Anxiety and Depression: Optimizing Treatments

Properly diagnosing and treating patients with anxiety, depression, or both is a challenging aspect of practicing medicine in the primary care setting. Patients often present with somatic complaints rather than classic psychiatric symptoms. In addition, there is significant overlap between anxiety and depression in this patient population. Comorbid anxiety and depression is often more resistant to pharmacologic treatment, and patients with coexisting disorders have a poorer medical prognosis than do patients with either disorder alone. Fortunately, many new therapies are available to assist the clinician in managing these patients. The newer antidepressants, in particular, are playing an increasingly important role in the treatment of both anxiety disorders alone and comorbid anxiety and depression. These new choices enable our goal of treatment to encompass not only improvement but also sustained complete remission. Of the newer agents, the selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors have been studied quite extensively in these patient populations. The specific profiles of individual agents may assist the clinician in individualizing treatment. Characteristics such as robust efficacy, speed of onset of activity, the potential for drug-drug interactions, dose response, and tolerability are important considerations in optimizing treatment.     

GABAA receptors as targets for novel anxiolytic drugs.

Anxiety disorders are highly prevalent and disabling disorders which are commonly treated with pharmacotherapy and/or psychotherapy. While benzodiazepines are of great value for the treatment of acute anxiety states, their long-term use is hampered by their well-known side effect profile. Meanwhile, antidepressants represent first line treatment options for anxiety disorders. However, their slow onset of action is a disadvantage for their use in these disorders. Therefore, there is need for novel anxiolytics with a rapid onset of action and a favourable side effect profile. Currently, there is a renaissance of gamma-aminobutyric acid type A (GABAA) receptors as targets for the development of novel anxiolytic drugs. While compounds structurally related to GABA, e.g., pregabalin, have already entered large scale clinical development, GABA transporter inhibitors, subtype specific benzodiazepines and GABAA receptor modulating neuroactive steroids are promising new candidates. However, their clinical efficacy has still to be shown in clinical trials.     

Anxiolytics: past,present, and future agents

Although anxiety disorders were classified as neurotic disorders and not systematically studied before DSM-III, researchers and clinicians have been searching for effective, safe agents to treat anxiety symptoms and disorders for over a century. In that time, barbiturates, benzodiazepines, and many classes of antidepressants have been used as anxiolytics, all with side effect profiles that made them less than optimal treatments for anxiety. The recognition of the role of GABA in anxiety disorders has led researchers to develop anxiolytics that target GABA. The long-sought-after class of anxiolytics that are both effective and safe may be found in the new research being conducted with agents that selectively target GABA receptors and their subtypes.     

Pharmacological treatment of anxiety in the medically ill patient.

Treatment guidelines which are available are intended for treatment of medically healthy patients. There is little information in the literature regarding the treatment of patients who are medically ill. Anxiety and anxiety disorders are frequently encountered in patients with serious medical disorders. These medically ill patients may have substantial changes in pharmacokinetic factors as a result of their current illness or treatment. Also, treatment considerations related to their accompanying medical treatment(s) are sometimes required. These various factors may result in a different initial choice of agents, alterations in the dosage of a given agent, or even preclude the use of some standard agents. In this chapter, we first present a review of the current psychopharmacologic treatment of anxiety disorders. In the second section, we review the potential pharmacokinetic consequences of serious hepatic renal, pulmonary and cardiac disease relevant to the pharmacological treatment of anxiety.     

Pharmacotherapy of anxiety disorders: a critical review

Given the enormous contribution of anxiety disorders to the burden of disease, it is key to optimize their prevention and treatment. In this critical review we assess advances in the pharmacotherapy of anxiety disorders, as well as remaining challenges, in recent decades, the field has seen rigorous clinical trial methods to quantify the efficacy and safety of serendipitously discovered agents, more focused development of medications with selective mechanisms of action, and the gradual translation of insights from laboratory research into proof-of-principle clinical trials. On the positive side, a considerable database of studies shows efficacy and relative tolerability of the selective serotonin reuptake inhibitors in the major anxiety disorders, and secondary analyses of such datasets have informed questions such as optimal definition of response and remission, optimal dose and duration, and comparative efficacy of different agents. Significant challenges in the field include barriers to appropriate diagnosis and treatment of anxiety disorders, failure of a significant proportion of patients to respond to first-line pharmacotherapy agents, and a limited database of efficacy or effectiveness studies to guide treatment in such cases.     

The role of GABA in anxiety disorders

Anxiety stems from and perpetuates dysregulation of neurobiological systems, but the exact mechanisms of anxiety disorders are still only partially understood. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter known to counterbalance the action of the excitatory neurotransmitter glutamate. Several pharmacologic agents target the GABA system and modulate the overall effect of GABA. This article highlights multiple neurobiological interactions that play a role in anxiety and reviews selected studies of plasma neurosteroid levels, plasma GABA levels, and benzodiazepine binding site sensitivity and density in patients with anxiety disorders. The article concludes with further support for the role of the GABA system in anxiety by summarizing the current evidence supporting the use of novel GABAergic agents including tiagabine in the treatment of anxiety disorders.     

Propranolol in psychiatry. Therapeutic uses and side effects

There are speculations that beta-adrenergic blocking agents are useful in the treatment of psychiatric disorders. Clinically, propranolol, an agent of this group, has been investigated in the treatment of various clinical disorders including schizophrenia, other psychoses, anxiety disorders, and stress reactions. This paper critically evaluates its efficacy in these disorders and provides a useful clinical perspective. In addition, propranolol produces a number of psychiatric side effects which are due to its central action or due to the peripheral receptor blockade. In addition, idiosyncratic reactions as well as withdrawal effects have also been reported to produce psychiatric side effects. It is important that the physician who wishes to use this drug know the existing knowledge of its usefulness in the treatment of psychiatric disorders as well as its psychiatric side effects.     

The neuropsychiatry of human immunodeficiency virus

With the advent of HIV infection, a new causal group of neurobehavioral disorders has emerged. These are the neurogenic and psychogenic neurobehavioral disturbances associated with HIV. Neurogenic disorders are those caused by the direct effects of HIV on the CNS, or by other infectious agents, neoplasms, vascular events, or side effects of biologic treatments in HIV-infected persons. Psychogenic disorders include anxiety, depression, adjustment reactions, and other behavioral disturbances related to knowledge of HIV seropositivity and recognition of being afflicted with a serious illness. In many instances, the psychogenic disorders appear to represent recrudescences of preexisting psychopathology. The comprehensive management of the patient with HIV infection requires early recognition and proper treatment of such complications.     

Anxiety disorders in older adults

In the population of older adults, anxiety disorders are underdiagnosed and undertreated. Epidemiologic studies have generally found that the prevalence of anxiety disorders declines with age. Recognition of anxiety disorders in older adults is, however, complicated by several age-related factors including the presence of depression, cognitive impairment, and physical illness. A variety of medications have been used to treat anxiety disorders across the life span; however, few studies have evaluated their use specifically in older adults. Choice of medication requires consideration of the effects of aging on safety, tolerability, and adherence. Available data suggest that cognitive and behavioral treatments may be effective for anxiety disorders in older adults. Appropriate medical evaluation and psychosocial interventions are recommended prior to initiating pharmacotherapy. When pharmacologic treatment is warranted, antidepressant medications at low doses may be useful for late-life anxiety disorders; other agents may be considered for augmentation or second-line use in certain types of patients.     

Treatment of non-schizophrenic disorders: focus on atypical antipsychotics

Antipsychotics are commonly used for conditions other than schizophrenia, yet support for such use in the literature is unclear. This article reviews the literature on the pharmacologic treatment of specific types of non-schizophrenic disorders: those associated with psychotic depression, obsessive-compulsive disorder, body dysmorphic disorder, bipolar disorder, and dementia. It focuses on the evidence for using antipsychotics in these conditions, placing emphasis on atypical antipsychotics. Medline/HealthStar and PsycInfo databases were used to identify published trials and reports of antipsychotics used specifically for non-schizophrenic disorders. Numerous studies were found supporting the use of atypical antipsychotics for non-schizophrenic disorders; however, with the exception of dementia, few randomized, double-blind controlled trials have been published examining the efficacy and safety of these agents in non-schizophrenic disorders. In general, most trials were restricted to short-term use as adjunctive therapy. The literature reviewed was primarily comprised of small open-label trials, thus making it difficult to draw definitive conclusions. Despite the limitations of the trials reviewed, atypical antipsychotics represent a promising treatment modality when considering their improved side effect profile compared to conventional agents. Appropriate dosing and the use of antipsychotics in combination with psychosocial treatments are important treatment considerations. Due to the frequent clinical use of atypical antipsychotics as adjunctive therapy, well-designed trials of these agents in non-schizophrenic disorders are necessary.     

Psychotic symptoms in patients with medical disorders

Psychotic symptoms frequently occur in patients with comorbid medical disorders and present a diagnostic and treatment challenge. They may be a part of an independent psychiatric illness associated with the underlying medical condition or induced by substance use or medications. The presence of psychotic symptoms can contribute to misdiagnosis or complicate the management of the comorbid medical illness. Psychiatrists must be familiar with the assessment and management of psychotic disorders in patients with comorbid medical disorders. Medications that may be used to treat psychosis include antipsychotic agents, benzodiazepines, or possibly certain anticonvulsants. Selecting the appropriate medication requires knowledge of the pharmacokinetics of different agents and their side effect profile. Understanding the neuropsychiatric effects of medications and drug-drug interactions may help in preventing psychotic symptoms.     

Mania in the medically ill

Manic symptoms frequently occur in patients with comorbid medical disorders and present a diagnostic and treatment challenge. Manic symptoms may be due to an independent psychiatric illness, may be induced or precipitated by a medical condition, or may result from medication or substance use. The presence of manic symptoms in medically ill patients can lead to misdiagnosis or complicate the management of comorbid medical illness. It is of paramount importance to identify the etiology of the mania and, in particular, differentiate primary from secondary mania. Management of mania in the medically ill should focus on treating the underlying medical condition, medication management (antipsychotic agents, mood stabilizers, and/or benzodiazepines), and psychotherapy (if needed). Selecting appropriate medication for treatment requires basic knowledge of the pharmacokinetics of the medications, their side effect profile, and drug-drug interaction. The majority of deficits accompanying secondary mania resolve with treatment of the underlying cause, and supportive psychopharmacology may be all that is needed, but if symptoms persist, patients may need medications for a longer duration.     

Natural remedies for anxiety disorders: potential use and clinical applications

Background: Natural remedies have been widely used and generally accepted as established treatments of depressive disorders, leading to the investigation of their potential role and efficacy in the treatment of the various anxiety disorders. Methods: Numerous case reports, open‐label, and placebo‐controlled trials investigating the use of natural remedies in the treatment of anxiety disorders have yielded some encouraging results. Results: Overall, these studies have indicated a potential role for natural remedies in the treatment of anxiety and suggest that such agents may possess a safer side effects profile when compared to conventional agents. However, these early findings, albeit promising, are yet to be supported by further investigation in large‐scale, placebo‐controlled studies. Conclusions: This article reviews past and present research being performed in this area of clinical interest, while also revealing a remarkable paucity of data. Depression and Anxiety, 2009. © 2009 Wiley‐Liss, Inc.     

Interest of propranolol in the treatment of school refusal anxiety: about three clinical observations

School refusal anxiety is a pathopsychological disorder which touches the young child, between 8 and 13 years. Even if the school refusal is studied for a long time, there is not still consensus as for the specific definition of this disorder or on the best way of treating it. Nevertheless, accountable of long-lasting difficulties in school integration, its short and medium term consequences are serious and well known: school desertion, mood disorder and behavioral problems. Speed and quality of the medico-psychological and educational interventions represent a important factor for evolution and prognosis. Although, psychological interventions remain essential, sometimes the interest of an associated psychotropic medication should be discussed. This one can indeed either improve their results or supporting their installations. Despite more than twenty controlled trials in the pediatric population, no definitive psychopharmacological treatment data exist for anxiety disorder in childhood and especially for school refusal disorder. The majority of the studies stress as well the interest of benzodiazepines as tricyclic antidepressants but without being able to specify the possible superiority of a chemical on the other. On the other hand, the side effects of each one are well-documented, in particular for the benzodiazepines (potential abuse, sedation, potential desinhibition, mnemonic disorder), limiting thus their uses in child. In this work, we would like to emphasize the interest of propranolol in the treatment of somatic symptoms usually met in school refusal anxiety. Although beta-blockers have been used in the treatment of neurovegetative symptoms associated with situational anxiety disorders, there is no controlled data and only some open data to guide pediatric use for anxiety disorders in children. Nevertheless, prescribed with low posology and in substitution of benzodiazepine, this medication enabled us in three severe clinical cases to shorter notably the time of school rehabilitation. Well tolerated on the clinical level, with a greater efficiency on the somatic signs related to anxiety than benzodiazepines and with not having their side effects, this therapeutic can constitute a significant support in the psychological treatment of these children. However, these present results require to be confirm by other observations, which will be lead perhaps to a controlled study.     

Efficacy and tolerability of quetiapine in the treatment of behavioral and psychological symptoms of dementia

Behavioral symptoms start to appear in mild and moderate dementia and become increasingly severe with the progression of the disease. Agitation, aggressiveness, and psychosis can be seen in Alzheimer's disease, and in particular are common manifestations in Lewy body dementia. It is the behavioral disturbances rather than the cognitive disorders that are more often the cause of the institutionalization of these patients because of the heavy assistance and emotional burden they represent for caregivers. Traditionally, these kinds of symptoms were controlled by classical antipsychotic agents, which after long-term use cause severe extrapyramidal effects, late dyskinesia, sedation, orthostatic hypotension, and cognitive function impairment. More recently, atypical antipsychotic agents have shown a better tolerability profile, with a reduced incidence of extrapyramidal effects, orthostatic hypotension, sedation, and a reduced impact on cognitive function. The aim of this study is to evaluate the efficacy and tolerability of quetiapine in a group of patients with a diagnosis of dementia and concomitant psychotic disorders. The response to treatment was evaluated by the Neuropsychiatric Inventory (NPI) and the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). The NPI and BEHAVE-AD were administered at baseline and after 4 weeks and 12 weeks of therapy. Tolerability was assessed by the incidence of clinically evident side effects. The results show that quetiapine is effective in reducing behavioral symptoms, deliria and hallucinations, aggressiveness, and sleep disturbances. Quetiapine tolerability proved to be satisfactory. The only side effect of clinical significance was orthostatic hypotension, which was, however, partially preventable by a slower drug titration.     

Beta-blocking drugs and anxiety. A proven therapeutic value]

The therapeutic value of propranolol and other beta-adrenergic receptor blockers in anxiety disorders is reviewed. The potential side-effects of benzodiazepines, eg psychomotor impairment and dependance, suggest that the main indicators of these compounds are the acute anxiety states and the short term treatment of anxiety disorders requiring sedation. Thus, other psychotropic drugs may be of potential value in the treatment of these disorders. The results of the placebo-controlled studies reviewed here strongly suggest that propranolol is useful in the treatment of anxiety disorders, especially those: 1) characterized by the presence of somatic symptoms related to increased adrenergic tone; 2) of moderate intensity and/or seen in general practice; 3) of recent onset and not fulfilling DSM III criteria for specific chronic anxiety disorders. Propranolol and other beta-blockers may also be useful in the prevention of performance anxiety such as the fear of speaking in public or specific social phobias when limited in number in the same patients. Average therapeutic doses range from 20 to 40 mg, once to three times a day; the clinical efficacy of beta-blockers administered for periods longer than 4 weeks remains to be demonstrated. The potential impairment of cognitive functions by propranolol is still a matter of controversy as well as its ability to induce depressive states in predisposed patients. Furthermore, the efficacy of beta-blockers that do not cross the blood-brain barrier in the treatment of anxiety raises unresolved questions concerning the mode of action (central vs peripheric) of these medications. In short, beta-blocking agents, and especially propranolol, should be considered as potential therapeutic agents in the pharmacological treatment of anxiety disorders besides benzodiazepines, antidepressant compounds and the newer azapirones, eg buspirone.     

Everolimus improves memory and learning while worsening depressive- and anxiety-like behavior in an animal model of depression

Everolimus (EVR) is an orally-administered rapamycin analog that selectively inhibits the mammalian target of rapamycin (mTOR) kinase (mainly mTORC1 and likely mTORC2) and the related signaling pathway. mTOR is a serine/threonine protein kinase regulating multiple important cellular functions; dysfunction of mTOR signaling has also been implicated in the pathophysiology of several neurological, neurodegenerative, developmental and cognitive disorders. EVR is widely used as an anti-neoplastic therapy and more recently in children with tuberous sclerosis complex (TSC). However, no clear correlation exists between EVR use and development of central side effects e.g. depression, anxiety or cognitive impairment. We studied the effects of a 3 weeks administration of EVR in mice chronically treated with betamethasone 21-phosphate disodium (BTM) as a model of depression and cognitive decline. EVR treatment had detrimental effects on depressive- and anxiety-like behavior while improving cognitive performance in both control (untreated) and BTM-treated mice. Such effects were accompanied by an increased hippocampal neurogenesis and synaptogenesis. Our results therefore might support the proposed pathological role of mTOR dysregulation in depressive disorders and confirm some previous data on the positive effects of mTOR inhibition in cognitive decline. We also show that EVR, possibly through mTOR inhibition, may be linked to the development of anxiety. The increased hippocampal neurogenesis by EVR might explain its ability to improve cognitive function or protect from cognitive decline. Our findings suggest some caution in the use of EVR, particularly in the developing brain; patients should be carefully monitored for their psychiatric/neurological profiles in any clinical situation where an mTOR inhibitor and in particular EVR is used e.g. cancer treatment, TSC or immunosuppression.