SSRIs, SNRIs, and buspirone is required to produce and sustain anxiolytic effects. When an immediate anxiolytic effects is desired, benzodiazepines are typically selected.

Benzodiazepines, such as alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, lorazepam, and oxazepam, are effective in the treatment of generalized anxiety disorder, panic disorder, and situational anxiety. In addition to their anxiolytic effects, benzodiazepines produce sedative, hypnotic, anesthetic, anticonvulsant, and muscle relaxant effects. The benzodiazepines also impair cognitive performance and memory, adversely affect motor control, and potentiate the effects of other sedatives including alcohol. The anxiolytic effects of this class of drugs are mediated by allosteric interactions with the pentameric benzodiazepine-GABAA receptor complex, in particular those GABAA receptors comprised of 2, 3, and 5 subunits (Chapters 14 and 17). The primary effect of the anxiolytic benzodiazepines is to enhance the inhibitory effects of the neurotransmitter GABA.

One area of concern regarding the use of benzodiazepines in the treatment of anxiety is the potential for habituation, dependence, and abuse. Patients with certain personality disorders or a history of drug or alcohol abuse are particularly susceptible. However, the risk of dependence must be balanced with the need for treatment, since benzodiazepines are effective in both short- and long-term treatment of patients with sustained or recurring bouts of anxiety. Further, premature discontinuation of benzodiazepines, in the absence of other pharmacological treatment, results in a high rate of relapse. Withdrawal of benzodiazepines after chronic treatment, particularly those with short durations of action, can include increased anxiety and seizures. For this reason, it is important that discontinuation be carried out in a gradual manner.

Benzodiazepines cause many adverse effects, including sedation, mild memory impairments, decreased alertness, and slowed reaction time (which may lead to accidents). Memory problems can include visual-spatial deficits, but will manifest clinically in a variety of ways, including difficulty in word-finding. Occasionally, paradoxical reactions can occur with benzodiazepines such as increases in anxiety, sometimes reaching panic attackproportions. Other pathological reactions can include irritability, aggression, or behavioral disinhibition. Amnesic reactions (i.e., loss of memory for particular periods) can also occur. Benzodiazepines should not be used in pregnant women; there have been rare reports of craniofacial defects. In addition, benzodiazepines taken prior to delivery may result in sedated, under-responsive newborns and prolonged withdrawal reactions. In the elderly, benzodiazepines increase the risk for falls and must be used cautiously. These drugs are safer than classical sedative-hypnotics in overdosage and typically are fatal only if combined with other

CNS depressants.

Benzodiazepines have at least some abuse potential, although their capacity for abuse is considerably below that of other classical sedative-hypnotic agents. When these agents are abused, it is generally in a multi-drug abuse pattern. In fact, the primary reason for misuse of these agents often is failed attempts to control anxiety. Tolerance to the anxiolytic effects develops with chronic administration, with the result that some patients escalate the dose of benzodiazepines over time. Ideally, benzodiazepines should be used for short periods of time and in conjunction with other medications (e.g., SSRIs) or evidence-based psychotherapies (e.g., cognitive behavioral therapy for anxiety disorders).

SSRIs and the SNRI venlafaxine are first-line treatments for most types of anxiety disorders, except when an acute drug effect is desired; fluvoxamine is approved only for obsessive-compulsive disorder. As for their antidepressant actions, the anxiolytic effects of these drugs become manifest following chronic treatment. Other drugs with actions on serotonergic neurotransmission, including trazodone, nefazodone, and mirtazapine, also are used in the treatment of anxiety disorders. Details regarding the pharmacology of these classes of were presented earlier.

Both SSRIs and SNRIs are beneficial in specific anxiety conditions such as generalized anxiety disorder, social phobias, obsessive-compulsive disorder, and panic disorder. These effects appear to be related to the capacity of serotonin to regulate the activity of brain structures such as amygdala and locus coeruleus that are thought to be involved in the genesis of anxiety. Interestingly, the SSRIs and SNRIs often will produce some increases in anxiety in the short-term that dissipate with time. Therefore, the maxim "start low and go slow" is indicated with anxious patients; however, many patients with anxiety disorders ultimately will require doses that are about the same as those required for the treatment of depression. Anxious patients appear to be particularly prone to severe discontinuation reactions with certain medications such as venlafaxine and paroxetine; therefore, slow off-tapering is required.

Buspirone is used in the treatment of generalized anxiety disorder (Goodman, 2004). Like the SSRIs, buspirone requires chronic treatment for effectiveness. Also, like the SSRIs, buspirone lacks many of the other pharmacological effects of the benzodiazepines: it is not an anticonvulsant, muscle relaxant, or sedative, and it does not impair psychomotor performance or result in dependence. Buspirone is primarily effective in the treatment of generalized anxiety disorder, but not for other anxiety disorders. In fact, patients with panic disorder often note an increase in anxiety acutely following initiation of buspirone treatment; this may be the result of the fact that buspirone causes increased firing rates of the locus coeruleus, which is thought to underlie part of the pathophysiology of panic disorder.Clinical Summary

Mood and anxiety disorders are the most common psychiatric illnesses and are encountered frequently by clinicians in all disciplines. Depression represents a spectrum of conditions with a range of severity and a high frequency of comorbidities. Depressive conditions range from mild, self-limiting conditions to extremely severe illnesses that can include a high suicidal potential, psychosis, and serious functional impairment.

Whereas the likelihood of receiving treatment for depression or anxiety has improved, problems remain with regard to duration, dosing, and adherence to treatment. Unfortunately, persons with depressive or anxiety disorders continue to suffer considerable delays in diagnosis and adequate treatment. Prominently used agents inhibit transmitter reuptake via SERT and NET.

Current antidepressant and anxiolytic treatment strategies are imperfect. Many patients have significant residual symptoms after pharmacotherapy. Fortunately, antidepressant/anxiolytic drug development is expanding beyond standard 5-HT and NE uptake inhibitors. New antidepressant medications include triple (5-HT, NE, and DA) reuptake inhibitors, agents combining inhibition of 5-HT reuptake and modulation of 5-HT receptors, antagonists of CNS peptides (e.g., corticotropin-releasing hormone-1 receptor and neurokinin-1), modulators of cyclic nucleotide signaling, 1 and 2 receptor ligands, melatonin receptors (particularly, combined 5-HT receptor antagonists/melatonin receptor agonists), and glutamate receptor antagonists (Zarate, Jr. et al., 2006).

Drugs that target NMDA, AMPA, and metabotropic glutamate receptors are very promising. Other targets, such as specific 5-HT receptor agonists, partial agonists, or antagonists, and GABAA receptor agonists may prove useful in the future for anxiety. Modulating the endocannabinoid signaling system is also promising with regard to both antidepressant and anxiolytic actions. Finally, there is increasing evidence that some naturally occurring products such as S-adenosylmethionine, l-methylfolate, N-acetyl cysteine, and omega-3 fatty acids may be useful in depression and anxiety.Bibliography

Andrews JM, Nemeroff CB. Contemporary management of depression. Am J Med, 1994, 97:24S–32S.

Atack JR. Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site. Curr Drug Targets CNS Neurol Disord, 2003, 2:213–232. [PMID: 12871032]

Benmansour S, Cecchi M, Morilak DA, et al. Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level. J Neurosci, 1999, 19:10494–10501. [PMID: 10575045]

Brockmöller J, Meineke I, Kirchheiner J. Pharmacokinetics of mirtazapine: Enantioselective effects of the CYP2D6 ultra rapid metabolizer genotype and correlation with adverse effects. Clin Pharmacol Therap, 2007, 81:699–707.

Cannon TD, Keller MC. Endophenotypes in the genetic analyses of mental disorders. Annu Rev Clin Psychol, 2006, 2:267–290. [PMID: 17716071]

Chen YW, Dilsaver SC. Lifetime rates of suicide attempts among subjects with bipolar and unipolar disorders relative to subjects with other Axis I disorders. Biol Psychiatry, 1996, 39:896–899. [PMID: 8860192]

Cryan JF, Holmes A. The ascent of mouse: Advances in modelling human depression

and anxiety. Nature Rev, 2005, 4:775–790. [PMID: 16138108]

Danish University Antidepressant Group (DUAG). Clomipramine dose-effect study in patients with depression: clinical end points and pharmacokinetics. Clin Pharmacol Ther, 1999, 66:152–165.

Delgado PL, Price LH, Miller HL, et al. Rapid serotonin depletion as a provocative challenge test for patients with major depression: Relevance to antidepressant action and the neurobiology of depression. Psychopharmacol Bull, 1991, 27: 321–330. [PMID: 1775606]

DeRubeis RJ, Siegle GJ, Hollon SD. Cognitive therapy versus medication for depression: Treatment outcomes and neural mechanisms. Nat Rev Neurosci, 2008, 9:788–796. [PMID: 18784657]

Entsuah AR, Huang H, Thase ME. Response and remission rates in different subpopulations with major depressive disorder administered venlafaxine, selective serotonin reuptake inhibitors, or placebo. J Clin Psychiatry, 2001, 62:869–877. [PMID: 11775046]

Foley KF, DeSanty KP, Kast RE. Bupropion: Pharmacology and therapeutic applications. Expert Rev Neurother, 2006, 6: 1249–1265. [PMID: 17009913]

Frazer A. Pharmacology of antidepressants. J Clin Psychophar-macol, 1997, 17(Suppl 1):2S–18S.

Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry, 2007, 164:1356–1363. [PMID: 17728420]

Goldberg JF, Truman CJ. Antidepressant-induced mania: An overview of current controversies. Bipolar Disord, 2003, 5:407–420. [PMID: 14636364]

Goodman WK. Selecting pharmacotherapy for generalized anxiety disorder. J Clin Psychiatry, 2004, 65(Suppl 13):8–13.

Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther, 2000, 85:11–28. [PMID: 10674711]

Hollister LE. Current antidepressant drugs: Their clinical use. Drugs, 1981, 22:129–152. [PMID: 6114851]

Jarema M. Atypical antipsychotics in the treatment of mood disorders. Curr Opin Psychiatry, 2007, 20:23–29. [PMID: 17143078]

Katz MM, Tekell JL, Bowden CL, et al. Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology, 2004, 29:566–579. [PMID: 14627997]

Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity

Survey. Arch Gen Psychiatry, 1994, 51:8–19. [PMID: 8279933]

Leonard BE, Richelson E. Synaptic effects of anitdepressants. In, Schizophrenia and Mood Disorders: The New Drug Therapies in Clinical Practice. (Buckley PF, Waddington JL, eds.) Butterworth-Heinemann, Boston, 2000, pp. 67–84.

Livingston MG, Livingston HM. Monoamine oxidase inhibitors. An update on drug interactions. Drug Saf, 1996, 14:219–227. [PMID: 8713690]

Manganas LN, Zhang X, Li Y, et al. Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science, 2007, 318:980–985. [PMID: 17991865]

Mann JJ, Emslie G, Baldessarini RJ, et al. ACNP Task Force report on SSRIs and suicidal behavior in youth. Neuropsychopharmacology, 2006, 31:473–492. [PMID: 16319919]

Millan MJ. The neurobiology and control of anxious states. Prog Neurobiol, 2003, 70:83–244. [PMID: 12927745]

Millan MJ. Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther, 2006, 110:135–370. [PMID: 16522330]

Miller HL, Delgado PL, Salomon RM, et al. Effects of alpha-methyl-para-tyrosine (AMPT) in drug-free depressed patients. Neuropsychopharmacology, 1996, 14:151–157. [PMID: 8866698]

Miller EJ, Saint Marie LR, Breier MR, Swerdlow NR. Pathways from the ventral hippocampus and caudal amygdala to forebrain regions that regulate sensorimotor gating in the rat. Neuroscience, 2010, 165:601–611. [PMID: 19854244]

O'Donnell JM, Zhang HT. Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). Trends Pharmacol Sci, 2004, 25:158–163. [PMID: 15019272]

Owens MJ, Morgan WN, Plott SJ, Nemeroff CB. Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther, 1997, 283:1305–1322. [PMID: 9400006]

Rakofsky JJ, Holtzheimer PE, Nemeroff CB. Emerging targets for antidepressant therapies. Curr Opin Chem Biol, 2009, 13:291–302. [PMID: 19501541]

Rudorfer MV, Potter WZ. Metabolism of tricyclic antidepressants. Cell Mol Neurobiol, 1999, 19:373–409. [PMID: 10319193]

Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry, 2006, 163:1905–1917. [PMID: 17074942]

Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the

behavioral effects of antidepressants. Science, 2003, 301:805–809. [PMID: 12907793]

Schmidt HD, Duman RS. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav Pharmacol, 2007, 18:391–418. [PMID: 17762509]

Sen S, Duman R, Sanacora G. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: Meta-analyses and implications. Biol Psychiatry, 2008, 64: 527–532. [PMID: 18571629]

Shelton RC. Cellular mechanisms in the vulnerability to depression and response to antidepressants. Psychiatr Clin North Am, 2000, 23:713–729. [PMID: 11147243]

Shelton RC. Augmentation strategies to increase antidepressant efficacy. J Clin Psychiatry, 2007, 68(Suppl 10):18–22.

Shelton RC, Lester N. SSRIs and newer antidepressants, In, APA Textbook of Mood Disorders. APA Press, Washington, D.C., 2006.

Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry, 2006, 163:41–47. [PMID: 16390887]

Suominen KH, Isometsa ET, Henriksson MM, et al. Inadequate treatment for major depression both before and after attempted suicide. Am J Psychiatry, 1998, 155:1778–1780. [PMID: 9842794]

Vaswani M, Linda FK, Ramesh S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: A comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry, 2003, 27:85–102. [PMID: 12551730]

Witkin JM, Marek GJ, Johnson BG, Schoepp DD. Metabotropic glutamate receptors in the control of mood disorders. CNS Neurol Disord Drug Targets, 2007, 6:87–100. [PMID: 17430147]

Zarate CA Jr., Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry, 2006, 63:856–864. [PMID: 16894061]

Zhao Z, Baros AM, Zhang HT, et al. Norepinephrine transporter regulation mediates the long-term behavioral effects of the antidepressant desipramine. Neuropsychopharmacology, 2008, 33:3190–3200. [PMID: 18418364]

Zhao Z, Zhang HT, Bootzin E, et al. Association of changes in norepinephrine and serotonin transporter expression with the long-term behavioral effects of antidepressant drugs. Neuropsychopharmacology, 2009, 34:1467–1481. [PMID: 18923402]

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15. Drug Therapy of Depression and Anxiety Disorders