Lili C. Kopala

Olfactory Dysfunction in Neuropsychiatric Disorders: Review and Methodological Considerations

A growing body of research documents the quality and magnitude of olfactory dysfunction manifest by individuals with neurologic and psychiatric disorders. Evidence from studies of patients with neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases indicate that olfactory deficits are marked (see Doty 1991). In contrast, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced parkinsonism (MPTP-P; Doty et al 1992a) Korsakoff’s amnestic syndrome (Jones et al 1975), amyotrophic lateral sclerosis (ALS; Sajjadian et al 1994), and Huntington’s disease (HD; Doty 1991; Moberg et al 1987) are associated with less severe olfactory decrements. Individuals with multiple sclerosis (MS; Kesslak et al 1988) and progressive supranuclear palsy (PSP; Doty et al 1993) are reported to have intact olfactory ability. With reference to psychiatric disorders, only those with schizophrenia (Hurwitz et al 1988; Kopala et al 1992; Seidman et al 1992) and obsessive–compulsive disorder (Goldberg et al 1991) have impaired olfactory function. The magnitude of the dysfunction is in the mild range. Studies of panic disorder (Kopala and Good in press), anorexia nervosa (Kopala et al 1995a; Federoff et al 1995), and possibly depression (Amsterdam et al 1987; Warner et al 1990) report no impairment on tasks assessing olfactory function. Given the wide range of disorders of the central nervous system that are associated with olfactory compromise, a single etiology for observed olfactory dysfunction is unlikely; however, overlapping neuropathological substrate may assist in delineating the abnormal brain regions responsible for olfactory deficits. From a clinical perspective, assessing olfactory function in certain patient groups may be valuable for differential diagnosis and early intervention. In light of the existing literature and promise of olfactory measures as indices of central nervous system (CNS) function, this review is proffered with the following objectives:

Olfactory deficits in neuroleptic naive patients with schizophrenia

Because previous studies have shown deficits in olfactory identification for male patients with schizophrenia, either withdrawn from or receiving neuroleptic medication, the purpose of the current study was to determine if such deficits occurred in male patients who had never received neuroleptics. A sample of male (n = 30) and female (n = 10) patients as well as age appropriate controls (males, n = 28, females, n = 30) was assessed in terms of olfactory acuity and identification ability. No differences were found in olfactory acuity, but an olfactory identification deficit was present in 31% of the male patients with schizophrenia. As the olfactory pathways project through the limbic system and to the orbitofrontal cortex, odour identification may be a measure of the functional integrity of these structures. Therefore, these results suggest that for a sub-sample of male patients, the functional integrity of these structures is compromised.

Duration of untreated psychosis predicts treatment outcome in an early psychosis program

For patients first presenting with a non-affective psychotic disorder, the duration of untreated psychosis (DUP; the time between the onset of positive psychotic symptoms and the initiation of appropriate treatment) varies widely, from a few weeks to several years. A number of studies report that a longer DUP is associated with poorer clinical outcomes. We studied DUP and its association with clinical outcomes in a group of patients with schizophrenia and related psychotic disorders treated in the naturalistic clinical setting of an early psychosis program. DUP was determined for 19 patients with a non-affective psychotic disorder (schizophrenia, schizoaffective disorder or schizophreniform disorder) and no previous treatment for psychosis, by use of the IRAOS, a retrospective structured interview carried out with patients and their families. Positive and Negative Syndrome Scale (PANSS) and Global Assessment of Function (GAF) ratings were available at baseline and 6month follow-up. For analysis, patients were categorized into a short DUP (n=9) or long DUP (n=10) group. The median DUP (57weeks) was used as the dividing point. At baseline, the two groups did not differ significantly on positive symptoms or total PANSS ratings. However, negative symptoms were more severe in the long DUP group at baseline (P=0.029), and the long DUP group had a significantly higher mean rating for the passive/apathetic social withdrawal item of the PANSS (P=0.024). At 6month follow-up, the long DUP group had significantly higher ratings for positive symptoms (P=0.028) and had lower GAF scores (P=0.044). Significantly more (P=0.033) long DUP patients had enduring positive psychotic symptoms. The results confirm both the wide range of DUP among patients first presenting with schizophrenia and related psychotic disorders and the association of long DUP, defined as greater than approximately 1year, with a poorer clinical outcome. This study highlights the importance of collecting data regarding DUP and supports the view that patients with a long DUP are likely to be less responsive to treatment in general and will require greater resources and more intensive interventions.

Olfactory deficits in schizophrenia

Olfactory discrimination was measured in patients with schizophrenia who were on neuroleptic medication and was compared with other psychiatric patients receiving neuroleptics and normal controls. The performance of the patients with schizophrenia was significantly lower than the psychiatric and normal controls. The latter two groups performed at equivalent levels. The findings are discussed with respect to olfactory deficits found in patients with cerebral lesions and with abnormalities of specific neurotransmitter systems.

Olfactory hallucinations and olfactory identification ability in patients with schizophrenia and other psychiatric disorders.

Olfactory identification ability and the prevalence of olfactory hallucinations were examined in 183 hospitalized patients from three diagnostic groups. One hundred and thirty-one patients with schizophrenia, 21 patients with major depression, 31 women with eating disorders along with 77 normal control subjects were examined using the University of Pennsylvania Smell Identification Test (UPSIT) and were questioned regarding the presence of olfactory hallucinations. Olfactory identification deficits were observed only in patients with schizophrenia. In contrast, olfactory hallucinations were reported by members of all psychiatric diagnostic categories (34.6% of patients with schizophrenia; 19% of depressed patients and 29% of eating disorders patients). For patients with schizophrenia, women were more likely to report olfactory hallucinations and had higher UPSIT scores than men.

Extrapyramidal signs and clinical symptoms in first-episode schizophrenia : Response to low-dose risperidone

The purpose of this study was to determine the prevalence of extrapyramidal signs or symptoms (EPS) and clinical symptoms in first-episode schizophrenia, before any treatment, during and after treatment with a novel antipsychotic, risperidone. Twenty-two (17 men; 5 women) patients were examined using the Extrapyramidal Symptom Rating Scale, Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity of Illness and Improvement, and Global Assessment of Functioning. Three patients (14%) had distinct EPS at baseline, whereas all were free of EPS after treatment with risperidone. On the maximum dose of risperidone (5-8 mg), 32% of the total sample developed mild akathisia or parkinsonism, both of which diminished with dosage reduction. No clinically significant EPS were observed in patients receiving 2 to 4 mg of risperidone. Analysis of symptom response of the lower (2-4 mg) versus the higher (5-8 mg) doses of risperidone resulted in superior outcome in the 2- to 4-mg group for all three symptom clusters of the PANSS. In addition, 91% of the low-dose group achieved a 20% or greater reduction in total PANSS score compared with 27% for the high-dose group. These findings have clinical relevance directed at the early and longer-term treatment of schizophrenia.

Effects of catecholamine depletion on D2 receptor binding, mood, and attentiveness in humans: a replication study

The effect of catecholamine depletion, achieved by per-oral administration of 5250 mg alpha-methyl-para-tyrosine (AMPT) given in the 29 h prior to [11C]raclopride positron emission tomography (PET) was studied on measures of dopamine (DA) release, mood, and attention. Neostriatal DA levels in vivo were estimated by comparing the neostriatal DA D(2) receptor binding potential (D(2)RBP) before and after catecholamine depletion using PET and the radiotracer [11C]raclopride. Six healthy subjects completed the protocol. The AMPT treatment increased D(2)RBP significantly by 13.3+/-5.9% (average+/-standard deviation) and decreased plasma levels of the DA metabolite homovanillic acid (HVA) by 62+/-17%, and levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) by 66+/-5%. Catecholamine depletion resulted in decreased happiness, euphoria, energy, talkativeness, vigor, and attentiveness, and in increased sleepiness, fatigue, sedation, and eye blink rate (EBR). These changes were not correlated with the D(2)RBP increments. The results of this study are overall consistent with previous findings by our group using the same methodology in a different cohort of six healthy subjects.

The relationship of neuropsychological test performance with the PANSS in antipsychotic naïve, first-episode psychosis patients.

BACKGROUND Chronic schizophrenia patients have been sampled for factor analytic studies to identify the factor structure of the Positive and Negative Syndrome Scale (PANSS). Many of these studies have identified a cognitive factor, which may provide useful information about patients for whom formal neuropsychological testing is unavailable. However, the relationship between the clinically rated cognitive factor and performance-based cognitive test scores has not been thoroughly examined, particularly in patients who are early in the course of illness. OBJECTIVES The validity of the PANSS cognitive factor was examined in a sample of antipsychotic naïve, first-episode psychosis patients and the PANSS items that best predicted cognitive functioning were identified. METHOD PANSS scores and performance on a battery of cognitive tests from the baseline assessment of a clinical trial of 167 neuroleptic naïve patients with schizophrenia-like illnesses were analyzed. RESULTS Factor analysis revealed a five-factor model that was consistent with previously described factor models from samples of chronically treated patients. There were modest correlations (less than r=0.44) between the derived cognitive factor and six of the neuropsychological test variables (Wisconsin Card Sorting Test total errors and number of categories correctly sorted, WMS-R immediate and delayed recall scores, Category Fluency total score, and WAIS-R digit symbol). Five PANSS items (P6, N5, N6, G2, and G10) were identified that predicted global cognitive functioning; however, 66% of the variance in cognitive functioning remained unexplained. CONCLUSIONS A PANSS cognitive factor can be identified in first-episode, neuroleptic naïve patients. However, clinical ratings of cognitive deficits lack sensitivity and specificity and thus should not be relied upon fully.

Olfactory deficits in schizophrenia are not a function of task complexity.

The purpose of the current study was to determine if olfactory identification deficits in patients with schizophrenia were related to task complexity. Given that we had previously reported that male patients with schizophrenia are the most impaired on olfactory identification tests (the University of Pennsylvania Smell Identification Test, UPSIT), we wished to determine whether a similar deficit would exist for this group on a task of similar format and complexity, the Colour Identification Test (CIT). Sixty-five neuroleptically medicated patients with a DSM-III-R diagnosis of schizophrenia and 30 normal control subjects participated. The dependent measures were scores on the UPSIT and CIT. Overall, patients with schizophrenia had significantly lower USPIT scores than did the normal control subjects whereas no mean difference was observed for colour identification. Male patients with schizophrenia had olfactory identification deficits but performed comparably to all other groups on the CIT. Furthermore, microsmic patients with schizophrenia had CIT scores that did not differ from normal control subjects. Finally, CIT and UPSIT scores were not significantly correlated for the study sample as a whole. The results of this study suggest that the olfactory identification deficits observed in patients with schizophrenia likely reflect abnormalities of brain areas involved in olfactory pathways and are not a function of task complexity.

Extrapyramidal symptoms and signs in first-episode, antipsychotic exposed and non-exposed patients with schizophrenia or related psychotic illness.

Movement disorders in first-episode psychosis are increasingly recognized; however, the prevalence and clinical correlates areuncertain. We compared antipsychotic exposed (< 12 weeks) with nonexposed first-episode patients, and report prevalence as well as clinical and demographic variables associated with extrapyramidal dysfunction. Data are baseline assessments from a multicentre, international drug trial of first-episode psychosis (n = 535). Analysis included the Extrapyramidal Symptom Rating Scale, Premorbid Adjustment Scale, and the Positive and Negative Syndrome Scale. Of non-exposed patients, 28.1% (n = 47/167) had at least one mild sign of extrapyramidal dysfunction, as did 46.3% (n = 169/365) of previously exposed patients. Hypokinetic Parkinsonism was the most prevalent disorder. The severity of movement disorders and negative symptoms were correlated; however, the effect sizes were small. Logistic regression analysis indicated that the salient risk factors for all patients were: previous antipsychotic exposure [odds ratio (OR) = 2.4; 95% confidence interval (CI) 1.6–3.6] and poor premorbid functioning (OR = 1.8; 95% CI 1.2–2.6). For the non-exposed group (n = 167), the significant risk factors were: having severe mental illness in the family (OR = 2.9; 95% CI 1.2–7.2) and poor premorbid functioning (OR = 2.3; 95% CI 1.0–5.3). For the previously exposed group (n = 368), thesignificant variables were: poor premorbid functioning (OR = 1.8; 95%CI 1.2–2.8) and shorter duration of untreated psychosis (OR = 0.78; 95% CI 0.64–0.94). Although antipsychotic exposure was associated with extrapyramidal signs, the results indicate that many first-episode patients with no exposure to antipsychotics also had extrapyramidal dysfunction. In this group, family history and poor premorbid functioning appear to be associated with increased risk for movement disorders.