Selective Serotonin Reuptake Inhibitors. 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.
Serotonin-Norepinephrine Reuptake Inhibitors. 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.
Serotonin Receptor Antagonists. 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.
Tricyclic Antidepressants. 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 α 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.
Monoamine Oxidase Inhibitors. 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.
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. β 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 β adrenergic antagonists are effective acutely; the use of β 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 α2, α3, and α5 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 attack proportions. 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.