Does treatment of schizophrenia with antipsychotic medications eliminate or reduce psychosis? A 20-year multi-follow-up study.

BACKGROUND: This research assesses whether multi-year treatment with antipsychotic medications reduces or eliminates psychosis in schizophrenia. It provides 20 years of longitudinal data on the frequency and severity of psychotic activity in samples of schizophrenia patients (SZ) treated versus those not treated with antipsychotic medications. METHOD: A total of 139 early young schizophrenia and mood-disordered patients were assessed at index hospitalization and then reassessed six times over 20 years for psychosis and other major variables. RESULTS: At each follow-up assessment over the 20 years, a surprisingly high percentage of SZ treated with antipsychotics longitudinally had psychotic activity. More than 70% of SZ continuously prescribed antipsychotics experienced psychotic activity at four or more of six follow-up assessments over 20 years. Longitudinally, SZ not prescribed antipsychotics showed significantly less psychotic activity than those prescribed antipsychotics (p < 0.05). CONCLUSIONS: The 20-year data indicate that, longitudinally, after the first few years, antipsychotic medications do not eliminate or reduce the frequency of psychosis in schizophrenia, or reduce the severity of post-acute psychosis, although it is difficult to reach unambiguous conclusions about the efficacy of treatment in purely naturalistic or observational research. Longitudinally, on the basis of their psychotic activity and the disruption of functioning, the condition of the majority of SZ prescribed antipsychotics for multiple years would raise questions as to how many of them are truly in remission.

Do all schizophrenia patients need antipsychotic treatment continuously throughout their lifetime? A 20-year longitudinal study.

BACKGROUND: The prevailing standard of care in the field involves background assumptions about the importance of prolonged use of antipsychotic medications for all schizophrenia (SZ) patients. However, do all SZ patients need antipsychotics indefinitely? Are there factors that help to identify which SZ patients can enter into prolonged periods of recovery without antipsychotics? This 20-year longitudinal research studied these issues. METHOD: A total of 139 early young psychotic patients from the Chicago Follow-up Study, including 70 patients with SZ syndromes and 69 with mood disorders, were assessed, prospectively, at the acute phase and then followed up six times over the next 20 years. Patients were assessed with standardized instruments for major symptoms, psychosocial functioning, personality, attitudinal variables, neurocognition and treatment. RESULTS: At each follow-up, 30-40% of SZ patients were no longer on antipsychotics. Starting at the 4.5-year follow-ups and continuing thereafter, SZ patients not on antipsychotics for prolonged periods were significantly less likely to be psychotic and experienced more periods of recovery; they also had more favorable risk and protective factors. SZ patients off antipsychotics for prolonged periods did not relapse more frequently. CONCLUSIONS: The data indicate that not all SZ patients need treatment with antipsychotics continuously throughout their lives. SZ patients not on antipsychotics for prolonged periods are a self-selected group with better internal resources associated with greater resiliency. They have better prognostic factors, better pre-morbid developmental achievements, less vulnerability to anxiety, better neurocognitive skills, less vulnerability to psychosis and experience more periods of recovery.

Viewing the functional consequences of traumatic brain injury by using brain SPECT.

High-resolution brain SPECT is increasingly benefiting from improved image processing software and multiple complementary display capabilities. This enables detailed functional mapping of the disturbances in relative perfusion occurring after TBI. The patient population consisted of 26 cases (ages 8-61 years)between 3 months and 6 years after traumatic brain injury.A very strong case can be made for the routine use of Brain SPECT in TBI. Indeed it can provide a detailed evaluation of multiple functional consequences after TBI and is thus capable of supplementing the clinical evaluation and tailoring the therapeutic strategies needed. In so doing it also provides significant additional information beyond that available from MRI/CT. The critical factor for Brain SPECT's clinical relevance is a carefully designed technical protocol, including displays which should enable a comprehensive description of the patterns found, in a user friendly mode.

Statistical versus fuzzy measures of variable interaction in patients with stroke.

UNLABELLED: Evidence-based medicine, founded in probability-based statistics, applies what is the case for the collective to the individual patient. An intuitive approach, however, would define structure in the (physiologic) system of interest, the human being, directly relevant to other systems (patients) composed of similar variables. A difference in measure of variable interaction in the patient from that in the collective would show how extrapolation of information from the latter to the single patient is counterintuitive. METHODS: We compare statistical to 'fuzzy' measures of variable interaction. Three diagnostic variables are considered in 30 stroke patients who underwent the same diagnostic tests. 'Fit' (fuzzy information) values [0, 1] for degree of variable severity were expertly assigned by 2 blinded raters for real and fabricated patients. Fabricated patients were composed of real-patient 'fit' values after shuffling. Real and fabricated patients were each numerically represented as a set. Three groups of fabricated patients and the real patient group were studied. Statistical [Pearson's product-moment (regression analysis) and Spearman's rank correlation] and three different fuzzy measures of variable interaction were applied to patient data. RESULTS: Interaction for blood-vessel measured strong in real patients, and weak after one shuffle, using all fuzzy measures. By comparison, the same interaction was found in real patients by only 1 rater (Rater 2) using 1 statistical technique (Spearman's rank correlation) which, as did Pearson product-moment correlation, found a 'significant' interaction between blood-heart in fabricated patients. CONCLUSION: Our study suggests that the measure of variable interaction in nature - as combined in the individual (real) patient - is captured robustly by fuzzy measures and not so by standard statistical measures.

Thought disorder in schizophrenia and mania: impaired context.

This research studied hypotheses that positive thought disorder in schizophrenia is influenced by patients' not taking in immediate target contextual material, thereby losing vital cues that guide thought processes. We assessed 164 acute inpatients (including 55 schizophrenia and 31 bipolar disorder patients), using standardized measures of thought disorder. We also used new measures that assessed (1) total ignoring of context, and (2) straying from the context. Results were as follows: (1) only 9 percent of the schizophrenia patients showed strong evidence of completely ignoring the external context; (2) straying from the external context while simultaneously maintaining part of the context was significantly more common than complete absence of context (p < 0.01); (3) patients with thought disorder strayed from the context significantly more than patients without thought disorder (p < 0.001); and (4) straying from the context was involved in the thought disorder of some, but not all, schizophrenia and mania patients. The data suggest that thought disorder in schizophrenia is not typically due to a failure to "hear" or to take in the relevant contextual material necessary for an appropriate response. Loss of context is involved in some, but not all, thought disorder in schizophrenia and mania.

Causal interactions, fuzzy sets and cerebrovascular 'accident': the limits of evidence-based medicine and the advent of complexity-based medicine.

In evidence-based medicine, stroke subtype is diagnosed after a sequential search for etiology; the first positive test result of significant severity rounds off to one overwhelming cause. Degree of severity, interaction among variables, and concomitant variable conditions are not considered in defining the cause of stroke. Yet, thrombus formation, and possibly vascular rupture, is an interactive process involving the vascular wall, flow properties of the blood and blood constituents; this process occurs in homeostasis and pathology. Evidence-based medicine ignores this process and instead studies stroke using crisp 'all or none' classification where subtypes are distinct and interactively relate only to outcome. As a result, scientific inquiry is focused on prediction for the collective of patients. The statistical approach of evidence-based medicine is founded on probability theory, itself rooted in classical set theory where elementhood is all (1) or none (0), and opposites interact only to form the null set. Fuzzy set theory, where set membership is to degree [0, 1], encompasses classical set theory, allows for an interactive process between variables, and therefore becomes the measure of complexity. Fuzzy set theory can change the scientific method of evidence-based medicine.

Incorporation of SPECT imaging in a longitudinal cognitive rehabilitation therapy programme.

In this clinical study, five consecutive referrals to a cognitive rehabilitation therapy (CRT) programme were followed in a longitudinal protocol involving a resting SPECT and neuropsychological evaluation at pre-treatment, post-treatment, and post non-treatment intervals. All clients had acquired brain injury and initially demonstrated neuropsychological deficits and various degrees of hypoperfusion on SPECT. Statistical Parametric Mapping (SPM) was used to evaluate change in successive SPECT images. Following CRT, all clients were able to return to productive employment or schooling. Examination of the neuropsychological testing results revealed significant improvement in performance following CRT which were generally maintained during the non-treatment period. SPM analysis of the SPECT data revealed that, in a majority of cases, most of the significant increases in relative cerebral blood flow redistribution were seen during the treatment period, rather than the non-treatment period. The results suggest that, even in individuals who are more than 2 years post-brain damage, relative increases in rCBF can be demonstrated following individualized CRT and that most of these changes can be related to improvements on neuropsychological tests.

Pharmacologic management of Alzheimer's disease.

Alzheimer's disease is a chronically progressive neurodegenerative disorder. Examinations of brains of Alzheimer's disease patients have shown various neuropathologic and neurochemical deficits, especially decreases in acetylcholine, norepinephrine, serotonin, and some neuropeptides. During the long course of the illness, almost every patient experiences psychiatric symptoms and exhibits behavioral disturbance, most of which can be treated effectively with antidepressant, antipsychotic, and mood-stabilizing drugs. This article is divided into several sections to discuss specific symptoms and relevant medications used to treat each of these symptoms: cholinergic drugs, anti-inflammatory agents, antiamyloidigenic strategy and antioxidant therapy, estrogen, management of psychosis and agitation, and management of depression.

Impact of cognitive rehabilitation therapy on neuropsychological impairments as measured by brain perfusion SPECT: a longitudinal study.

Three patients, with known brain injury and neuropsychological impairments, are followed through an individualized cognitive rehabilitation programme and post discharge from the treatment programme. Single Photon Emission Computed Tomography (SPECT) of the brain was employed to evaluate resting relative cerebral blood flow (rCBF) during the process of recovery from brain injury. All patients experienced significant improvements on measures of neuropsychological functioning and improvements in rCBF during this longitudinal study. The specific changes in rCBF appear to be related to the location of the patient's brain injury and strategies particular to cognitive rehabilitation therapy. Continued improvements in rCBF, functional abilities, and cognitive skills were documented in these three cases up to 45 months post brain injury.

Cerebral perfusion SPECT imaging in epileptic and nonepileptic seizures.

Patients with epileptic and nonepileptic seizures are commonly encountered in clinical practice, and they can pose a difficult diagnostic problem. We present two cases that show the difficult task of differentiating between true epileptic and nonepileptic or psychogenic seizures in some patients. The clinical presentations were complex and the use of video-monitored EEG alone was insufficient to make definitive diagnoses. Ictal and interictal Tc-99m HMPAO brain perfusion SPECT imaging examinations were used to help establish the correct diagnoses. This report describes the advantage of using the brain perfusion SPECT imaging examination. The injection of stabilized Tc-99m HMPAO during an ictal event followed by appropriate medical therapy provides a method of obtaining a reasonable image of relative perfusion (activity) during the seizure. These images can then be compared with interictal examinations and an epileptic or nonepileptic focus may be localized. The Tc-99m HMPAO brain perfusion SPECT imaging study was helpful in establishing the correct diagnosis in both cases.

Psychosis in medical conditions: response to risperidone.

We report the response to risperidone in seven hospitalized, adult patients who presented psychotic symptoms etiologically related to a general medical condition. The conditions included brain surgery in two, and anticardiolipin syndrome, renal failure, epilepsy, lupus, and metastatic carcinoma in one each. Four patients had failed previous treatment with at least one typical antipsychotic agent. Response to risperidone was assessed by the Brief Psychiatric Rating Scale (BPRS). Serum was collected for measurement of steady-state trough risperidone and 9-hydroxyrisperidone concentrations at effective doses in three patients. Amelioration of psychotic symptoms was noted in all seven patients. Mean (+/- SD) BPRS scores were reduced significantly from baseline (63.0 +/- 15.1) to endpoint (27.0 +/- 3.5; p < 0.01). The mean effective daily dose of risperidone was 3.1 +/- .7 mg and time to response was 4.7 +/- 2.4 days. Risperidone was not present at detectable concentrations in the three patients studied. The mean steady-state trough serum concentration of 9-hydroxyrisperidone in the three patients assessed was 20.3 +/- 9.8 ng/ml. These preliminary findings, which suggest that risperidone is a safe and effective agent in patients with psychotic symptoms due to various medical conditions, need to be confirmed by randomized, antipsychotic comparison trials involving a larger number of patients.

Application of ictal brain SPECT for differentiating epileptic from nonepileptic seizures.

The authors report 2 clinical cases that illustrate the difficulties with video-monitored EEG and the advantages of brain SPECT in differential diagnosis of true epileptic seizures and nonepileptic seizures. Injection of [99mTc]HMPAO at the time of the ictal event provides a means to obtain a SPECT image postictally for comparison with interictal examinations so that an epileptic or nonepileptic focus may be localized.

Compton scatter correction in case of multiple crosstalks in SPECT imaging.

A strategy for Compton scatter correction in brain SPECT images was proposed recently. It assumes that two radioisotopes are used and that a significant portion of photons of one radioisotope (for example, Tc99m) spills over into the low energy acquisition window of the other radioisotope (for example, Tl201). We are extending this approach to cases of several radioisotopes with mutual, multiple and significant photon spillover. In the example above, one may correct not only the Tl201 image but also the Tc99m image corrupted by the Compton scatter originating from the small component of high energy Tl201 photons. The proposed extension is applicable to other anatomical domains (cardiac imaging).

Neuropoiesis: proposal for a connectionistic neurobiology.

Given current assumptions about the biology of neural organization, some connectionists believe that it may not be possible to accurately model the brain's neural architecture. We have identified five restrictive neurobiological dogmas that we believe have limited the exploration of more fundamental correlations between computational and biological neural networks. We postulate that: 1) the dendritic tree serves as a synapse storage device rather than a simple summation device; 2) connection strength between neurons depends on the number and location of synapses of similar weight, not on synapses of variable weights; 3) axonal sprouting occurs regularly in adult organisms; 4) the postsynaptic genome directly controls the presynaptic cell via mRNA, rather than indirectly by the expression of NCAMs, reverse neurotransmitters, etc.; 5) dendritic spines serve a trophic function by controlling development of new sprouts via a process we term retroduction. We entertain an alternative formulation of a computational neural element that is fully consistent with modern neuroscience research. We then show how our model neuron can learn under Hebbian conditions, and extend the model to explain non-Hebbian, one-trial learning. This work is significant because by stretching the theoretical boundaries of modern neuroscience, we show how connectionists can potentially create new, more biologically-based neural elements which, when, interconnected into networks, exhibit not only properties of existing backpropagation networks, but other physiological properties as well.

A theory of cooperativity modulation in neural networks as an important parameter of CNS catecholamine function and induction of psychopathology.

Recent research in computational neuroscience has suggested that psychosis associated with disturbed catecholamine neurotransmission may result from disturbances in the gain parameters of neural networks that these same secondary neurotransmitters are thought to control. We propose a mathematical model based upon cooperativity theory used in thermodynamics to explain how the gain parameter that momentarily increases the effect upon the post-synaptic cell of a given weighted connection from the presynaptic cell could be instantiated in the fluctuating electrical conductance of the dendrite of a neuron without requiring extensive ion transport or utilization of the ATP energy cycle. More specifically we propose that catecholamine neurotransmission serves to maintain the dendrite in a cooperative state with regard to changes in electrical conductance due to impulse traffic alone. In this way we supply the neuron with an activity driven gain parameter that not only increases volume of neuronal output at very low energy cost but that also upscales cooperative effects at the mechanico-chemical level of the dendrite to the network level itself. An important implication of this model is that two extreme states for dendritic electrical conductance will occur if cooperativity is lost at the level of catecholamine depletion or excess due to drug effects. These are the AND gate effect in which dendritic conductance is so low that the neuron requires extensive synaptic activity in order to output significantly. We correlate this state with negative symptoms in schizophrenia and psychomotor retardation in depression as well as the rigidity in Parkinsonism. The other extreme is represented by the OR gated dendrite in which conductance is so high that even noisy input to the dendrite will lead to significant nerve cell output. We correlate this condition with the positive symptoms of schizophrenia, the agitated features of psychotic depression and the tremors of Parkinsonism.

Schizophrenic deficits: neuroleptics and the prefrontal cortex.

Modern techniques have been applied to brain modeling, based on recent approaches in the artificial intelligence field that use brain-like "connectionistic" computational architectures. The model proposed by Cohen and Servan-Schreiber uses a gain parameter which they identify with dopamine function. They apply their model to neuroleptically treated schizophrenia patients who show improved task performance which they link to increased dopamine function and increased gain in the prefrontal cortex. However, evidence indicates that antipsychotic medications block dopamine (especially D2) receptors, decreasing mesolimbic and mesocortical dopamine function. If therapeutic dosages of neuroleptics diminish dopamine function, this would decrease gain in context modules needed for adequate task performance. Schizophrenia patients would perform more poorly by further reducing gain in their already compromised context modules. The current investigators suggest three possible ways to resolve this difficulty, to explain why normals perform more poorly when taking neuroleptics, although acute schizophrenia patients' performance may be enhanced in several areas. Evidence would suggest that multiple processes occur simultaneously in neuroleptically treated patients with some processes counterbalancing others.