Does lithium help anxiety

Risks and Benefits of Taking Lithium for Anxiety

Many medications designed to treat depression-related conditions are often also prescribed for anxiety conditions. Lithium salts are a component of many psychiatric medications for depression-related conditions including mania and bipolar depression, and their effectiveness is the standard against which other medications for these conditions have been measured since even before anxiety disorders were recognized as psychiatrically treatable.

The article below will explore the effects of lithium on the brain, as well as its potential negative side effects, to help gauge its potential benefits as well as its risk factors for people suffering from anxiety.

What is Lithium?

Lithium is just one of many options that a doctor may prescribe for your anxiety. It should never be taken without a prescription, and is not right for everyone.

In its purest form, lithium is a soft, light and silvery-white metal belonging to the alkali group on the periodic table. Knowing this, it may seem strange that the lithium salts lithium carbonate, lithium citrate and lithium sulfate, all inorganic substances, are often prescribed by psychiatrists for oral ingestion. So why exactly do professionals suggest eating metallic compounds to overcome psychiatric conditions, and what are the risks?

Lithium in Your Body

While ingesting metallic substances can be dangerous, a dosage of 15–20 mg of lithium per kg of body weight falls below the level of toxicity for anyone eight years old and over, though in children the levels of lithium in the blood need to be closely monitored. In addition, when taken in the correct dosage, lithium is processed and released by the body usually within 24 hours, meaning that the metal will not become a part of your body in any harmful way if you take no more than the required dose.

While lithium is in your body, it affects neurotransmitters that are involved in the body’s stress reactions. The function of these neurotransmitters in stress reactions and lithium’s effects on them are outlined below.

  • Norepinephrine Norepinephrine is usually responsible for increasing the heart rate and sending blood enriched with sugar energy or glucose to tensing muscles during the fight or flight response that can occur when you are afraid of something, sometimes resulting in panic attacks. Lithium limits the amount of norepinephrine that the body can process, which decreases the severity of the anxiety symptoms caused by the body’s fear response.
  • Serotonin The more serotonin is present in your brain, the more relaxed you are. Research has discovered that men have more serotonin receptors in their brains than women, which is part of the reason why women are more prone to anxiety disorders than men. Lithium improves the body’s ability to synthesize serotonin. This simply means that the body’s levels of serotonin increase in response to lithium, which has the effect of improving mood and reducing feelings of anxiousness.

Possible Side Effects

During the early stages of lithium treatment, side effects may include:

  • Dryness of the mouth
  • Mild weakness and/or shaking
  • More frequent urination
  • Dehydration (headaches, nausea)

In the long term, lithium may also cause:

  • Increased appetite and thirst
  • Weight gain
  • Hypothyroidism

Drinking extra water to compensate for dehydration can reduce the number of symptoms experiences early on, while regular exercise and a healthy diet can help to control any weight gain that results. The lowest possible dose of lithium is recommended in order to limit and reduce the likelihood of negative side effects.

It is still important to note that weight gain and hypothyroidism (a condition that can also cause weight gain) can increase feelings of depression and may pose a risk if your anxiety is complicated by depression.

Though lithium is not addictive, overdosing can be highly dangerous. Too much lithium in the body functions as a poison, which is why it can be a risky medication if you suffer from anxiety complicated by depression. Similarly, lithium itself can have what’s known as a “paradoxical” reaction where it actually creates more anxiety and depression, which is another important reason not to use lithium without talking to your doctor.

Lithium can take weeks to reach its full effectiveness. For this reason, supplementing lithium medication with healthy anxiety-reducing activities may help you to feel better in the meantime. Knowing about these potential alternatives to medication may help to prevent relapses if you are stopping lithium treatment, and are also useful to know about if you are looking to avoid medication entirely.

  • Pick an Enjoyable Exercise Going to a gym can be pricey and sound like a lot of work. Fortunately, exercise can come in almost any form you can think of. Whether you choose swimming, biking, jumping rope or mountain climbing, doing it for at least 30 minutes 3 times a week will help your body stay fit, as well as causing it to naturally trigger the release of serotonin in the brain, mimicking the effects of lithium without any dangerous potential side effects. NOTE: If you are taking lithium and also exercising regularly, it is especially important that you drink extra water to compensate for lithium’s side effect of dehydration.
  • Make a Diet Plan Most people cringe when they hear the word “diet,” but usually it’s because they associate it with fad diets that involve something like eating only carrots or starving themselves. A good diet should require neither. Picking a diet that is right for you means picking one that allows you to eat a healthy amount as well as a healthy variety of foods, giving your body the nutrients it needs while keeping your mood from being affected by malnutrition. Eating right will keep your body feeling good and better suited to handle any anxiety symptoms that crop up unexpectedly.
  • Write About It When you are feeling anxious or undergoing the physical and mental changes that can occur while starting or stopping a medication, writing about it can help to settle your mind. While it’s funny to think that what essentially amounts to “talking to yourself” can actually make you feel less crazy, it is absolutely true. Seeing your thought patterns written out can help you spot the parts where your logic seems fuzzy, or catch obsessive thoughts that repeat themselves and address those parts directly, either by writing about them specifically or by consulting with a mental health professional.

Lithium can have beneficial effects for people suffering from anxiety. However, because people with anxiety are at a higher risk for depression, it is good to bear in mind that special care must be taken to offset the potential side effects that may aggravate this condition even as the medication works to treat it. Supplementing your treatment with the above activities can help with this, as well as providing you with good anti-anxiety habits to carry with you into the future.

As always, please make sure that you consult with your doctor before considering lithium for your mental health issue.

PMC

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  • Kramlinger KG, Post RM (1990). Addition of lithium carbonate to carbamazepine: hematological and thyroid effects. Am J Psychiatry 147: 615–620.
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  • Miklowitz DJ, Schneck CD, Singh MK, Taylor DO, George EL, Cosgrove VE et al (2013). Early intervention for symptomatic youth at risk for bipolar disorder: a randomized trial of family-focused therapy. J Am Acad Child Adolesc Psychiatry 52: 121–131.
  • Norlen O, Sidhu S, Sywak M, Delbridge L (2014). Long-term outcome after parathyroidectomy for lithium-induced hyperparathyroidism. Br J Surg 101: 1252–1256.
  • Nunes MA, Viel TA, Buck HS (2013). Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Curr Alzheimer Res 10: 104–107.
  • Post RM (2016. a). Epigenetic basis of sensitization to stress, affective episodes, and stimulants: implications for illness progression and prevention. Bipolar Disord 18: 315–324.
  • Post RM (2016. b) Preventing sensitization and kindling-like progression in the recurrent affective disordersIn:Chiccetti D(ed) Developmental Psychopathy. John Wiley & Sons: Hoboken, NJ, Vol 3 pp 971–996.
  • Post RM (2016. c). Treatment of bipolar depression: evolving recommendations. Psychiatr Clin North Am 39: 11–33.
  • Post RM (2017). New perspectives on the course and treatment of bipolar disorder. Minerva Med 58: 40–53.
  • Post RM, Altshuler LL, Kupka R, McElroy SL, Frye MA, Rowe M et al (2017). More childhood onset bipolar disorder in the United States than Canada or Europe: implications for treatment and prevention. Neurosci Biobehav Rev 74(Pt A): 204–213.
  • Post RM, Fleming J, Kapczinski F (2012). Neurobiological correlates of illness progression in the recurrent affective disorders. J Psychiatr Res 46: 561–573.
  • Post RM, Kalivas P (2013). Bipolar disorder and substance misuse: pathological and therapeutic implications of their comorbidity and cross-sensitisation. Br J Psychiatry 202: 172–176.
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  • Post RM, Leverich GS, Altshuler LL, Frye MA, Suppes T, Keck PE et al (2011). Differential clinical characteristics, medication usage, and treatment response of bipolar disorder in the US versus The Netherlands and Germany. Int Clin Psychopharmacol 26: 96–106.
  • Post RM, Leverich GS, Kupka RW, Keck PE Jr, McElroy SL, Altshuler LL et al (2010). Early-onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood. J Clin Psychiatry 71: 864–872.
  • Prosser JM, Fieve RR (2016). Patients receiving lithium therapy have a reduced prevalence of neurological and cardiovascular disorders. Prog Neuropsychopharmacol Biol Psychiatry 71: 39–44.
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  • Rowe MK, Chuang DM (2004). Lithium neuroprotection: molecular mechanisms and clinical implications. Expert Rev Mol Med 6: 1–18.
  • Rybakowski JK, Suwalska A (2010). Excellent lithium responders have normal cognitive functions and plasma BDNF levels. Int J Neuropsychopharmacol 13: 617–622.
  • Schrauzer GN, Shrestha KP (1990). Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions. Biol Trace Elem Res 25: 105–113.
  • Severus E, Taylor MJ, Sauer C, Pfennig A, Ritter P, Bauer M et al (2014). Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. Int J Bipolar Disord 2: 15.
  • Squassina A, Pisanu C, Congiu D, Caria P, Frau D, Niola P et al (2016). Leukocyte telomere length positively correlates with duration of lithium treatment in bipolar disorder patients. Eur Neuropsychopharmacol 26: 1241–1247.
  • Tiihonen J, Lahteenvuo M, Hoti F, Vattulainen P, Taipale H, Tanskanen A(eds (2016) Real-World Effectiveness of Pharmacological Treatments in Severe Unipolar Depression in a Nationwide Cohort of 123,712 Patients. American College of Neuropsychopharmacology: Hollywood, FL.
  • Toffol E, Hatonen T, Tanskanen A, Lonnqvist J, Wahlbeck K, Joffe G et al (2015). Lithium is associated with decrease in all-cause and suicide mortality in high-risk bipolar patients: a nationwide registry-based prospective cohort study. J Affect Disord 183: 159–165.
  • Tondo L, Abramowicz M, Alda M, Bauer M, Bocchetta A, Bolzani L et al (2017). Long-term lithium treatment in bipolar disorder: effects on glomerular filtration rate and other metabolic parameters. Int J Bipolar Disord 5: 27.
  • Vieweg V, Glick JL, Herring S, Kerler R, Godleski LS, Barber J et al (1987). Absence of carbamazepine-induced hyponatremia among patients also given lithium. Am J Psychiatry 144: 943–947.
  • Vita A, De Peri L, Sacchetti E (2015). Lithium in drinking water and suicide prevention: a review of the evidence. Int Clin Psychopharmacol 30: 1–5.
  • Yatham LN, Mackala S, Basivireddy J, Ahn S, Walji N, Hu C et al (2017). Lurasidone versus treatment as usual for cognitive impairment in euthymic patients with bipolar I disorder: a randomised, open-label, pilot study. Lancet Psychiatry 4: 208–217.
  • Zarse K, Terao T, Tian J, Iwata N, Ishii N, Ristow M (2011). Low-dose lithium uptake promotes longevity in humans and metazoans. Eur J Nutr 50: 387–389.
  • A Little Lithium Goes a Long Way – 5 Benefits of Low Dose Lithium

    Lithium is a misunderstood naturally occurring element that’s used as a medication. It’s known for its mood stabilizing properties as a psychotropic drug. While you probably consider lithium to be a serious mind altering medication, the fact of the matter is lithium can often be found in low levels in our drinking water ranging from trace amounts to 0.17 mg/L.

    You might think of bipolar disorder when you think of lithium because high doses can be used to treat psychiatric conditions. So finding out lithium is in your water in low doses may shock you at first, but research indicates certain types of lithium in low doses may actually be incredibly beneficial to our health.

    The word lithium is often used interchangeably to refer to a number of different chemical compounds. True lithium is a silvery alkali metal but it almost never occurs freely in nature. Instead, lithium binds readily with other elements. When it comes to lithium used for human health, the most common forms are:

    1. Lithium carbonate – The form commonly used to treat bipolar disorder.
    2. Lithium orotate – This is an over-the-counter supplement that potentially has positive impacts on the brain.

    The thing about lithium orotate is most of the research done on it occurred between 1973 and 1986 on neurological conditions. Because of its relative safety, lithium orotate remains an over-the-counter supplement and in some cases is used for dementia, alcoholism, and depression.

    Lithium also has some pretty famous side effects including weight gain, feeling zombie-like, and thyroid issues. But it’s important to note that most of lithium’s negative side effects are dose-dependent and factors that can be monitored. Meaning, low-dose lithium provides a unique opportunity for many health conditions under the guidance of an experienced practitioner.

    Here are some of the health benefits of low-dose lithium we know of today.

    5 Benefits of Low Dose Lithium

    1. Low dose lithium may reduce inflammation

    Reducing inflammation is one of the best things anyone can do for their health. More than ever we have toxins, foods, and environmental assaults that raise inflammation levels and contribute to disease. Studies have shown that lithium appears to decrease inflammatory proteins while boosting anti-inflammatory proteins.

    In one study, lithium appeared to have neuroprotective effects against nervous system autoimmunity. This animal study observed lithium suppressed IFN-γ production, which is associated with Alzheimer’s disease.

    2. Low-dose lithium for anxiety

    Lithium is most famous for its antipsychotic effects in bipolar patients. Because of these mood-stabilizing effects, lower doses are being explored in people with anxiety. Lithium has been shown in studies to calm manic behavior associated with anxiety, bipolar disorder, and even attention deficit disorder (ADHD).

    Even though many of these studies include more extreme cases and often use lithium carbonate, which is the considerably more aggressive form of lithium – I personally know many practitioners who are using low-dose lithium orotate for anxiety.

    3. Low-dose lithium may improve depression

    Low-dose lithium appears to be very effective in treating depression. Some studies have even found that low-dose lithium is equally as effective as a higher dose without as many of the unwanted side effects.

    Low-dose lithium increases 5-HT neurotransmission in animals, which is a group of serotonin (your “happy” neurotransmitter) receptors. This effect causes antidepressant activity in the brain, which is how low-dose lithium combats depression.

    4. Low-dose lithium appears to boost cognitive function

    The effects of low dose lithium on the brain are downright fascinating. Low dose lithium has been shown to stabilize mood, be neuroprotective, and there are even small studies and anecdotal stories of lithium improving Alzheimer’s disease, Huntington’s disease, and Tourette’s syndrome.

    While we could definitely use more studies on the effects of low dose lithium on the brain, the potential to boost cognitive function is promising. Lithium appears to increase brain-derived neurotrophic factor (BDNF), which is essential to proper brain function. Lithium also appears to inhibit glycogen synthase kinase-3 activity, which is involved in intracellular signaling.

    Lithium also inhibits N-methyl-D-aspartate receptor-mediated calcium influx, which has been associated with the hallmark symptom of Alzheimer’s disease. Finally, lithium also suppresses calcium-dependent activation of pro-apoptotic signaling pathways, which a very scientific way of saying it helps to keep cell death in check.

    5. Lithium may reduce suicide rates

    In 1990, researchers examined the different rates of lithium in the drinking water of 27 Texas counties. They found that counties with the least amount of lithium had significantly higher levels of suicide. In counties where lithium levels were highest, there were 40% fewer suicides!

    In 2013, a similar study was done in Japan that found lithium in drinking water had a protective effect against suicide risk in women. While I am definitely not implying we should start adding lithium to our water, these studies do indicate low dose lithium is a novel treatment we should be considering when it comes to many neurological conditions.

    Sometimes a Little Goes a Long Way

    The medical community continues to discover new ways of using low doses of certain medications in new applications.

    Another example of this are the benefits doctors are finding with low dose naltrexone (LDN). From autoimmune disease to cancer, low dose naltrexone is proving to be another very effective and little-known option for many conditions.

    You can read more about low dose Naltrexone here.

    Resources:

    Does lithium help anxiety?

    Lithium carbonate is commonly used to treat bipolar disorder and can be used to treat severe depression, too. In this article, we will look at the effect it has on mental health and whether it could play a role in our anxiety levels.

    What is it?

    Lithium is a metal. It is a naturally occurring element and can be found on the periodic table under the chemical symbol Li. It is the lightest natural metal.

    You may have run into it during a high school science class. If you drop it into water, it fizzes steadily and becomes smaller, until it eventually disappears.

    It has many uses in manufacturing including glass, ceramics, working with metal and nuclear power.

    It is also used within the human body. In this article, I will be concentrating on the medicinal uses.

    Does our body need it?

    Yes, but it’s not that important. There are no known diseases that you acquire from lack of lithium, for example. So, having low lithium levels does not seem to be immediately harmful.

    However, it does seem to increase the risk of suicide, committing crimes and drug use. Therefore, it is likely that it has some effect on our brain chemistry.

    What is it used for?

    In a medicinal context, it is referred to as lithium salts, lithium carbonate or lithium compounds.

    It is used to treat bipolar disorder1 and is typically prescribed for a long period (six months2, for example).

    It may also be used to treat severe depression. However, it is only used after first-choice antidepressants, such as SSRIs, have failed to produce results.

    If you are prescribed it, it may be under a brand name, of which there are many3.

    What does it do?

    The primary benefit is that it reduces the risk of suicide.

    It helps to stabilise your mood, reducing the swings. For bipolar, it may help to increase the “normal” period between the highs and lows.

    How does it work?

    We don’t know, exactly4.

    It seems to increase the levels of serotonin by triggering greater production. In this sense, it works along the same lines as SSRI antidepressants in increasing the amount of serotonin in the brain.

    It also affects your levels of norepinephrine, similar to the way SSNI antidepressants do.

    Given that both of these are commonly believed to have an affect on our mood, hence the regulating of them by antidepressant drugs, it seems plausible that lithium works similarly. However, there are several competing theories about how it exactly works.

    It may also be that it helps to reduce mood by helping the body control its levels of dopamine and glutamate. If so, this should suggest that at least some of the benefit is limited to bipolar disorder, and not depression or anxiety.

    Will it help with anxiety?

    Maybe. The real problem with answering this question is that we just do not know yet.

    There are theories about how it might work5. However, there is a lack of research to support whether it can reduce anxiety and improve mental health as a whole.

    If part of your mental health issues are directly related to mood, then lithium could be an avenue to explore.

    What are the side effects?

    There are a lot, and they can be severe.

    Very common side effects include constipation, diarrhoea, headaches, shaking, nausea, vomiting and weight gain. Acne and hair loss can also be common.

    This is not an exhaustive list, so if you have been prescribed it, see the informational leaflet for a full list of side effects.

    If you are taking lithium, you will need regular check-ups with your doctor. The dosage of lithium can run uncomfortably close to toxic levels, so it is important for your doctor to ensure your lithium level is correct.

    You shouldn’t take it while pregnant, and you should not take ibuprofen while taking it.

    It may increase your risk of hypothyroidism and kidney damage. Finally, it also increases your risk of acute dehydration.

    Conclusion

    Lithium is a powerful treatment for bipolar disorder and stabilising our mood.

    However, it is also a powerful substance and one that comes with a long list of side effects. Therefore, it should only be considered when other options have failed.

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    Published 4 September 2017. Written by Chris Worfolk.

    ARTICLES

    Treatment-resistant anxiety disorders: social phobia, generalized anxiety disorder and panic disorder

    Gabriela Bezerra de Menezes; Leonardo F Fontenelle; Sara Mululo; Márcio Versiani

    Anxiety and Depression Program, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (IPUB/UFRJ), Rio de Janeiro (RJ), Brazil

    Correspondence

    ABSTRACT

    OJECTIVES: Anxiety disorders are common psychiatric conditions that cause significant disability, poor quality of life and enormous social cost. Although treatments with demonstrable efficacy are available a great number of patients fail to respond or remains with clinically significant residual symptoms after treatment. The objective of this study is to review aspects related to treatment resistance and pharmacological strategies to deal with anxiety disorders resistant to treatment.
    METHOD: Narrative review.
    RESULTS: We discuss conceptual aspects related to treatment resistance or refractoriness, predictors of poor treatment outcome, and finally, some strategies to deal with anxiety disorders (including social anxiety disorder, generalized anxiety disorder and panic disorder) that do not respond to standard therapeutic interventions.
    CONCLUSION: Treatment resistance in anxiety disorders remains a challenge to clinical practice going from non standardized concepts of response and resistance to a paucity of controlled studies concerning therapeutic strategies.

    Descriptors: Social phobia; Psychopharmacology; Panic disorder; Generalized anxiety disorder; Drug resistance

    Introduction

    Different types of anxiety disorders are characterized by the presence of chronic anxiety symptoms that are clinically significant1 and are part of the most prevalent group of psychiatric disorders.2 In the beginning of the 90s, the National Comorbidity Survey3 demonstrated a 24.9% prevalence rate of anxiety disorders throughout life, and the social anxiety disorder (SAD) was the most frequent one, with a 13.3% prevalence rate. In the same study, generalized anxiety disorder (GAD) and panic disorder (PD) presented prevalence rates of 5.1 and 3.5%, respectively, throughout life.3

    Anxiety disorders are responsible for a significant social cost due to individual suffering, as well as indirect social costs.4 There is a huge impact on the health system not only because of the expenses with the treatment, but also because of the more frequent search for medical care caused by the physical symptoms resulting from anxiety.5

    Patients with anxiety disorders exhibit a significant reduction in their quality of life, less productivity, higher morbidity and mortality, and higher rates of comorbidity.6 Part of these huge direct and indirect social costs can become even more significant due to the fact that it is a group of disorders typically underdiagnosed, underevaluated, and, often, inadequately treated.4 Although there are several therapeutic strategies available for the treatment of anxiety disorders, the management of patients who do not respond adequately to the treatment remains a challenge in the clinical practice. Some authors compare the decrease in productivity and quality of life of patients with severe or resistant anxiety disorders to those of patients with schizophrenia.5 Structured studies regarding resistance in the anxiety disorders, however, are still rare and non-conclusive.

    In the present study, we intend to review 1) several conceptual aspects related to treatment resistance; 2) possible resistance predictors; and 3) pharmacological strategies in the management of treatment-resistant SAD, GAD and PD.

    Treatment resistance

    Several randomized, double-blind, placebo-controlled clinical trials7 and meta-analysis studies have demonstrated the efficacy of the antidepressants for SAD,8 PD9 and GAD.10 The serotonin selective reuptake inhibitors (SSRI) are considered the first-choice treatment for these three disorders in clinical algorithms and guidelines. Serotonin and noradrenaline reuptake inhibitors, high-potency benzodiazepines and some anticonvulsant agents also have demonstrated to be efficient.7 In clinical trials, response rates of 40 to 70% and remission rates of 20 to 47% are described.11 Resistance to the pharmacological treatment (i.e., no response or insufficient response) affects about one out of three patients with anxiety disorders.

    Although the treatment-resistant anxiety disorders are the focus of an increasing number of studies, many questions have not been answered yet, the first of them being the concept of therapeutic resistance itself. If in the depressive disorders there are debates regarding the ideal definitions for response, remission, and resistance to treatment12 (refer to the study by Vieira-Machado and Soares in the issue), with regard to the anxiety disorders this is even a more complex problem. The reason for such a complexity is that a decrease or absence of anxiety does not necessarily mean response or symptom remission, as it can be seen in patients who effectively avoid the phobic stimuli. The presence of anxiety is not a synonym of resistance or refractoriness either, since it can express inadequate treatment or normal response to an environmental stress factor.5

    In several studies, the criteria that characterize the treatment resistance of the subject with SAD, PD or GAD are not mentioned13 or are not very accurate, including absence of response to an “adequate” trial,14 to “more than one trial”13 to “several trials”,15 to “first line agents”,16 or to “defined anxiolytic agents”.17 Similarly, the concept of adequate or non-adequate trial is not described2 or is very heterogeneous, including the administration of a first-choice drug during four,18 six,19 eight13,16,17 or even 12 weeks.14 The variety and the absence of operationalization of the resistance criteria are only other limiting factors for the understanding of the scarce findings on the treatment of resistant anxiety disorders.

    In clinical practice the assessment of the response and remission should be multidimensional, including anxiety symptoms, functional parameters and comorbidities.5,11,20 Pollack et al. suggested that the concept of response to treatment in the anxiety disorders must include remission or important improvement of the central anxiety symptoms, functional impairment and comorbid depressive symptoms.11 This would imply a decrease in different magnitudes of the specific scales assessing this parameters, such as the Hamilton Rating Scale for Anxiety, for anxiety symptoms; the Panic Disorder Severity Scale, for PD symptoms; The Liebowitz Social Anxiety Scale, for SAD symptoms; the Sheehan Disability Scale, for functional assessment; and the Hamilton Rating Scale for Depression, for associated depressive symptoms.11 See Table 1.

    Predictors of treatment-resistance

    In studies that analyze the predictors of treatment resistance, some clinical variables have been systematically identified, such as higher disease severity, presence of axis I comorbidities and personality disorders, and factors like incorrect diagnosis, inadequate use of antidepressants and absence of cognitive behavioral therapies.21-23

    In recent reviews, Bystritsky and Pollack listed some of these factors and divided them into aspects related to the disease, the patient and the treatment, or to factors not related to these three items.5,11 Several variables listed by Bystritsky and Pollack present certain conceptual overlapping, and others are, to date, only clinical impressions that need to be confirmed in future studies.5,11

    Some predictors of treatment resistance can only be corrected with more wide initiatives at a long-term, such as training of professionals about the diagnosis and the treatment of anxiety disorders, reduction in external stress factors, and maintenance of a functional health system that can provide the patients with regular medical and psychological care. With regard to the psychiatrist, the performance of more accurate diagnosis, either related to anxiety disorders or possible comorbid disorders, so that the treatment can be conducted in a correct and efficient manner, is crucial for the achivement of better response rates. Efforts to assess the treatment and to optimize the patient’s adherence to the treatment must be made before considering the patient as refractory. In addition, confrontation and exposure strategies must be stimulated and psychotherapeutic support must be provided, mainly when prominent stress factors are identified,11 with the purpose of reducing the risk of resistance.

    Management of resistant anxiety disorders

    An important clinical issue is related to the best pharmacological intervention when there is resistance to the treatment of anxiety disorders, since there is a small number of controlled studies regarding this issue.4 Currently, no drug has been approved by the Food and Drugs Administration for the treatment of resistant anxiety, and most pharmacological strategies are based on a limited number of trials, often small and open trials.11

    Although some reviews suggest that dose increase is an efficient strategy in the management of resistance,5 there are no controlled studies that support this procedure in treatment-resistant GAD, PD and SAD. As opposed to that, controlled studies that assessed different regular doses of medication, which have been proven to be efficient, did not find a relation between the dose and the response to the treatment in these three disorders.

    Regarding GAD, for instance, some studies involving escitalopram24 and venlafaxine25 defined that higher doses of these drugs, i.e., higher than 10 mg and 75 mg, respectively, did not show a better response to treatment. With regard to SAD, studies that compared regular doses of venlafaxine26 and paroxetine27 also were not able to establish a significant relation between the dose and the response. In the studies involving PD, the scenario is not different. Studies that assess the efficacy of different doses of sertraline concluded that doses higher than 50 mg/day do not mean an increase in the efficacy.28,29

    There are several options available for the management of resistant anxiety disorder, although not all of them have been adequately tested. These approaches depend on the specific clinical scenario, for example, if there is absence or only insufficiency of response to the treatment. The augmentation, that is, adding up a second drug with a different mechanism of ation would be recommended for patients with partial response to the SSRI and NSRI.7 In patients with absence of response to the SSRI and NSRI, the most appropriate strategy would be to switch the drugs being used with a drug presenting another mechanism of action.

    Augmentation: The augmentation strategy is widely supported in the literature that suggests the involvement of multiple systems of neurotransmission in anxiety disorders,7 including dopamine, noradrenaline and GABA.30,31 The association of SSRI and atypical antipsychotics such as risperidone,18 aripiprazole32 and olanzapine19 in the treatment of resistant anxiety disorders has received attention lately33,34 and has been proven effective in controlled studies.18,35 Although the use of benzodiazepines, such as clonazepam,36 is controversial and not supported by controlled clinical trials in all the anxiety disorders reviewed in this study, it has been recommended as a possible approach for resistant patients after considering the possible risks and adverse effects such as sedation and possibility of developing addiction.5

    Drug switching: The efficacy of different SSRI (e.g.: citalopram and escitalopram) in patients who do not respond to the drugs of the same class was demonstrated in some open studies.37,38 The monotherapy with atypical antipsychotics (e.g.: olanzapine) or GABAergic agents (such as tiagabine and pregabalin), for instance, was successfully used in some case reports.39,40 With greater safety regarding the risk of causing addiction and with a less significant anxyolitic action, these substances need to be tested in further studies so that their use can be assessed in a broader manner.5 The monoamine oxidase enzyme inhibitors (MOAIs), which had their efficacy demonstrated in several anxiety disorders, often are described in text books and literature reviews as an efficient alternative when there is absence of response to the first line drugs. Case reports in which phenelzine is used in treatment-resistant patients with PD41 and SAD42 showed the efficacy of these substances in a preliminary manner. However, there are no controlled studies assessing the efficacy of the MOAIs in the resistant anxiety disorders, therefore, new clinical trials are needed so that these drugs can be described as an alternative to the absence of response.

    Due to the strategies reviewed here and the high occurrence of comorbidity, the use of polypharmacy is a frequent and inevitable reality, in spite of the risks of increasing the adverse effects.7 Although there is no scientific evidence to validate polypharmacy, several authors defend the idea that this practice is an effective solution for a complex clinical problem.5

    1. Social anxiety disorder

    Randomized, double-blind, placebo-controlled clinical trials have clearly demonstrated the efficacy of several classes of drugs in the treatment of SAD patients who were not under any other drug.43,44 However, information based on controlled studies remain necessary in order to define the best approach for patients who do not respond to the first line therapies.23

    The augmentation with atypical antipsychotics was investigated in two open studies, the first one retrospectively assessed the association of aripiprazol with SSRI for 12 weeks,32 and the second study associated risperidone with SSRI or benzodiazepines for eight weeks.17 In both cases, the augmentation strategies have been proven efficient, suggesting the necessity of controlled studies that confirm these observations. In an open study conducted by Van Ameringen et al.,45 the augmentation of SSRI with buspirone in social phobic patients with inadequate response to the treatment also was efficient to improve the symptoms.

    Open studies and case reports involving monotherapy have also demonstrated preliminary efficacy in the treatment-resistant SAD. Positive results have been observed whith the use of escitalopram7 and citalopran46 in open trials assessing the efficacy in patients who do not respond to other SSRIs. In open studies that described the use of antidepressants agents different from the SSRIs in treatment-resistant social phobic patients (such as phenelzine42 and venlafaxine47), favorable therapeutic response has also been observed. Initial positive studies with atypical antipsychotics (e.g.: olanzapine48) and anticonvulsants (e.g.: topiramate49 and valproic acid50) as a monotherapy in non-resistant SAD suggest new perspectives for the therapy provided to treatment-resistant patients.

    Augmentation strategies have been preliminarily suggested.17,45 In the only randomized, placebo-controlled clinical trial involving treatment-resistant SAD, Stein et al. assessed the association of pindolol with paroxetine in 14 social phobic patients resistant to paroxetine administered for 12 weeks. This association did not show efficacy higher than placebo.51

    2. Generalized anxiety disorder

    More than half of the patients with GAD presents with chronic and persistent symptomatology. However, the optimal management of treatment-resistant GAD has not been well-established yet and there are few studies that assessed possible strategies to deal with the resistance to the GAD treatment.

    There is one open study suggesting the efficacy of ziprasidone used as monotherapy (mean dose of 40 mg/day) for seven weeks in resistant patients.37 Aripiprazol32,52 and risperidone17 in association with other treatments were preliminarily assessed in open studies, and were proven to be efficient for resistant GAD. Case reports preliminarily suggest the efficacy of GABAergic agents, including gapapentine15 and tiagabine.40

    The efficacy of augmentation strategies with atypical antipsychotics has also been confirmed in two randomized, double-bind, placebo-controlled clinical trials in patients with treatment-resistant GAD.7 In the first study, patients that remained symptomatic after the use of fluoxetine were randomized so that this treatment could be associated with olanzapine (mean dose of 8.7 mg) or placebo. The augmentation with olanzapine resulted in significantly less severe generalized anxiety symptoms.53 This finding was replicated by Brawman-Mintzer et al. in a five-week study with risperidone. In this clinical trial, the patients who had not responded to the conventional treatment for GAD and had risperidone (dose between 0.5 and 1.5 mg) associated with their initial treatment presented significant improvement of the symptoms.54

    3. Panic disorder

    Even though several medications have shown positive results in the treatment of PD in controlled clinical trials, a significant percentage of patients remain symptomatic after an adequate period of treatment.

    Similarly to SAD and GAD, the management of resistant PD has not been deeply studied and there is no consensus regarding what to do when there is no response.

    The combination of drugs has been described in anecdotal studies. The association of imipramine and moclobemide,55 tricyclics and fluoxetine,56 benzodiazepines and sodium valproate57 or d-fenfluramine,58 and lithium carbonate and clomipramine59 were described in case reports with preliminary positive results. Cases of positive response due to the augmentation with phenelzine, tiagabine and gabapentine were also reported by Buch, Schwartz and Pollack, respectively.15,40,42

    Some substances were described as efficient when used as monotherapy to treat resistant PD. Case reports suggested the efficacy of trimipramine,60, tiagabine61 and clonazepan.36 In an open study with reboxetine (8 mg/day) for six weeks, there was a significant improvement of the symptoms in patients who had presented treatment resistance previously.62 In a study conducted by Baets et al. involving patients with PD and mood instability, divalproate has proven to be efficient in the treatment of PD symptoms.63

    Similarly to the other resistant anxiety disorders, the use of atypical antipsychotics has been receiving attention, with open studies demonstrating the efficacy of aripiprazol32 and risperidone17 associated with SSRI or benzodiazepines, and case reports in which the association of olanzapine with paroxetine37,64 or the previously used treatment65 has shown to be efficient. In an open study, Sepede et al. found favorable results after treating, with 5 mg of olanzapine for 12 weeks, 31 patients who had not responded to the previous treatment with SSRI.19 Olanzapine has also shown to be efficient as monotherapy in an open study conducted by Hollifield39 with 10 patients who received a mean dose of 12.3 mg for eight weeks.

    The only randomized, double-blind, placebo controlled clinical trial involving augmentation strategies in treatment-resistant PD assessed the association of beta-blocker pindolol with SSRI. Pindolol (7.5 mg per day) associated with fluoxetine (20 mg per day) for a period of four weeks was effective in the decrease in the severity of PD symptoms compared to placebo.13

    Conclusion

    Anxiety disorders, in addition to being prevalent, are associated with important functional impairments. Even though there have been recent advances in the management and understanding of these disorders, the treatment of anxiety remains a challenge for the clinical practice. Several interventions have proven to be efficient to reduce anxiety symptoms; however, many patients remain symptomatic and disabled.

    Treatment resistance is especially relevant for anxiety disorders. The reason why it is so important is that the clinical conditions are associated with higher mortality and morbidity rates, worse quality of life and high social cost in a large group of individuals. There are several factors involved in the absence of treatment response and the adequate understanding of this phenomenon is crucial to help the patients. Although the relevance of the topic is undeniable, there are few studies systematically investigating the inadequate response to the treatment in anxiety disorders. The development of new and effective strategies to deal with this problem is very important. New therapeutic approaches and clear evidence-based strategies can mean higher response rates and less impairment associated with these disorders.

    5. Bystrisky A. Treatment-resistant anxiety disorders. Mol Psychiatry. 2006;11(9):805-14.

    12. Keller MB. Issues in treatment-resistant depression. J Clin Psichiatry. 2005;66(Suppl 8):5-12.

    14. Pallanti S, Quercioli L. Resistant social anxiety disorder response to Escitalopram. Clin Pract Epidemiol Ment Health. 2006;2:35.

    20. Bandelow B, Baldwin D, Dolberg O, Andersen HF, Stein DJ. What is the threshold for symptomatic response and remission for major depressive disorder, panic disorder, social anxiety disorder, and generalized anxiety disorder? J Clin Psychiatry. 2006;67(9):1428-34.

    21. Pollack MH, Meoni P, Otto MW, Simon N, Hackett D. Predictors of outcome following venlafaxine extended-release treatment of DSM-IV generalized anxiety disorder: a pooled analysis of short- and long term studies. J Clin Psychopharmacol. 2003;23(3):250-9.

    25. Baldwin DS, Huusom AK, Maehlum E. Escitalopram and paroxetine in the treatment of generalised anxiety disorder:randomised, placebo-controlled, double-blind study. Br J Psychiatry. 2006;189:264-72.

    26. Stein MB, Pollack MH, Bystritsky A, Kelsey JE, Mangano RM. Efficacy of low and higher dose extended-release venlafaxine in generalized social anxiety disorder: a 6-month randomized controlled trial. Psychopharmacology (Berl). 2005;177(3):280-8.

    32. Worthington JJ 3rd, Kinrys G, Wygant LE, Pollack MH. Aripiprazole as an augmentor of selective serotonin reuptake inhibitors in depression and anxiety disorder patients. Int Clin Psychopharmacol. 2005;20(1):9-11.

    33. Blier P, Szabo ST. Potential mechanisms of action of atypical antipsychotic medications in treatment-resistant depression and anxiety. J Clin Psychiatry. 2005;66(Suppl 8):30-40.

    35. Pollack MH, Simon NM, Zalta AK, Worthington J, Hoge EA, Mick E, Kinrys G, Oppenheimer J. Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study. Biol Psychiatry. 2006;59(3):211-5.

    38. Pallanti S, Quercioli L. Resistant social anxiety disorder response to Escitalopram. Clin Pract Epidemol Ment Health. 2006;2:35.

    39. Hollifield M, Thompson PM, Ruiz JE, Uhlenhuth EH. Potential effectiveness and safety of olanzapine in refractory panic disorder. Depress Anxiety. 2005;21(1):33-40

    53. Pollack MH, Simon NM, Zalta AK, Worthington JJ, Hoge EA, Mick E, Kinrys G, Oppenheimer J. Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study. Biol Psychiatry. 2006;59(3):211- 5.

    55. Boerner RJ. Treatment refractory panic disorder -success of a combined treatment with imipramine, moclobemide and behavior therapy. Psychiatr Prax. 1995;22(1):30-2.

    56. Tiffon L, Coplan JD, Papp LA, Gorman JM. Augmentation strategies with tricyclic or fluoxetine treatment in seven partially responsive panic disorder patients. J Clin Psychiatry. 1994;55(2):66-9.

    58. Hetem LA. Addition of d-fenfluramine to benzodiazepines produces a marked improvement in refractory panic disorder—a case report. J Clin Psychopharmacol. 1996;16(1):77-8.

    59. Cournoyer J. Rapid response of a disorder to the addition of lithium carbonate: panic resistant to tricyclic antidepressants. Can J Psychiatry. 1986;31(4):335-8.

    60. Cerra D. Trimipramine for refractory panic attacks. Am J Psychiatry. 2006;163(3):548.

    63. Baetz M, Bowen RC. Efficacy of divalproex sodium in patients with panic disorder and mood instability who have not responded to conventional therapy. Can J Psychiatry. 1998;43(1):73-7.

    65. Etxebeste M, Aragues E, Malo P, Pacheco L. Olanzapine and panic attacks. Am J Psychiatry. 2000;157(4):659-60.

    Correspondence:
    Gabriela Bezerra de Menezes
    Rua Projetada 32-1 – São Francisco
    24360-490 Niterói, RJ, Brazil
    E-mail: [email protected]

    Financing: None
    Conflict of interest: None

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