Panic attacks and panic disorder are common problems in the primary care setting. Patients with panic disorder may present with classic discrete episodes of intense fear that begin abruptly and last several minutes to an hour; however, they more commonly complain of one or more physical symptoms. By learning to recognize the DSM-IV criteria for panic disorder, the associated behavioral avoidance patterns, and psychiatric comorbid disorders such as major depression and agoraphobia, the primary care physician can make an accurate diagnosis and effectively treat patients with this disorder.
It is important to distinguish between panic attacks and panic disorder Panic attacks are characterized by the sudden onset of intense fear and by the abrupt development of specific somatic, cognitive, and affective symptoms.
While panic attacks are common, patients who present with a panic attack are often mistakenly given the diagnosis of panic disorder. Panic disorder is a chronic condition in which patients have recurrent panic attacks in association with one of the following: worry about future attacks, phobic avoidance of situations that could trigger an attack, or other change in behavior due to the attacks such as frequent medical or emergency room visits.
- A large study of psychiatric illness in the general population found that a surprisingly large number of the community respondents (7.3 percent) experienced infrequent panic attacks without meeting full DSM-IV criteria for panic disorder. The 12-month prevalence of panic disorder was 3.2 percent in women and 1.3 percent in men, with a lifetime prevalence of 5 and 2 percent, respectively. Other reports have found that a somewhat higher prevalence of panic disorder exists in the primary care setting, in the range of 4 to 7 percent. Single attacks, which do not meet criteria for panic disorder, are much more common, occurring in up to one-third of individuals at some point in their lifetime.
Patients with panic disorder may have cognitive, affective, and somatic symptoms. The somatic symptoms often predominate and mimic other medical disorders. Thus, it is not surprising that most patients present to medical rather than mental health providers. In one report, for example, 35 percent of patients with panic disorder presented to their family physician, 32 percent to a hospital emergency department, and only 26 percent to a mental health setting.
Healthcare utilization — Unexplained medical symptoms are common in the primary care setting. The magnitude of this problem was illustrated in a 3-year study of primary care physicians which examined the 10 most common symptoms prompting patient visits to primary care providers: an organic cause for the symptoms was found in only 10 percent of individuals at the end of a one year follow-up period. These 10 symptoms, which included complaints common in patients with panic disorder such as chest pain, fatigue, dizziness, headache, and abdominal pain, prompted nearly one-half of all physician visits.
Many patients with unexplained medical symptoms have panic disorder; they are often unsatisfied with a negative physical work-up and repeatedly seek care for continuing frightening symptoms. In one report, for example, 40 of 57 patients (70 percent) saw an average of 10 physicians before finally receiving a diagnosis of panic disorder. Others have shown that these patients have a significant increased utilization of medical services (eg, consultation rates, specialty physicians referrals, emergency department visits, hospital admissions, medication prescriptions, and laboratory tests) compared to age- and gender-matched controls; their extensive use of resources often precedes the diagnosis of panic disorder by as long as 10 years.
These data are consistent with several analyses from the Epidemiological Catchment Area data which found that patients with panic disorder had the largest odds ratio for high utilization of medical services when compared with controls without psychiatric illness (8.2 for men and 5.2 for women). Utilization of primary care services among patients with panic disorder is roughly three times that of most patients in the United States health care system.
Panic disorder also reduces the quality of life and function in affected patients and their families. Decrements in familial, social, and vocational functioning occur, comparable to that seen with major depression. In one report, the number of disability days taken by patients with anxiety disorders was significantly greater than in those with diabetes, cardiac disease, or renal disease.
- Several neuroanatomic areas (including the amygdala, cingulate gyrus, midbrain raphe, locus ceruleus, and hippocampus) and a number of neurotransmitters (including norepinephrine, serotonin, and GABA [gamma-aminobutyric acid]) have been the focus of research into the pathophysiology of panic attacks and panic disorder.
Other lines of research have focused on the brainstem as the neural trigger for panic attacks, suggesting that patients may inherit brainstem loci that are hyperexcitable (accounting for sensitivity to lactate, increased carbon dioxide levels, and yohimbine in provoking panic attacks in experimental situations). The prefrontal cortex, an area of the higher brain involved with learning and complex emotions, has been viewed as a neuroanatomical substrate for phobic avoidance in panic disorder.
Amygdala - The amygdala, a structure in the temporal lobe, probably serves a central role in coordinating mammalian fear behaviors and responses. It receives afferent projections from the sensory and association cortices, the thalamus, and the hypothalamus, as well as from nuclei responsible for noradrenergic, dopaminergic, and serotonergic neurotransmission. Efferent output from the amygdala via the locus ceruleus projects to the following areas: The lateral hypothalamus, which is responsible for fear-induced sympathetic activation (tachycardia, increased blood pressure, sweating, piloerection and pupillary dilatation) The paraventricular nucleus of the hypothalamus, mediating the "hormone stress response" (eg, corticotropin-releasing hormone) The dorsal nucleus of the vagus, leading to fear-induced increases in urination, defecation, and bradycardia
Electrical stimulation of the locus ceruleus produces fear behaviors in animal models; decreased fear behaviors result from bilateral lesions of the locus ceruleus.
Anterior and posterior cingulate cortices — The anterior and posterior cingulate cortices have been implicated in the modulation of anxiety in electrophysiologic and brain-mapping studies in human and nonhuman primates. A study using quantitative PET image analysis found a marked reduction in the density of the serotonin type 1a receptor (a specific serotonin receptor) in the anterior and posterior cingulate areas and in the midbrain raphe of patients with panic disorder compared with controls. Stimulation of the serotonin type 1a receptor in these areas regulates the synthesis and release of serotonin.
Hippocampus -o The septohippocampal area has also been proposed as an integrator of incoming novel and unpleasant stimuli. This area has intimate interconnections with the temporal lobe; it is believed that the septohippocampal system predicts the next sensory event to which the organism is exposed, checks whether it actually occurs, and inhibits behavior if there is a mismatch or if the event is aversive.
This biologic system has many similarities to the cognitive model of panic disorder which suggests that panic symptoms result from errors in cognitive appraisal, leading to increased levels of anxiety, arousal, and somatic complaints that result in a vicious cycle of anxiety symptoms. Supportive research has demonstrated that electrical stimulation of this region most commonly produces sensations of fear in the awake human subject.
Genetic and environmental factors - First-degree relatives of patients with panic disorder meet criteria for the disorder in 18 to 41 percent of cases. Twin studies have shown a higher concordance for monozygotic than dizygotic twins (31 and 0 percent, respectively, in one series).
The modest concordance among monozygotic twins suggests that environmental factors also play a role in the etiology of panic disorder. Patients with panic disorder recall more childhood fears, more anxiety in childhood, and have a higher rate of grossly disturbed childhood environments than controls. Patients also report significantly more stressful life events than controls in the six months prior to developing anxiety attacks (see below).
- Panic attacks are characterized by the sudden onset of intense apprehension, fear or terror, and by the abrupt development of specific somatic, cognitive, and affective symptoms (show table 1). In a study of 55 primary care patients with panic disorder, presenting complaints included the following: Cardiologic — 39 percent (chest pain in 22 percent, tachycardia in 25 percent) Neurologic — 44 percent (headaches in 20 percent, dizziness in 18 percent, faintness and pseudoseizures in 9 percent) Gastrointestinal - 33 percent (epigastric pain in 15 percent)
Paresthesias, irritable bowel symptoms, and shortness of breath were also frequently seen.
It is important to appreciate the relationship between panic disorder and atypical chest pain. In a review of the literature, panic disorder was present in 30 percent or more of patients with chest pain who have no or minimal coronary disease; it can also coexist with coronary disease.
Patients with panic disorder also may have a higher prevalence of other disorders. These include asthma, labile hypertension, mitral valve prolapse, and migraine headaches compared to controls.
Panic attacks often occur at times of significant life stress. Various controlled studies have found that these individuals have a higher frequency than controls of stressful life events that connote danger and threat, events viewed as uncontrollable or undesirable and that cause severe lowering of self esteem, and events that involve the death or severe illness of a friend or relative.
Panic attacks may also occur after a physical illness, accident, trauma, rape, or assault, and after endocrinologic changes (eg, hyperthyroidism). Some patients selectively minimize or deny stressful life events, directing their focus toward somatic symptoms; alternatively, they perceive their distress as secondary to the frightening physical sensations.
Natural history - Panic disorder is a recurrent or chronic disease in the majority of cases. In a review of sixteen studies using modern diagnostic criteria, most patients had improvement of symptoms, but few experienced complete resolution. Comorbid agoraphobia, major depression, and personality disorders were found to predict a poorer outcome. In a second study, 55 patients with panic disorder initially evaluated in a specialty clinic were reinterviewed 15 to 60 months after naturalistic treatment in the community. Most patients had improved, but only 5 were asymptomatic at follow-up.
Associated morbidity and mortality - The occurrence of at least one full-blown panic attack over a six month period was associated with an increase in the incidence of coronary heart disease over a five year follow-up period (HR 4.2, 95% CI 1.8-10) among 3400 postmenopausal women participating in the Women's Health Initiative observational study. All cause mortality was also increased (HR 1.75) and there was a trend toward an increased risk for stroke. The risk for coronary heart disease was intermediate for women reporting limited-symptom panic episodes.
- There is significant psychiatric comorbidity in individuals with panic disorder: One-third to one-half of patients meet DSM-IV criteria for major depression at initial presentation, while 60 to 90 percent have had one or more lifetime episodes of major depression. Approximately 40 percent meet DSM-IV criteria for agoraphobia (anxiety and avoidance of places from which escape might be difficult or help unavailable in the event of panic symptoms).
The majority of patients in the primary care setting who meet criteria for generalized anxiety disorder have a primary diagnosis of panic disorder or major depression.
Another problem in some patients with panic disorder (16 percent in one series) is a history of substance abuse. Alcohol and sedative hypnotics are sometimes used in desperation to control symptoms of panic disorder. These agents have a short-lived anxiolytic action, but are subsequently associated with rebound exacerbation of anxiety and panic attacks during declining blood levels. In addition, coexisting alcohol abuse with recurrent withdrawal can lead to a kindling effect on central controls of the sympathetic nervous system, resulting in more frequent and severe panic attacks.
Somatization disorder - One of the most difficult psychiatric diagnoses to differentiate from panic disorder is somatization disorder. In one study, for example, 32 of 78 women (41 percent) with somatization disorder also met criteria for panic disorder.
Three types of somatization are commonly seen in the primary care setting: Acute transient somatic symptoms in response to stress Subacute somatization in patients with major depression and panic disorder Chronic somatization in patients with developmental histories of physical, sexual, and emotional abuse and emotional neglect
The last group of patients may feel interpersonally powerless. As a reult, they may use somatic symptoms to persuade or even manipulate a spouse, to avoid intimacy, to obtain disability covereage, or to obtain prescribed medications that might be also used to regulate emotions (eg, opiates and benzodiazepines).
Treatment of panic disorder in patients with subacute somatization frequently cures the physical symptoms and the tendency to be hypochondriacal. In contrast, treatment of panic disorder or major depression in those with chronic somatization may only lead to a 30 to 40 percent reduction in somatic symptoms because of chronic social stressors and maladaptive patterns of coping with stress.
Medical disorders - The possibility of organic etiologies should always be considered prior to making the diagnosis of panic attacks. A number of conditions can mimic panic symptoms, such as angina, arrhythmias, chronic obstructive pulmonary disease, temporal lobe epilepsy, pulmonary embolus, asthma, hyperthyroidism, and pheochromocytoma (show table 2). Treatment side effects must also be considered in patients with certain medical disorders. Examples include hypoglycemia in the patient with diabetes and toxic serum aminophylline concentrations in the patient with asthma.
- The DSM-IV criteria for panic disorder focus upon three areas of symptom characteristics (show table 1): Recurrent unexpected panic attacks At least one month of persistent concern or anxiety over the possibility of additional attacks A significant change in behavior in relation to the panic attacks
Agoraphobia may become a comorbid problem when the persistent concern and worry of having another attack and avoidance become significant.
A correct diagnosis of panic disorder is made in 95 percent of cases if anxiety or depression are the presenting complaints; however, the likelihood of correct diagnosis decreases to 48 percent with a primarily somatic presentation. This is an important distinction because, in the primary care setting, approximately 90 percent of patients with panic disorder have mostly somatic symptoms.
History and physical examination — A complete medical and psychiatric history will lead to an accurate diagnosis of panic disorder in most cases. The history taking process should begin in an open-ended manner and be unhurried.
Information should be elicited about current life stress, separations, recent deaths, patient concerns and fears, interpersonal problems, recent substance abuse, use of medications (hypoglycemia from insuling or oral hypoblycemic medication can mimic panic attacks), and caffeine intake. The patient should also be asked about avoidance patterns that have developed since the onset of panic attacks. Involving family members can provide valuable information about precipitating events or may help clarify the current symptomatology.
Differentiating patients with concurrent somatization disorder requires questions regarding the existence of chronic somatization symptoms since adolescence, a family history of females with somatization disorder, a family history of males with antisocial personality disorder or substance abuse problems, chaotic family histories, childhood sexual or physical abuse or emotional neglect, and abuse of prescription drugs, street drugs, or alcohol.
A thorough physical and neurologic examination is essential to rule out an organic cause of symptoms.
Diagnostic testing - Limited laboratory testing such as thyroid function tests, complete blood count, and a chemistry panel are sufficient in most cases. Other laboratory and radiological tests may be indicated in more complicated cases. An electrocardiogram is required in anyone with significant cardiovascular symptoms, although it is likely to have a low yield in female patients under 40 years of age.
Costly and extensive diagnostic evaluations have low yield. As an example, 20 to 30 percent of patients who undergo coronary arteriography for chest pain are found to have normal coronary arteries. In one report, over 40 percent of such patients met the DSM-III-R criteria for panic disorder compared with 6.5 percent of those with chest pain and positive arteriograms.
Similar findings were noted in another study of 300 patients evaluated for pheochromocytoma. Only one had the disease, while 40 percent met the criteria for panic disorder compared with 5 percent of hypertensive controls.
- Treatment of panic disorder varies depending upon the stage of development of the disorder. Primary care providers will often see patients after the first panic attack, or in the earliest stages of the syndrome before phobic avoidance, anticipatory anxiety, or agoraphobia have developed. In the case of infrequent attacks in which there is no phobic avoidance, education about anxiety, supportive psychotherapy to deal with current life stressors, and instruction in relaxation techniques may be all that is necessary.
Providers can help patients who are experiencing a panic attack by reassuring them that they are not going to die, and that the panic attack will soon subside. Helping the patient relax in a quiet room either in the presence of a provider or a significant other, with emphasis on slowing down one's breathing can be helpful. Patients subjectively experience shortness of breath during a panic attack, when in fact they are usually hyperventilating. Pointing this out during or after the attack may help prevent a vicious cycle during the current or subsequent panic attacks in which the distressed patient hyperventilates instead of consciously slowing their breathing. In an emergency department or other clinical setting, sublingual, intravenous, or oral benzodiazepine (eg, lorazepam) may be used in addition, to help abort a panic attack.
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The development of antidepressant medications has proceeded through several historical phases. The older antidepressants such as monoamine oxidase inhibitors and early tricyclic antidepressants were discovered largely by serendipity. While effective antidepressants, these medications affect a wide range of neurotransmitter systems and cause many undesirable side effects. Subsequently, psychopharmacologic research and development efforts focused upon identifying the neurochemical properties associated with the antidepressant actions of these medications and upon developing compounds with variations on their chemical structure.
As theories were developed about the neurotransmitter systems involved in depression (eg, the monoamines serotonin, norepinephrine, and dopamine), drug development techniques progressed in parallel, leading to the formation of compounds with targeted affinities for receptors involved in specific aspects of monoaminergic neurotransmission (eg, the selective serotonin reuptake inhibitors). The incidence of side effects were greatly reduced since these medications had less effect upon other types of receptors (eg, cholinergic, histaminic, alpha adrenergic).
Advances in the basic neurosciences have further elucidated the pathophysiology of depression and have expanded our view of the many neurotransmitter systems involved in affective illness. Current evidence suggests that the initial receptor and neurotransmitter effects of antidepressants lead to "downstream" changes in protein production at a cellular level; these changes in turn appear to influence elements of neuronal protection and synaptic plasticity. Modern psychopharmacologic research has capitalized on this information, leading to the development of "designer" antidepressants with effects on specific combinations of selected neurotransmitter and neuropeptide systems.
The pharmacology of MAO inhibitors and other newer antidepressants are discussed here. The pharmacology and use of SSRIs, SNRIs and heterocyclic antidepressants, as well as the serotonin syndrome, are discussed separately. Switching between antidepressants, and discontinuing medication are also discussed separately. Finally, an overview of options for treatment in depression is discussed separately.
- Monoamine oxidase inhibitors (MAOIs) were the first class of antidepressants in clinical use. They were discovered in 1952 after iproniazid (a derivative of the antibiotic isoniazid) was found to be ineffective for treating tuberculosis, but was a potent antidepressive agent. The next MAOI, tranylcypromine, was identified as an antidepressant after it proved to be ineffective as a nasal decongestant. What these two medications have in common is the property of irreversibly blocking monoamine oxidase, the enzyme responsible for the oxidative deamination of neurotransmitters such as serotonin, norepinephrine, and dopamine. This property is thought to be largely responsible for the MAOIs' antidepressant effects.
The enzyme MAO comes in two forms, MAOa and MAOb. MAOb metabolizes phenylethylamine and, together with MAOa, breaks down dopamine. MAOa is responsible for the breakdown of serotonin and norepinephrine.
MAO is distributed in tissues throughout the body. The blockade of MAOIa in the gastrointestinal tract is responsible for the "cheese reaction" associated with MAOIs. This refers to a severe hypertensive crisis that can occur after patients on MAOIs ingest foods containing the sympathomimetic tyramine. Tyramine is usually metabolized in the gastrointestinal tract, but the blockade of MAOa allows it to flow into the general circulation. Although the accepted "MAOI diet" has been liberalized in recent years, there are still several dietary restrictions to which patients on these medications must adhere.
MAOIs are not considered to be first-line antidepressant medications because of the dietary restrictions, drug-drug interactions, and their relatively extensive side-effect profile. MAOIs have potent hypotensive effects, and up to 50 percent of patients experience dizziness. This is particularly important when treating elderly patients as they may be both more sensitive to the hypotensive effects and more likely to fall and sustain fractures. Other common side effects are dry mouth, gastrointestinal upset, urinary hesitancy, headache, and myoclonic jerks. MAOIs suppress REM sleep, but the clinical significance of this is unknown. Afternoon fatigue is common.
Despite their side-effect profile, MAOIs can be particularly useful agents for the treatment of "atypical" depression (eg, depression with hyperphagia, hypersomnia, leaden paralysis, and rejection sensitivity), and are frequently effective in treatment-resistant depressed patients.
Several compounds with selective MAOa and MAOb inhibiting properties have been developed, as well as reversible MAOIs. Properties of the MAOIs most commonly prescribed in the United States for treatment of depression are discussed below.
Tranylcypromine - Tranylcypromine has a chemical structure similar to amphetamine and has some stimulant properties. It is predominantly an irreversible inhibitor of MAOa, but also irreversibly inhibits MAOb to a degree. It also appears to block reuptake of serotonin and catecholamines.
Tranylcypromine has a rapid onset of MAOI activity, although clinical effects may not be present for two to four weeks. The mechanism by which tranylcypromine is metabolized is not clearly understood. The medication appears to maximally inhibit MAO activity at even subtherapeutic doses.
A conservative starting dose of tranylcypromine is 10 mg daily. If tolerated, the dose can then be raised to 30 mg daily in divided doses. The dose can be further increased by 10 mg every week up to 60 mg daily as needed. Although some MAO activity is restored three to five days after discontinuing the medication, it is prudent to allow two weeks for full restoration of MAO activity after stopping tranylcypromine.
Tranylcypromine shares the side-effect profile of other MAOIs. It has the potential to interact with sympathomimetics leading to hypertensive crisis, to interact with serotonergic medications leading to the serotonin syndrome, and can cause dose-related hypotension, sexual dysfunction, and sleep disturbance. Patients on tranylcypromine may have transient blood pressure increases after dosing, which subsides in three to four hours.
Tranylcypromine is more likely than phenelzine to cause activation and insomnia, so the last dose should be given early in the day. It is less likely than phenelzine to cause weight gain; some patients even experience weight loss.
Care must be taken in starting and stopping tranylcypromine, to avoid precipitating a hypertensive reaction of serotonin syndrome.
Phenelzine - Phenelzine is a substituted hydrazine, and it irreversibly inhibits MAOa and MAOb. Clinical antidepressant effects may not be seen until three to six weeks of continued treatment. The metabolism of phenelzine is not clearly understood, but it is apparent that at least 85 percent inhibition of platelet MAOb activity is necessary for clinical effect; this is usually achieved with doses greater than 45 mg daily.
Patients can be started on 15 mg on day one, and increased to 15 mg three times daily over two to three days as tolerated. The dose can be titrated upwards to a dose of 60 to 90 mg as tolerated.
Phenelzine shares the common MAOI side effects of potential for interactions with sympathomimetics leading to hypertensive crisis, interactions with serotonergic medications leading to serotonin syndrome, dose-related hypotension, sexual dysfunction, and sleep disturbance. It may cause less insomnia than tranylcypromine, but it seems more likely to cause weight gain, sedation, and sexual dysfunction. Phenelzine can very rarely cause hepatotoxicity.
Care must be taken in starting and stopping phenelzine, to avoid precipitating a hypertensive reaction of serotonin syndrome.
Selegiline - Selegiline is a selective MAOb inhibitor at low doses and a non-selective MAO inhibitor at higher doses. Selegiline primarily increases dopaminergic neurotransmission at lower doses, and increases serotonergic, noradrenergic, and dopaminergic neurotransmission at higher doses. Low dose selegiline does not appear to have antidepressant properties and is primarily used in treatment of Parkinson disease; it does not require dietary restrictions because of its lack of inhibition of MAOa.
Selegiline functions as a traditional MAOI at higher dose. It inhibits both MAOa and MAOb, has antidepressant properties, and, when taken orally, requires dietary restrictions to prevent hypertensive reactions.
A transdermal patch form of selegiline (EMSAM) was approved by the FDA in 2006 for use in the treatment of depression. Daily transdermal administration of selegiline allows for dosing that is high enough to produce antidepressant effects (by inhibiting MAOa and MAOb), but bypasses the gut. Direct inhibition of MAOa in the GI tract is avoided when transdermal selegiline is used at a dose of 6 mg/24 hours.
There are no dietary restrictions when transdermal selegiline is used at the recommended starting and target dose, 6 mg/24 hours. MAOI dietary restrictions are required if the 9 mg/24 hours or 12 mg/24 hours patch is used, because of limited clinical and experimental experience with higher doses. While it is not known if doses higher than 6 mg/24 hours are clinically more effective, clinicians may prescribe higher doses based on clinical judgment. Dose increases should occur in increments of 3 mg/24 hours (up to a maximum dose of 12 mg/24 hours) at intervals of no less than two weeks.
Care must be taken in starting and stopping selegiline, to avoid precipitating a hypertensive reaction of serotonin syndrome.
The selegiline patch is the first transdermal antidepressant and is of particular benefit to patients who cannot take oral medications. Patients who respond to the 6 mg/24 hour dose may avoid dietary restrictions. Limited data are available to determine which patients are likely to respond at this dose, and whether higher doses, necessitating MAOI dietary restrictions, are indicated for patients who do not respond.
Two randomized studies, both using the 6 mg/24 hour patch, found that short term selegiline (six and eight weeks), compared to placebo, improved depression scores and, in patients with less severe depression, increased remission rates.
Initiating or discontinuing MAO Inhibitors- Antidepressants should be stopped one week before beginning tranylcypromine, phenelzine or selegiline to avoid precipitating a hypertensive reaction or serotonin syndrome. Because of its longer half life, fluoxetine should be stopped five weeks before using tranylcypromine. Two weeks should elapse after stopping tranylcypromine before starting another antidepressant or stopping the MAOI diet.
- With advances in the understanding of brain neurophysiology, several unique medications have been developed that capitalize on affecting a more specific subset of neurotransmitters or receptors. This has led to a significant increase in the number of pharmacologic options available for the treatment of depression.
Bupropion - Bupropion is an aminoketone compound structurally resembling amphetamine and distinctly different from other antidepressant medications. It was approved by the United States Food and Drug Administration (FDA) for the treatment of depression in 1985, but a study in which 4 out of 55 bulimic patients developed seizures on bupropion led to withdrawal of the drug from the market. Later studies showed the rate of seizures caused by bupropion in the usual dosing range to be approximately 0.4 percent, slightly higher than other antidepressants. It was reintroduced in 1989 and has been used safely in clinical practice. A slow-release (SR) formulation of bupropion was released in 1998. This formulation allows for lower peak blood levels and is associated with a seizure incidence of 0.1 percent at usual doses. An extended release formulation of bupropion (XL), designed for once-daily dosing, was released in 2003.
Overall, bupropion appears to be as safe as other antidepressants. However, because of the initial reports of seizures in bulimic patients, it is contraindicated in patients with bulimia or anorexia. Bupropion is also contraindicated in patients with seizure disorders, or those undergoing abrupt withdrawal from alcohol, benzodiazepines, or other sedatives.
Bupropion is metabolized in the liver to hydroxybupropion, an active metabolite. The exact neurochemical actions responsible for its antidepressant activity are not fully known, but the medication has several known effects on neurotransmitters. It has weak dopamine reuptake inhibition and enhances extracellular dopamine levels in the nucleus accumbens; this increase of dopamine in the "reward area" of the brain is thought to underlie the medication's utility as an aid to smoking cessation. Bupropion also decreases the rate of activity of norepinephrine in the locus ceruleus, although overall noradrenergic efficiency appears to be increased. Bupropion has no apparent effects upon the serotonergic system.
Because of its mildly stimulating properties, bupropion is often prescribed to depressed patients who have fatigue and poor concentration as part of their presentation. It also has been used with some success in the treatment of attention deficit hyperactivity disorder. It does not appear to have anxiolytic properties due to its lack of serotonergic properties, and it does not block panic attacks as can the SSRIs, TCAs, and MAOIs. A review that pooled data from 10 randomized trials found that patients with major depression and high anxiety had better response rates to SSRIs than to bupropion for both depression and anxiety.
The immediate-release form of bupropion is usually started at 100 mg twice daily and increased to a usual maintenance dose of 200 to 300 mg in two or three divided doses. Because of a risk of seizures with high blood levels, the recommended maximum total daily dose of the immediate-release form is 450 mg. The maximum single dose is 150 mg.
The slow-release (SR) form has a different pharmacokinetic profile. With chronic dosing, the peak level of the slow-release form is about 15 percent less than that of the immediate release, although the trough level of the SR form is about 7 percent higher. The lower peak blood level of the SR form allows for higher single doses, up to 200 mg. The SR also allows for twice or even once daily dosing in some patients. The usual therapeutic dose of SR bupropion is 150 mg twice daily; some patients respond to as little as 100 mg or 150 mg once per day. The maximum recommended total daily SR dose is 400 mg in divided doses.
The extended-release (XL) preparation is formulated for once-daily dosing. It has a half-life of 21 (+/- 9) hours and a usual therapeutic dose of 300 mg once daily. The maximum recommended XL dose is 450 mg once daily.
The side-effect profile of bupropion is relatively benign. Headache is a relatively common initial side effect and usually diminishes with continued treatment. Some patients notice a stimulant-like effect from the medication, which may be interpreted as anxiety or can lead to insomnia if given before bedtime. It also tends to have a mild appetite-suppressing effect, and patients on the medication can experience mild weight loss. Bupropion is unique among antidepressants in that it does not cause sexual dysfunction. It has been used successfully to treat patients with SSRI-induced sexual dysfunction.
The potential effects of bupropion on suicidal ideation and behavior in adults is discussed separately.
Bupropion appears to cause inhibition of p450 enzyme IID6. The extent of this inhibition has not been well characterized in vivo, but it is possible that bupropion could increase the blood level of coadministered medications that are metabolized by IID6. Bupropion is metabolized extensively in the liver; some medications with p450 inhibiting properties could increase the blood level of bupropion, raising the risk of seizure.
There appear to be no significant withdrawal symptoms upon discontinuation of bupropion. Nevertheless, a gradual taper is the preferred method of discontinuation of all psychotropic medications.
Trazodone - Trazodone was synthesized in 1966 and introduced in the United States in 1981. The structure is unrelated to that of the SSRIs, cyclic antidepressants, or MAOIs. Its mechanism of action is not clearly delineated, but its overall effect seems to be that of modulation of serotonergic neurotransmission. There has been debate over whether trazodone is as effective for treatment of depression as other available agents. Because of this, and its side-effect profile, trazodone is not considered a first-line antidepressant.
Trazodone is metabolized by the liver and is approximately 90 percent protein bound. Its peak plasma concentration is reduced when coadministered with food. The t 1/2 of trazodone is five to nine hours.
Dosage is usually begun at 50 to 100 mg daily and increased up to 300 mg daily over one to two weeks as tolerated. The effective antidepressant dose is thought to be in the range of 200 to 600 mg daily.
The most common side effect of trazodone is sedation. Because of this, it is often used in lower doses (50 to 100 mg at hour of sleep) as a sleep aid or to treat SSRI-induced insomnia. Trazodone is also associated with postural hypotension and nausea. A rare but dangerous side effect associated with trazodone is priapism, which occurs in approximately 1 in 10,000 patients. Priapism is considered a medical emergency, and patients who experience this should be instructed to go to an emergency department. Trazodone has been associated rarely with cardiac arrhythmias and should be used with caution in patients with cardiac disease.
Nefazodone — Nefazodone is structurally related to trazodone but has a unique mechanism of action. Nefazodone's clinical effects are thought to be due to its actions on serotonergic neurotransmission. It is a direct antagonist of serotonin 5HT-2 receptors and has serotonin reuptake blocking properties. It blocks alpha-1 receptors, but less so than trazodone, and has no effect on cholinergic, alpha-2, histamine or dopamine receptors. Nefazodone is unique in that it may increase REM sleep (many antidepressants suppress REM sleep and disrupt sleep architecture). It also may cause less sexual dysfunction than other antidepressants.
Nefazodone is metabolized in the liver to three metabolites that interact with serotonin receptors. It is approximately 99 percent protein bound. Food decreases the absorption of nefazodone and decreases its bioavailability by approximately 20 percent. Nefazodone is a potent inhibitor of the p450 enzyme 3A4 and therefore can have interactions with other drugs metabolized by that enzyme. Coadministration with cisapride is contraindicated due to the risk of QT prolongation and arrhythmia. Nefazodone increases the blood level of alprazolam and triazolam by one- to twofold.
Dosing is usually begun at 100 mg twice daily. The dose can be increased to 150 mg twice daily after one week, and increased further if necessary to the therapeutic dose range of 300 to 600 mg daily.
Side effects include dry mouth, constipation, nausea, sedation, and dizziness. Coadministration of nefazodone with drugs that block p450 enzyme 2D6 can lead to accumulation of the nefazodone metabolite MCPP, which can induce anxiety.
The potential effects of nefazodone on suicidal ideation and behavior in adults is discussed separately.
There have been at least 25 cases of liver failure leading to death or transplant in patients taking nefazodone, although a direct relationship has not been established. The manufacturer has issued a warning that physicians and patients be alert to signs and symptoms of liver dysfunction. Physicians may consider liver function testing, but there is no clear evidence that periodic transaminase measurements will prevent hepatic injury. The drug has been withdrawn from the market in Europe, Canada, and several other countries.
Mirtazapine - Mirtazapine is one of the newer antidepressants, introduced to the market in 1997. It is a tetracyclic compound (a piperazinoazepine), but it is unrelated to TCAs. It has a unique mechanism of action in that it blocks pre- and postsynaptic alpha-2 receptors, as well as the serotonin receptors 5HT2 and 5HT3. In contrast to TCAs, it has low affinity for alpha-1 receptor blockade. Mirtazapine has little interaction with acetylcholine receptors, but it is a potent blocker of histamine receptors.
It is proposed that the medication's antagonism of presynaptic alpha-2 receptors leads to a significant increase in noradrenergic neurotransmission. This heightened adrenergic neurotransmission, in concert with mirtazapine's action of increasing serotonin release, is thought to be responsible for the medication's antidepressant effect. Mirtazapine may also possess anxiolytic effects. It can be particularly helpful in depressed patients with insomnia because of its sedative properties.
Mirtazapine is metabolized in the liver primarily by oxidation and demethylation. It is metabolized by several p450 enzymes including 2D6, 1A2, 3A4, and 2C9, but it has no apparent inhibition of p450 enzymes. Its demethylated metabolite is approximately three times less active than the parent compound. Mirtazapine's t 1/2 is 20 to 40 hours, and it is approximately 85 percent protein bound.
Mirtazapine has an unusual dosing profile. As experience with the medication has accumulated, it has become apparent that some of the medication's side effects may be greater at lower doses. Most notably, sedation appears more pronounced at doses of 15 mg daily than at 30 mg daily. Dosing is most frequently started at 15 mg at hour of sleep, and can be increased to 30 mg or 45 mg daily as needed in one to two week intervals. Dosing may be initiated at 30 mg or more in order to reduce sedation.
The most notable side effects of mirtazapine are sedation, weight gain, and dry mouth. Sedation appears to be greater at lower doses. The mechanism of weight gain is unknown, but many patients report a significant increase in appetite. It is not clear whether or not side effects other than sedation are reduced at higher doses. Mirtazapine may have relatively less propensity to cause sexual dysfunction than the SSRIs, TCAs, and MAOIs, but this has not been rigorously studied. In premarketing trials, 2 out of 2796 patients developed agranulocytosis, and a third developed neutropenia. All recovered after the medication was discontinued. There are no FDA recommendations to monitor white blood cell counts. Mild transaminase elevations have been noted in some patients, but there are no FDA recommendations about monitoring liver function tests.
The potential effects of mirtazapine on suicidal ideation and behavior in adults is discussed separately.
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