Concomitant psychiatric or medical disorders can be present in patients who are being assessed for GAD and may complicate accurate diagnosis and treatment. Initially, the patient should have a full psychiatric and medical history with appropriate consideration or referral for laboratory and physical examination. After a failed trial of treatment, the clinician should look for common coexisting conditions, such as depression, alcohol problems, bipolar disorder, and undiagnosed medical illness, e.g. endocrine (thyroid), pulmonary or cardiac disease.

Psychological therapies are an important first-line option in the management of GAD. “Psychoeducation,” including information to patients about the causes and treatment of their condition, has been recommended for all patients. This  includes paying attention to alcohol, caffeine, and tobacco consumption; regulating sleep; and the control of external stimuli for improving sleep. Simple coping techniques can be taught in the primary care setting for the control of worry, such as setting aside time to rationalize concerns, organizing these into minor and major worries, and identifying priorities and next steps toward addressing them.  Handouts may be helpful for patients to read and reference.

Antidepressants: The following antidepressants have demonstrated efficacy in GAD: SSRIs, SNRIs, tricyclic antidepressants, and trazodone. Of these, SSRIs and SNRIs are generally preferred as first-line therapy. They are usually better tolerated than the other classes of antidepressants.

Although the SSRIs are generally well tolerated, these agents are nonetheless associated with a range of adverse effects, including GI symptoms, somnolence, disrupted sleep, and agitation. Weight gain and sexual side effects can occur and can persist during the treatment period.

The SNRIs venlafaxine and duloxetine may also be effective. Adverse effects include those associated with the SSRIs, as well as orthostatic hypotension, increased blood pressure, sweating, and urinary hesitancy. Patients taking venlafaxine or duloxetine should be monitored for increases in blood pressure.

Benzodiazepines:  Historically, benzodiazepines have been widely used in the management of anxiety disorders. They have a rapid onset of action and are effective in GAD. While benzodiazepines improve core symptom, they are not recommended as monotherapy for depression, dysthymia, obsessive-compulsive disorder, and posttraumatic stress disorder, which co-commonly occur with GAD. However, benzodiazepines can be effective for panic and social anxiety disorders, as well as for insomnia, a common symptom. In severe cases, benzodiazepines are often prescribed as adjunctive therapy to help patients in acute crisis or while waiting for a SSRI orSNRI to take effect.

Benzodiazepine use can be problematic, particularly in older people, due to side effects such as falls, memory impairment, incoordination, drowsiness, and confusion.  Benzodiazepines can disrupt sleep architecture, and rebound insomnia may occur after stopping treatment.

Benzodiazepines have modest abuse potential and should not generally be administered to patients with a history of misuse of these drugs within the primary care setting. They are generally recommended only for short-term use and are not recommended for first-line long-term treatment of GAD, but they may have a role in the management of acute anxiety and in some cases in which somatic symptoms are more prominent than psychic symptoms

Buspirone: Buspirone, an azapirone that acts as a partial agonist at the 5HT1a receptor, is effective for the treatment of GAD though may be less effective than the benzodiazepines. Common side effects of buspirone included drowsiness, dizziness, and nausea.

Antihistamines: Hydroxyzine is an H1 antagonist that has been reported to be effective in the treatment of GAD symptoms in well-controlled studies.  It is typically used as a prn medication for breakthrough anxiety.

Atypical antipsychotics: Recent studies have suggested that atypical antipsychotics may also have a role in GAD. In patients who do not respond adequately to initial pharmacologic treatment, the addition of an atypical antipsychotic agent may provide additional benefit.

GAD is usually chronic with a waxing and waning course, and continued support and education is often required. Patients should be given clear information on how long treatment will take to become effective and how to cope with their symptoms in the meantime.

The use of appropriate screening tools and providing information to patients with GAD on their condition and its treatment are an important starting point toward increasing recognition and appropriate treatment of GAD.

This case leads nicely into a discussion about how to approach the treatment of an anxiety disorder. The first step is to determine a specific diagnosis and determine the level of impairment of the symptoms. If the impairment is mild-moderate, one could start with a therapy approach and determine if medication treatment is needed in the future.

If the impairment is moderate-severe, the standard of care is to begin therapy and medication treatment concurrently. Medication treatment should minimally involve an approach to treat the underlying anxiety – first line would be an SSRI medication.

Other options, if that doesn’t work, could include: SNRIs, Remeron, and Buspar. For many patients, it is helpful to initially prescribe an adjunctive medication to provide some relief for their anxiety while the primary medication is “kicking in”. These include: Buspar (which can be useful for the underlying anxiety management as well as for acute anxiety management), Vistaril, Propranolol, and the benzodiazepines.

Some providers may consider low doses of the atypical antipsychotics, but the concern about that practice is that the patient is still exposed to the possible metabolic side effects of that class of medications even at low doses, as many of the metabolic side effects of antipsychotics are dose-independent. For patients for whom they are effective, these adjunctive medications yield benefits more quickly than the traditional anti-anxiety medications.

In many cases, these medications can be tapered off once the base medication has fully “kicked in”.  Buspar is typically dosed 7.5 mg bid and increased by 5 mg every 2-3 days as tolerated up to 30 mg bid. Onset of action may take 2 weeks. It is relatively well tolerated with less cognitive impairment than benzodiazepines. Major side effects include dizziness, fatigue, and nausea. Vistaril is typically dosed 25-50 mg bid-tid on a prn basis. It is less sedating than Benadryl, therefore is better tolerated during the daytime. Propranolol is typically dosed 20-40 mg if used on a prn basis and 20 mg bid-tid titrated up to 40 mg bid-tid as tolerated and needed if used on a standing basis.

We hope this extensive discussion about this case and the thinking process that occurred in the background was helpful for other similar cases you might encounter in your practice.

Withdrawal from benzodiazepines is similar to withdrawal from alcohol—problems may include: feeling jittery, elevated blood pressure and heart rate, anxiety, insomnia and irritability. With more severe dependence, life-threatening effects like withdrawal seizures and delirium tremens may occur.  The longer a patient has been taking daily benzodiazepines, the longer the taper process should be. If a patient is using a short-acting benzodiazepine, the taper process is smoother and more successful if the patient is first transitioned to a long-acting benzodiazepine and then tapered off the long-acting medication.

Clonazepam is a good medication to use for tapering purposes, and it is helpful to dose it twice per day to establish a more even blood level and to give the patient psychological relief by taking the medication more frequently. Clonazepam has a 1:1 ratio dose equivalence to alprazolam (i.e. 1mg clonazepam = 1mg alprazolam) and a 1:2 ratio dose equivalence to lorazepam (i.e. 1 mg clonazepam = 2 mg lorazepam).  Care should be taken when the patient is taking high doses of a benzodiazepine medication and, in certain cases, dosing clonazepam more frequently during the tapering process may be more successful.

Diazepam can also be used in a similar fashion.  It has a 10:1 ratio dose equivalence to alprazolam and a 5:1 ratio dose equivalence to lorazepam.   Some advantages of diazepam are that it has an even longer half-life than clonazapam and is available in smaller effective doses, and so often allows a smoother taper with fewer withdrawal symptoms.  Some disadvantages are that diazepam has a relatively fast onset of action, causing many patients to experience an initial “high” when they take it, much like they may experience with shorter acting medications like alprazolam.  In addition, because of the extremely long half-life (up to 100 hours including its active metabolites), the drug can often accumulate, especially in elderly and patients with liver dysfunction.

Benzodiazepine Dose Equivalents

Depending on how long the patient has been taking daily benzodiazepines, one can reduce the dose by 10% of the current dose every 4-7 days. For example if a patient has been taking 4mg of alprazolam per day in split doses for five years, one option is to change the patient over to clonazepam 2mg BID and then reduce the dose initially by 0.5 mg per week, slowing down the taper to 0.25mg at a time towards the end. This relatively slow taper would take about 2 months to complete. If a patient is having withdrawal symptoms at any point during a taper, consider slowing down the taper.

In certain circumstances, it may be appropriate for a patient to be on a long-term daily benzodiazepine. One example is a patient who has tried non-benzodiazepine medications as adjunctive to a sub-therapeutic response to an SSRI, but they do not work as well as a benzodiazepine medication and the patient is not misusing it. In this clinical situation, the provider could consider switching from a short-acting medication to a longer-acting medication like clonazepam for long-term use, with a decreased risk for dependence.

If it is determined that a patient needs a long term PRN medication for anxiety and long-term benzodiazepine use is deemed problematic, consider alternatives including propranolol or hydroxyzine.  Buspirone (Buspar) can be effective for anxiety, but must be taken daily.

We hope that this step-by-step review on tapering benzodiazepines has been helpful. The important take home point is to not rush a taper, otherwise the patient might give up if he feels uncomfortable in any way or, more seriously, there could be dangerous consequences.

While the intention behind prescribing a benzodiazepine for a patient is to help alleviate emotional or physical pain for the patient, many times the use of the medication gets out of hand. Generally, benzodiazepines, which work to enhance GABA, are helpful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures.

Here we will focus on its uses for anxiety disorders. Benzodiazepines can be useful in the short-term for 1-3 months for a variety of anxiety disorders, like Generalized Anxiety Disorder, Social Anxiety Disorder and Panic Disorder, while waiting for the SSRI or other antidepressant/anti-anxiety medication to “kick in”. Benzodiazepines are not particularly helpful for depressive disorders or Obsessive-Compulsive Disorder. When starting a benzodiazepine, it is important to inform the patient that it is a short-term intervention, explaining the reason is to avoid long-term side effects, like tolerance, cognitive effects, and physiological and psychological dependence. When choosing a benzodiazepine, it is important to try to avoid short-acting medications like alprazolam if possible, because patients can develop a quick dependence to it because they can experience a “high” with it, and it has a short half-life, which can lead to rebound anxiety and can make it very difficult to taper off the medication. Also alprazolam is not a good medication for insomnia because of its short half-life. Patients may complain of being able to fall asleep okay but then waking up in the middle of the night. Alternative benzodiazepines to consider on a short-term basis for sleep include: clonazepam and temazepam.

If a patient is requiring adjunctive medication on a long-term basis for anxiety, consider non-benzodiazepine alternatives like diphenhydramine, hydroxyzine, propranolol, or buspirone. In the rare case when a long-term daily benzodiazepine is indicated, for example with Generalized Anxiety Disorder which responds well to a combination of SSRI + benzodiazepine, consider clonazepam. If a patient has infrequent panic attacks and a daily SSRI is not indicated, one could consider lorazepam on a prn basis. Lorazepam works well as a prn medication for acute anxiety and panic attacks, because it works relatively quickly but does not build up in the bloodstream. If one is prescribing long-term benzodiazepines, it is important to make sure the use is not slowly escalating, because that is a sign of tolerance and dependence.  Also, when helping a patient taper off a medication after he has been on it for some time, it is important to conduct a slow taper to avoid serious withdrawal symptoms, and to provide an alternative to treat the ongoing anxiety symptoms. Guidelines for appropriately tapering off benzodiazepines are discussed in another e-Weekly.

The goal of this article is to help the primary care provider be more informed about the decision to prescribe a benzodiazepine to a patient in a safe and helpful way, because this class of medication has a role in treatment for anxiety disorders and can be helpful when used appropriately. It is therefore useful to look at some guidelines for appropriate prescribing practices for this class of medications.

Treatment options include therapy or a combination of therapy and medication:

• For patients with mild-moderate symptoms, a therapy approach is preferred, with the option incorporate medication if the therapy is not effective.
• For patients with moderate-severe symptoms with significant impairment in daily functioning, it may be warranted to consider starting with a combination of medication and therapy.

The key is that therapy is the important component to treatment of anxiety disorders in pediatrics, with medication used as an adjunctive treatment when needed. Therapy to address anxiety can easily be tailored to work with very young patients and is very effective. Types of therapy used include: cognitive behavioral therapy, exposure response prevention therapy, and relaxation techniques, among others.

Medications used to treat anxiety fall into two general categories: medications that treat the underlying anxiety and prevent future symptomatology and medications that treat acute symptoms, such as a panic attack. Medications in the first category include the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazipine, and buspirone.  The SSRIs are the first line agents. This class includes: fluoxetine, citalopram, escitalopram, sertraline, fluvoxamine, and paroxetine.  Although prompt relief may result, just as with treating depression, the medication may take 4-6 weeks to have full impact, so patience is important.  Also of note, often a higher dose may be needed to fully treat anxiety symptoms as compared to depressive symptoms.

The motto to “start low and go slow” remains relevant to limit activation and thereby increase anxiety during the titration process. So, for example if one is considering prescribing citalopram for anxiety for a 10 year-old patient, consider starting at 5 mg q-day for one week then 10 mg q-day for 1 week then 20 mg q-day and assessing the response. Some patients experience akathisia (internal feeling of restlessness), which can feel like a worsening of their anxiety, if the dose is titrated too quickly. Other side effects include sleep disturbance, GI upset and headache but most of these symptoms are dose related and will resolve over time.

The treatment of anxiety disorders in pediatric patients is mostly off label. Only fluoxetine (ages 7+), sertraline (ages 6+) and fluvoxamine (ages 8+) have FDA approval for treatment of obsessive-compulsive disorder (OCD).

When prescribing any antidepressant medication to treat anxiety, it is appropriate to review the FDA black box warning about the increased risk of spontaneous reporting of suicidal thoughts, even if the medication is not being prescribed to treat depression per se.

When prescribing a medication, it is standard practice to first use an SSRI.  If a patient has 2 or more adequate (in terms of dose and length of treatment) trials of SSRIs that are ineffective, one could consider an alternative, either an SNRI (venlafaxine or duloxetine) or mirtazapine, but consultation or referral to psychiatry would be advised in such situations. If there is some benefit from the SSRI, one could consider augmentation with mirtazapine or buspirone. The primary side effects to be concerned with mirtazapine include sedation and increased appetite. Buspirone has an onset of action of about 2 weeks. The primary side effects to be concerned with include: dizziness, fatigue and GI upset. Occasionally the atypical antipsychotics are considered as adjunctive treatment to treatment-resistant OCD.

Benzodiazepines, are rarely used in this population. Pediatric patients can have a paradoxical reaction to them and exhibit behavioral disinhibition. Other side effects include: physiological and psychological addiction, confusion, sedation and impaired fine motor coordination. If a medication to treat acute anxiety is needed, for example for a teenager who has very occasional panic attacks, one could consider hydroxyzine 25-50 mg on a prn basis, which is not associated with dependence. Side effects include: sleepiness, dizziness, and dry mouth.

When feasible, the use of rating scales can help in these efforts by documenting severity and monitoring clinical progress.   A good tool to review, the SCARED, is accessible at. http://www.pediatricbipolar.pitt.edu/content.asp?id=2333#3304 and a broader array of tools is listed at the following website http://www2.massgeneral.org/schoolpsychiatry/screening_anxiety.asp

Pharmacological options include benzodiazepines, non-benzodiazepines, antidepressants and antihistamines. There is limited evidence on their long-term safety particularly with cognitively-impaired older adults. For this reason, it is important to use these medications with caution, for the shortest period of time as needed, and to follow the motto “start low and go slow”. Benzodiazepines are commonly used, but they have little effect on the sleep maintenance problems that are most commonly seen in older adults with dementia. In addition, they can have problematic side effects, including sedation, confusion, anterograde amnesia, and rebound insomnia, which can make the behavioral disturbance seen with dementia worse. The newer generation non-benzodiazepines have shorter half-lives and fewer side effects, but there is limited data on their use in older patients with dementia.

Antidepressants, including Trazodone, the SSRIs and Remeron, are sometimes used to help with sleep problems, in some cases to take advantage of their side effect of sedation and in other cases because there is concern about co-morbid depression. Trazodone has been found in small studies to be helpful short-term with improving total sleep time and sleep efficiency. Antihistamines are commonly used in this situation, partly because of the availability over-the-counter, but there are side effect concerns, including sedation, cognitive impairment, and anticholinergic responses. Because of these side effect risks, they should be avoided as first-like agents in older patients. Supplemental melatonin has not been found to be helpful as a stand-alone treatment for insomnia in patients with dementia in studies, but ramelteon, a melatonin agonist, has been shown some promising results in general studies, to improve sleep efficiency and increase total sleep time. In addition, it is not associated with side effects that are seen with other medications used for sleep disturbance, like cognitive impairment and daytime sleepiness. It would be helpful for more studies to be done with this agent in older patients.

It is our hope that this article has been helpful in addressing the common issue of sleep disturbance in patients with dementia, to begin thinking about how to determine the cause and the best treatment approach.

Reference: Current Treatments for Sleep Disturbances in Individuals with Dementia. Cynthia L Deschenes, MSN, CCRN and Susan M. McCurry, PhD. Curr Psychiatry Rep 2009, Feb.

Contraceptive medications can be affected by certain psychotropic medications. Carbamazepine, oxcarbazepine, and topiramate (mood stabilizers which induce the P450 3A4 pathway) can increase the metabolism of oral contraceptives (many of which are substrates of the P450 3A4 pathway), thereby reducing their effectiveness. This effect is also seen with vaginal contraceptive rings, because the hormones contained in these preparations are also metabolized by the liver. In these situations, the patient should either change their contraceptive method or change their mood stabilizer. Contraceptive alternatives include the birth control patch (which largely avoids liver metabolism) and barrier methods. Mood stabilizers like valproate and lamotrigine do not affect oral contraceptives, but lamotrigine clearance is increased with oral contraceptives that contain estrogen. In patients who are taking a traditional mood stabilizer, including Lithium, highly effective contraception is important because these medications can have serious teratogenic effects, particularly in the first trimester, if a patient accidentally becomes pregnant. One option is a high-dose oral contraceptive, but because of the complexity of oral contraceptives and some traditional mood stabilizers as well as side effects of high-dose estrogen, it is important to consider non-hormonal approaches as a primary or adjunctive contraception. St. John’s Wort (an herbal supplement that many patients take for mild depression) can induce the P450 3A4 pathway, thereby inducing the metabolism of oral contraceptives.

There is some concern that progesterone-only pills and high-dose estrogen pills can lead to or worsen depression, although this has not been studied in a controlled fashion that clearly defines depression and addresses the confounding factors of mood symptoms during various parts of the menstrual cycle. These hormones can increase the metabolism of serotonin in the brain, thereby lowering serotonin levels, which can contribute to depression. It is thought that low-dose combined oral contraceptives have little risk for causing or worsening depression. However it is important to assess for changes in mood after a patient first starts contraception.

It is our hope that this discussion about the complexities related to psychiatric medication and symptoms with contraceptives is a helpful primer for the primary care setting.

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