Study Identified the Effect of Different Antipsychotic Medications for Schizophrenia on Working Memory
Most individuals with schizophrenia have some degree of cognitive impairment, often in working memory, but newer antipsychotic medications such as risperidone are believed to help improve cognitive functioning.
A team of researchers from the Institute of Psychiatry, Kings College London and South London and Maudsley NHS Trust undertook a study to examine the effect of different antipsychotic medications on working memory.
The study involved 32 individuals, half of whom were being treated with long-acting risperidone injections and half of whom were being treated with conventional antipsychotic medication. Eight healthy individuals also took part in the study as a control group. Each participant completed a range of working memory tests while inside a functional magnetic resonance imaging scanner, so that the researchers could see which areas of the brain were activated during the tests.The schizophrenia group receiving conventional antipsychotic depot treatment performed significantly worse than healthy controls in the most demanding of the working memory tests. The same group demonstrated significant differences from controls in two particular areas within the prefrontal cortex area of the brain. The pattern of brain activation seen in those being treated with long-acting risperidone was closer to the control group than it was to the group taking conventional medication. This suggests that long-acting risperidone may help to normalise functioning in the prefrontal cortex, resulting in improvements to working memory.
Note for Schizophrenia
Schizophrenia is a psychiatric diagnosis that describes a mental illness characterized by impairments in the perception or expression of reality, most commonly manifesting as auditory hallucinations, paranoid or bizarre delusions or disorganized speech and thinking in the context of significant social or occupational dysfunction. Onset of symptoms typically occurs in young adulthood, with approximately 0.4–0.6% of the population affected. Diagnosis is based on the patient’s self-reported experiences and observed behavior. No laboratory test for schizophrenia exists.
Studies suggest that genetics, early environment, neurobiology and psychological and social processes are important contributory factors. Current psychiatric research is focused on the role of neurobiology, but a clear organic cause has not been found. Due to the many possible combinations of symptoms, there is debate about whether the diagnosis represents a single disorder or a number of discrete syndromes. For this reason, Eugen Bleuler termed the disease the schizophrenias (plural) when he coined the name. Despite its etymology, schizophrenia is not synonymous with dissociative identity disorder, previously known as multiple personality disorder or split personality; in popular culture the two are often confused.
Increased dopaminergic activity in the mesolimbic pathway of the brain is a consistent finding. The mainstay of treatment is pharmacotherapy with antipsychotic medications; these primarily work by suppressing dopamine activity. Dosages of antipsychotics are generally lower than in the early decades of their use. Psychotherapy, vocational and social rehabilitation are also important. In more serious cases—where there is risk to self and others—involuntary hospitalization may be necessary, though hospital stays are less frequent and for shorter periods than they were in previous years.
The disorder is primarily thought to affect cognition, but it also usually contributes to chronic problems with behavior and emotion. People diagnosed with schizophrenia are likely to be diagnosed with comorbid conditions, including clinical depression and anxiety disorders; the lifetime prevalence of substance abuse is typically around 40%. Social problems, such as long-term unemployment, poverty and homelessness, are common and life expectancy is decreased; the average life expectancy of people with the disorder is 10 to 12 years less than those without, owing to increased physical health problems and a high suicide rate.
A person experiencing schizophrenia may demonstrate symptoms such as disorganized thinking, auditory hallucinations, and delusions. In severe cases, the person may be largely mute, remain motionless in bizarre postures, or exhibit purposeless agitation; these are signs of catatonia. The current classification of psychoses holds that symptoms need to have been present for at least one month in a period of at least six months of disturbed functioning. A schizophrenia-like psychosis of shorter duration is termed a schizophreniform disorder. No one sign is diagnostic of schizophrenia, and all can occur in other medical and psychiatric conditions.
Social isolation commonly occurs and may be due to a number of factors. Impairment in social cognition is associated with schizophrenia, as are the active symptoms of paranoia from delusions and hallucinations, and the negative symptoms of apathy and avolition. Many people diagnosed with schizophrenia avoid potentially stressful social situations that may exacerbate mental distress.
Late adolescence and early adulthood are peak years for the onset of schizophrenia. These are critical periods in a young adult’s social and vocational development, and they can be severely disrupted by disease onset. To minimize the effect of schizophrenia, much work has recently been done to identify and treat the prodromal (pre-onset) phase of the illness, which has been detected up to 30 months before the onset of symptoms, but may be present longer. Those who go on to develop schizophrenia may experience the non-specific symptoms of social withdrawal, irritability and dysphoria in the prodromal period, and transient or self-limiting psychotic symptoms in the prodromal phase before psychosis becomes apparent.
Note for Risperidone
Risperidone is an atypical antipsychotic medication developed by Janssen Pharmaceutica. It was approved by the United States Food and Drug Administration (FDA) in 1993 for the treatment of schizophrenia. On Wednesday, August 22, 2007, Risperdal was approved as the only drug agent available for treatment of schizophrenia in children ages 13–18; it was also approved that same day for treatment of bipolar disorder in youths ages 10–18, joining lithium. Risperidone contains the functional groups of benzisoxazole and piperidine as part of its molecular structure. In 2003 the FDA approved risperidone for the short-term treatment of the mixed and manic states associated with bipolar disorder. In 2006 the FDA approved risperidone for the treatment of irritability in children and adolescents with autism. Like other atypical antipsychotics, it has also been used off-label for the treatment of anxiety disorders, such as Obsessive-Compulsive disorder; severe, treatment-resistant depression with or without psychotic features; Tourette’s disorder; disruptive behavior disorders in children; and eating disorders, among others.
Janssen’s patent on Risperdal expired on December 29, 2007, opening the market for cheaper generic versions of the drug from other companies; however, Janssen will continue to have exclusive marketing rights until June 29, 2008, as the result of a pediatric extension.
Risperidone is available as a tablet in 0.25, 0.5, 1, 2, 3 and 4 mg sizes, and as a 25 mg, 37.5 mg and 50 mg ampoule Risperdal Consta, which is a depot injection administered once every two weeks. It is also available as a wafer known in the United States as Risperdal M-Tabs and elsewhere as Risperdal Quicklets.
Risperidone is a strong dopamine blocker (antagonist); i.e., it inhibits functioning of postsynaptic dopamine receptors.
It reaches peak plasma levels quickly regardless of whether it is administered as a liquid or pill. The strong dopamine-blocking reaction is known to make some people feel nauseated if they do things that normally trigger the dopamine response, such as eat a pleasing meal or experience orgasm. Risperidone is metabolised fairly quickly, so this potential for nausea subsides usually in two to three hours. However the active metabolite, 9-hydroxy-risperidone, which has similar pharmacodynamics to risperidone, lingers in the body for much longer.
An intramuscular preparation, marketed as Risperdal Consta, can be given once every two weeks. It is slowly released from the injection site. It can be useful in patients who have difficulty taking oral medication for any reason. Some people prefer a once-every-two-weeks injection to daily pills. It also helps the physician ensure compliance. Doses range from 25 to 50 mg given as an intramuscular injection once every two weeks.
Note for Working Memory
Working memory is a theoretical construct within cognitive psychology that refers to the structures and processes used for temporarily storing and manipulating information. There are numerous theories as to both the theoretical structure of working memory as well as to the specific parts of the brain responsible for working memory. However, most researchers agree that the frontal cortex, parietal cortex, anterior cingulate, and parts of the basal ganglia are crucial for functioning. Much of the understanding of the neural basis of working memory has come from lesion experiments in animals and imaging experiments in humans.
The term was first used in the 1960s in the context of theories that likened the mind to a computer. Before then, what we now call working memory was referred to as short-term memory, sometimes also as primary memory, immediate memory, operant memory, or provisional memory. Short-term memory is the ability to remember information over a brief period of time (in the order of seconds). Most theorists today use the concept of working memory to replace or include the older concept of short-term memory, thereby marking a stronger emphasis on the notion of manipulation of information instead of passive maintenance.
The earliest mention of experiments on the neural basis of working memory can be traced back to over 100 years ago, when Hitzig and Ferrier described ablation experiments of the prefrontal cortex (PFC). They concluded that the frontal cortex was important for cognitive processes rather than sensory ones. In 1935 and 1936, Jacobsen and colleagues were the first to conclude that the cognitive processes in the PFC were notable in delay-dependent tasks; in other words, they suffered from short-term memory loss.
Working memory is generally considered to have limited capacity. The earliest quantification of the capacity limit associated with short-term memory was the “magical number seven” introduced by Miller (1956). He noticed that the memory span of young adults was around seven elements, called chunks, regardless whether the elements were digits, letters, words, or other units. Later research revealed that span does depend on the category of chunks used (e.g., span is around seven for digits, around six for letters, and around 5 for words), and even on features of the chunks within a category. For instance, span is lower for long words than for short words. In general, memory span for verbal contents (digits, letters, words, etc.) strongly depends on the time it takes to speak the contents aloud, and on the lexical status of the contents (i.e., whether the contents are words known to the person or not). Several other factors also affect a person’s measured span, and therefore it is difficult to pin down the capacity of short-term or working memory to a number of chunks. Nonetheless, Cowan (2001) has proposed that working memory has a capacity of about four chunks in young adults (and less in children and old adults).
Recent studies suggest that working memory can be improved by training in ADHD patients. This study has found that a period of working memory training increases a range of cognitive abilities and increases IQ test scores. Consequently, this study supports previous findings suggesting that working memory underlies general intelligence. Improving or augmenting the brain’s working memory ability may prove to be a reliable method for increasing a person’s IQ scores. A recent theory of ADHD states that ADHD can lead to deficits in working memory. Another study of the same group has shown that, after training, measured brain activity related to working memory increased in the prefrontal cortex, an area that many researchers have associated with working memory functions.
Note for Psychiatric Medication
Psychiatric medication is a licenced psychoactive drug taken to exert an effect on the mental state and used to treat mental disorders. Usually utilized in psychiatric settings, these medications are made of synthetic chemical compounds, although some are naturally occurring.
Prescription psychiatric medications, like any prescription medication, usually require a prescription from a physician, such as a psychiatrist, before it can be obtained. Some U.S. states and territories, following the creation of the prescriptive authority for psychologists movement, have granted prescriptive privileges to clinical psychologists that have undergone additional training.
Psychopharmacology studies a wide range of substances with various types of psychoactive properties, though the professional and commercial fields of pharmacology and psychopharmacology don’t typically focus on psychedelic or recreational drugs; the majority of studies are conducted on psychiatric medication. While studies are conducted on all psychoactives by both fields, psychopharmacology focuses primarily on the psychoactive and chemical interactions with the brain. Physicians who research psychiatric medications are psychopharmacologists, specialists in the field of psychopharmacology.
Psychiatric medications sometimes have adverse side effects that may reduce patients’ drug compliance. Some of these side effects can be further treated by using other drugs such as anticholinergic (antimuscarinic) medications. Some side effects, including the possibility of a sudden or severe re-emergence of psychotic features, may appear when the patient stops taking the drug, particularly if a drug is suddenly discontinued instead of slowly tapered off.
Note for Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is primarily used in medical imaging to visualize the structure and function of the body. It provides detailed images of the body in any plane. MR has much greater soft tissue contrast than computed tomography (CT) making it especially useful in neurological, musculoskeletal, cardiovascular, and oncological imaging. Unlike CT it uses no ionizing radiation, but uses a powerful magnetic field to align the magnetization of hydrogen atoms in the body. Radio waves are used to systematically alter the alignment of this magnetization, causing the hydrogen atoms to produce a rotating magnetic field detectable by the scanner. This signal can be manipulated by additional magnetic fields to build up enough information to reconstruct an image of the body.
Magnetic resonance spectroscopy is used to measure the levels of different metabolites in body tissues. The MR signal produces a spectrum of resonances that correspond to different molecular arrangements of the isotope being “excited”. This signature is used to diagnose certain metabolic disorders, especially those affecting the brain, as well as to provide information on tumor metabolism.
Magnetic resonance imaging was developed from knowledge gained in the study of nuclear magnetic resonance. In its early years the technique was referred to as nuclear magnetic resonance imaging (NMRI). However, as the word nuclear was associated with ionizing radiation exposure it is generally now referred to simply as MRI. Scientists still use the term NMRI when discussing non-medical devices operating on the same principles. One of the contributers to modern MRI, Paul Lauterbur, originally named the technique zeugmatography, a Greek term meaning “that which is used for joining”. The term referred to the interaction between the static and the gradient magnetic fields necessary to create an image, but unsurprisingly this term was not adopted.
In clinical practice, MRI is used to distinguish pathologic tissue (such as a brain tumor) from normal tissue. One advantage of an MRI scan is that it is thought to be harmless to the patient. It uses strong magnetic fields and non-ionizing radiation in the radio frequency range. Compare this to CT scans and traditional X-rays which involve doses of ionizing radiation and may increase the risk of malignancy, especially in a fetus.
While CT provides good spatial resolution (the ability to distinguish two structures an arbitrarily small distance from each other as separate), MRI provides comparable resolution with far better contrast resolution (the ability to distinguish the differences between two arbitrarily similar but not identical tissues). The basis of this ability is the complex library of pulse sequences that the modern medical MRI scanner includes, each of which is optimized to provide image contrast based on the chemical sensitivity of MRI.
For example, with particular values of the echo time (TE) and the repetition time (TR), which are basic parameters of image acquisition, a sequence will take on the property of T2-weighting. On a T2-weighted scan, fat-, water- and fluid-containing tissues are bright (most modern T2 sequences are actually fast T2 sequences). Damaged tissue tends to develop edema, which makes a T2-weighted sequence sensitive for pathology, and generally able to distinguish pathologic tissue from normal tissue. With the addition of an additional radio frequency pulse and additional manipulation of the magnetic gradients, a T2-weighted sequence can be converted to a FLAIR sequence, in which free water is now dark, but edematous tissues remain bright. This sequence in particular is currently the most sensitive way to evaluate the brain for demyelinating diseases, such as multiple sclerosis.
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