Exploring psychotherapeutic issues and agents in clinical practice
Dementia, once described as the “silent epidemic,” is now well known and greatly feared (Larson, 2001). Interesting findings were recently published from the Framingham Heart Study, a community-based longitudinal cohort study initiated in 1948 (Satizabal et al., 2016). Among the participants in this study, the incidence of dementia had declined during the course of three decades. Although the total number of older adults with dementia will increase worldwide because of increased life expectancy and the aging of populations, at least eight population-based studies of dementia incidence or prevalence have suggested a declining age-specific risk in the United States and Europe during the past three decades (Larson, Yaffe, & Langa, 2013; Matthews et al., 2013; Satizabal et al., 2016). However, it is unknown whether this declining risk is true elsewhere.
Consistent with this decline, an autopsy study of older adults who died between 1972 and 2006 found a marked decrease in age-related brain amyloid deposition during these 34 years (Kovari, Herrmann, Bouras, & Gold, 2014). Amyloid deposits and neurofibrillary tangles are hallmark findings of Alzheimer's disease. Rising levels of education, decreased rates of smoking, and improved management of cardiovascular risk factors (e.g., hypertension, hypercholesterolemia, hyperglycemia) may account for the decline in dementia risk. Another possible explanation is the use of nonsteroidal anti-inflammatory drugs and statin drugs, both of which have been shown to decrease brain amyloid deposition (Kovari et al., 2014).
There is a viral strain of belief that psychotropic medications are harmful to the brain. Many patients are fearful of taking these drugs for this reason. To counter such a concern, I will discuss the possibility that psychotropic medication use may contribute to declining rates of dementia. For perspective, I will first describe historical trends in their use. I will then briefly review their neurotrophic and neuroprotective effects, which provide a plausible mechanism for understanding how they may prevent dementia.
Historical Trends in the Use of Psychotropic Medications
Clinical use of antidepressant medications began in the late 1950s, when tricyclic antidepressant (TCA) drugs and monoamine oxidase inhibitor (MAOI) drugs were first introduced. The subsequent development of non-TCA and non-MAOI drugs having antidepressant properties led to the introduction of other types of antidepressant medications in the 1980s and 1990s. These drugs included bupropion (Wellbutrin®), fluoxetine (Prozac®) and other serotonin reuptake inhibitors (SSRI) drugs, and venlafaxine (Effexor®) and other serotonin-norepinephrine reuptake inhibitor drugs. Antidepressant medications are commonly prescribed for many labeled and off-label psychiatric, neurological, and medical uses.
According to data from the National Health and Nutrition Examination Surveys (NHANES), approximately 11% of Americans 12 years and older took antidepressant medications in 2005–2008, and the rate of antidepressant drug use increased 400% from 1988–1994 through 2005–2008 (Pratt, Brody, & Gu, 2011). More recent NHANES data (National Center for Health Statistics [NCHS], 2015) indicate that antidepressant drug use has increased even further: 9% of Americans of all ages took an antidepressant medication in 2009–2012 (8.4% were 18 to 44 years old and 14% to 15% were older than 44). Data obtained for 29 European countries between 1980 and 2009 demonstrated continuous growth of antidepressant drug use; although growth varied across countries, the average per year was approximately 20% (Gusmao et al., 2013). Data from the Organisation for Economic Co-operation and Development (OECD; 2015) found that consumption of antidepressant medication increased considerably from 2000 to 2013 among 28 non-U.S. member countries around the world; the average consumption doubled during this period.
Clinical use of antipsychotic medications also began in the late 1950s, after chlorpromazine (Thorazine®) was first discovered and other first-generation antipsychotic (FGA) drugs were subsequently introduced. Various second-generation antipsychotic (SGA) drugs (also known as atypical antipsychotic drugs) have been introduced since 1990. Although FGA drugs were predominantly used for the treatment of schizophrenia (and to a lesser extent for bipolar mania) when they were marketed, the SGA drugs have enjoyed a considerably broader spectrum of approved and off-label clinical uses beyond psychosis and mania.
In a review of 17 pharmacoepidemiological studies that explored antipsychotic drug prescription trends during 1985–2005 in North America, Europe, and Australia, Verdoux, Tournier, and Begaud (2010) found that all but two of these studies showed an increase in antipsychotic prescriptions, mainly because of a dramatic increase in SGA prescriptions. The National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Survey found that during the 8-year period from 1996–2003, there was an estimated 47.7 million adult ambulatory care visits in the United States involving mention of an antipsychotic drug (Sankaranarayanan & Puumala, 2007). During this interval, visits involving SGA drugs and combination antipsychotic drugs (visits mentioning an FGA drug plus an SGA drug) increased by 195% and 149%, respectively. Relative to FGA or combination antipsychotic drug visits, more SGA drug visits involved antidepressant drugs. Data from the IMS Health National Diagnostic and Therapeutic Index found that annual SGA treatment visits in the United States increased from 1 million visits in 1995 to 13.3 million visits in 2008 (Alexander, Gallagher, Mascola, Moloney, & Stafford, 2011).
Lithium and Anticonvulsant Drugs
Lithium (Eskalith®; Lithobid®), first identified as a natural element in 1817, was used as a medical therapy for various conditions during and following the 1800s until it was largely abandoned in the 1940s due to its toxicity. Lithium was “rediscovered” in 1949 when it was found to be an effective treatment for mania. Use of lithium as an antimanic and mood stabilizer drug for bipolar disorder became widespread in Europe and Scandinavia during the 1960s, before spreading to the United States where its popularity grew after its 1970 approval. Interest in lithium augmentation for treatment-resistant depression developed in the 1980s, and its effectiveness for this use was subsequently confirmed in controlled studies. Lithium also is used for treating cluster headache and is sometimes used in the treatment of schizophrenia.
Since its synthesis in 1882, valproate had long been used as a chemical solvent until its therapeutic anti-seizure effects were discovered in 1962. Clinical use of the valproate formulations valproic acid (Depakene®) and divalproex sodium (Depakote®) as anticonvulsant treatments for seizures began in the late 1960s and increased in the 1970s, before achieving widespread use around the world in the 1980s. Use of valproate in the United States was extended to include the treatment of mania in 1995 and migraine headache in 1996, although its use for treating bipolar disorder outside the United States was limited until the early 2000s. Valproate is commonly used off-label in psychiatric and neurological practice.
Carbamazepine (Tegretol®), a tricyclic compound chemically related to imipramine (Tofranil®), was introduced as an anticonvulsant in the 1960s, but was also investigated at that time for trigeminal neuralgia and subsequently became a standard treatment for this condition. Studies of carbamazepine in bipolar disorder were conducted in the 1970s, and it became widely used off-label for treating bipolar disorder in the 1980s and 1990s. It was not until 2005 that an extended-release carbamazepine formulation (Equetro®) was granted an approved indication for bipolar disorder. Carbamazepine also is frequently used off-label in psychiatry and neurology.
In a rational drug discovery program in epilepsy, lamotrigine (Lamictal®) was synthesized in the early 1980s and later approved worldwide in the early 1990s for seizures. Based on experience with other anticonvulsant drugs in bipolar disorder, lamotrigine was also investigated and subsequently introduced for the treatment of bipolar disorder in 2003. Lamotrigine is commonly used for various off-label reasons in psychiatry and neurology.
Trends in the Use of Lithium and Anticonvulsant Drugs
Among six studies investigating lithium prescription trends in the United States, Canada, and Europe within the time interval of 1989–2004, four studies found a decrease in lithium use and two studies found an increase in use (Netto, Patil, Kamble, & Sonkusare, 2014). Studies finding decreased lithium use also noted increased use of valproate (in four studies) and SGA drugs (in one study).
Ilyas and Moncrieff (2012) found that the use of lithium and valproate increased significantly from 1998–2010 in England, although valproate was used more commonly. In a primary care database of patients with bipolar disorder in the United Kingdom, the use of any mood stabilizer (i.e., lithium, valproate, carbamazepine, lamotrigine) increased from 28% in 1995 to 58% in 2009 (Hayes et al., 2011). The greatest increase occurred with valproate, followed by lamotrigine, with smaller trends in use with lithium and carbamazepine. An analysis of national prescription databases in Denmark (1994–2006) and Norway and Sweden (1981–2006) found that lithium prescriptions tended to level out by the late 1990s (Bramness, Weitoft, & Hallas, 2009).
A study of primary care physicians, psychiatrists, and other medical specialists found that lithium and mood stabilizer drug use increased between 1985 and 1994 in the United States, but these medications were only a small proportion of visits compared to antianxiety/hypnotic, antidepressant, and antipsychotic drug visits (Pincus et al., 1998). Similarly, NHANES data found a slight increase in antimanic drug use between 1988–1994 and 1999–2002, but the overall proportion of antimanic use was much smaller than antidepressant, anxiolytic/sedative/hypnotic, and antipsychotic drugs (Paulose-Ram et al., 2007). The most recent NHANES data (NCHS, 2015) do not mention lithium, but 4.1% of Americans of all ages took an anticonvulsant drug in 2009–2012, compared to 2.4% in 1999–2002 and 1.4% in 1988–1994.
Neurotrophic and Neuroprotective Effects of Psychotropic Medications
Neurotrophic effects refer to intracellular mechanisms associated with proliferation, differentiation, growth, and regeneration of neurons, whereas neuroprotective effects refer to mechanisms that slow or halt the progression of neuronal atrophy or cell death.
These intracellular mechanisms include (but are not limited to) the mitogen activated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathway; the phospatidylinositol 3 kinase (PI3K) pathway; the wingless/glycogen synthase kinase 3 (Wnt/GSK3) pathway; brain-derived neurotropic factor (BDNF); nerve growth factor (NGF); B-cell lymphoma 2 (Bcl-2); serine-threonine kinase; and Bcl-2 associated athanogene 1. Various antidepressant drugs, SGA drugs, lithium, valproate, carbamazepine, lamotrigine, electroconvulsive therapy, and exercise have been found to activate or regulate these mechanisms (Costa et al., 2006; Hunsberger, Austin, Henter, & Chen, 2009; Leng, Fessler, & Chuang, 2013; Li et al., 2011; Monti, Polazzi, & Contestabile, 2009; Nasrallah, 2015; Woronowicz, Cawley, & Loh, 2012). Based on these mechanisms, various psychotropic drugs promote neurogenesis and are protective in models of neurodegenerative diseases (including dementia) and ischemia.
The amino acid N-acetyl-aspartate (NAA) is located in neurons, and concentration of NAA correlates with neuronal function. As measured with magnetic resonance spectroscopy, NAA reflects neuronal density and integrity of neuronal mitochondria. A reduction of NAA concentrations is found in some studies of psychiatric disorders. A majority of psychopharmacological studies (i.e., antidepressant drugs, SGA drugs, lithium, valproate, and acetylcholinesterase inhibitor drugs) observed increased NAA concentrations in response to treatment for major depression, bipolar disorder, obsessive compulsive disorder, schizophrenia, and Alzheimer's disease (Paslakis, Traber, Roberz, Block, & Jessen, 2014). The NAA increase was not specific for a certain disorder or specific drug, suggesting that NAA reduction may represent an altered functional state of neurons common to different disorders and that the increase after treatment indicates functional restoration as a general effect of these drugs.
Increased activity or over-expression of GSK-3 is associated with an increase in tau hyperphosphorylation and alterations in amyloid-beta processing, which are related to the formation of neurofibrillary tangles and plaques (Jope, Yuskaitis, & Beurel, 2007). Antidepressant drugs, SGA drugs, lithium, valproate, and lamotrigine inhibit GSK-3 activity (Beaulieu, Gainetdinov, & Caron, 2009). BDNF is involved in learning and memory (Park & Poo, 2013) and may be protective against the development of dementia (Weinstein et al., 2014). Hence, antidepressant drugs, lithium, valproate, and other psychotropic drugs have a strong potential for favorably modifying the neurobiological risk for developing dementia (Diniz, Machado-Vieira, & Forlenza, 2013; Kessing, Forman, & Andersen, 2011; Zhang, Li, & Zhang, 2010).
Physicians and nurses who manage psychotropic medications should have a solid historical understanding of their development since the mid-1950s and how their clinical use has broadened and increased dramatically over time. Nurses also should understand the concepts of neurotrophism and neuroprotection, which are a benefit of regular exercise and are the “silent” benefits of psychotropic drugs beyond their relief of psychiatric symptoms. A common criticism is that these drugs are overprescribed, with oversold benefits and underemphasized harms (Howland, 2015). Because of their neurotrophic and neuroprotective effects, however, the widespread use of psychotropic drugs provides a plausible explanation for declining rates of dementia observed during the past three decades. This association warrants further study.
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