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Does bright-light therapy influence autonomic heart-rate parameters?
JOURNAL
ELSEVIER
OF
AFFECTIVE DISORDERS
Journal of Affective Disorders 34 (1995) 131-137
Does bright-light therapy influence autonomic heart-rate parameters? Thomas Rechlin by*, Maria Weis b, Kurt Schneider a, Ulrich Zimmermann Wolfgang P. Kaschka b
b,
a Department of Psychiatry, University of Erlangen-Nuremberg, Erlangen, Germany b Department of Genetics, University of Erlangen-Nuremberg,
Erlangen, Germany
Received 24 March 1994; revised 16 January 1995; accepted 16 January 1995
Abstract 30 inpatients suffering from major depression (DSM-III-R), who did not fulfill the criteria of seasonal affective disorder &4D), were treated with either doxepin or amitriptyline as monotherapy and supportively with bright light for 14 days. From days 15 to 19, bright light was replaced by dim light. 18 drug-free control subjects underwent an analogous sequence of bright- and dim-light applications. Phototherapy was applied between 06:OO and 07:30. Heart-rate (HR) analysis was performed in the patients and control subjects before and after the 5th session of bright and dim lights, respectively. 12 patients (40%) experienced improvement of mood during bright-light therapy (group I) while 18 (60%) did not (group II). Patients of group I, who reached significantly higher scores in the seasonal pattern assesssment questionnaire than patients of group II, showed an increase of the coefficient of HR variation (HRV) during deep breathing as well as an increment of the high-frequency (HF) peak of spectral analysis exclusively after the bright-light sessions. Patients of group II did not show a significant alteration of these parameters, neither under the conditions of bright-light treatment nor under dim light. The control subjects experienced an increment of the HF power exclusively after bright light. The results suggest that a distinct subgroup of patients with non-SAD major depression shows a more pronounced light-associated increment of parasympathetitally controlled cardiac functions than the other depressed patients and the controls. HRV measurements seem to be a valuable tool for further psychophysiological studies on treatment response (e.g., to phototherapy). Keywords:
Bright-light
therapy;
Parasympathetic
function;
1. Introduction Seasonal affective disorders elicited theoretical and practical
(SAD) have interests as
* Corresponding author. Address: Psychiatrische Universitltsklinik, Schwabachanlage 6, 91054 Erlangen, Germany. Fax: (49) (9131) 854436. 0165-0327/95/$09.50
Heart-rate
Heart-rate
variation
bright-light therapy (> 2500 lux) proved to be an effective treatment of this special form of depression (Rosenthal et al., 1984; Terman et al., 1989; Sack et al., 1990; Kasper, 1994; Lam, 1994). It has been suggested that patients suffering from subsyndromal SAD (S-SAD) also benefit from phototherapy (Kasper et al., 1989; Delito et al., 1991; Kripke et al., 1992). However, others
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denied any therapeutic response in patients with non-SAD (Mackert et al., 1991). In normal subjects, who are rather unaffected by seasonal changes, bright-light application is not beneficial (Rosenthal et al., 1987; Genhart et al., 1993). It is generally supposed that the biological effects of bright light are mediated by the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. Several hypotheses concerning the therapeutic mechanisms of bright-light treatment have been discussed, including the melatonin hypothesis, the circadian phase-shift theory, the circadian amplitude reduction hypothesis, the photoperiod theory, but also placebo effects (for review, see Rosenthal and Wehr, 1992). It has also been suggested that the neurotransmitters serotonin (e.g., Rao et al., 1992) and dopamine (e.g., Depue et al., 1990) play an essential role in the SAD pathophysiology. However, the underlying pathogenetic SAD mechanisms have not been sufficiently clarified. The methodology of computerized heart-rate (HR) analysis (HRA) has been applied to investigate the autonomic state in psychiatric disorders and the impact of psychopharmacological therapies on autonomic cardiac regulation (Rechlin et al., 1994a; Rechlin et al., 1994b; Rechlin et al., 1994~; Rechlin et al., 1994d). Balogh et al. (1993) have employed measurements of HR variability (HRV) to investigate the treatment responses to different classes of antidepressants. Peripheral HRV control, which depends on the ability of the autonomic nervous system to vary the intervals between consecutive heart beats according to physiological requirements, is mainly exerted by the parasympathetic vagus nerve. The central mechanisms of cardiovascular and respiratory regulation have not yet been clarified in every detail, however, important influences are carried out by various brainstem areas, the limbic system and the hypothalamus (Spyer, 1988). It is still an unsettled question whether or not affective disorders are by themselves associated with an altered parasympathetic activity represented by decreased HRV parameters (Dalack and Roose, 1990; Yeragani et al., 1992a; Friedman et al., 1993; Yeragani et al., 1993; Rechlin et al., 1994d; Stein and Asmundson, 1994). How-
ever, investigations in patients treated with tricyclic antidepressants (TCA; Jakobsen et al., 1984; Yeragani et al., 1992b; Rechlin, 1994a; Rechlin, 1994b; Rechlin et al., 1994a) or clozapine (Zahn and Pickar, 1993; Rechlin et al., 1994b) revealed decreased R-R variation which is probably, at least in part, due to the anticholinergic effects of these drugs. On the other hand, treatment with 20 mg paroxetine, a selective inhibitor of serotonin reuptake (SSRI), did not influence HRV (Rechlin et al., 1994~). The HRA method might also be a valuable tool in chronobiologically oriented research on affective disorders since HRV parameters show diurnal variation (Cornelissen et al., 1990; Kleiger et al., 1991; Noritake et al., 1992). In a previous study, we noted higher evening values of HRV parameters in TCA-treated depressed patients with typical diurnal variation of mood (improvement in the evening) whereas patients without diurnal mood variations did not show extensive differences between morning and evening values (Rechlin et al., 1995). Since it has been shown that the central circadian regulation of HR parameters is triggered by light and destruction of the SCN suspends circadian HR regulation (Saleh and Winget, 1977), studies on HRV parameters in depressed patients treated with bright light are of great theoretical and practical interests. The present study was designed to compare HRV parameters in severely depressed inpatients (major depression, DSM-III-R) and in normal control persons matched for age and sex before and after standardized treatment with bright as well as dim light. 2. Methods 2.1. Patients and therapy 30 inpatients (25 F, 5 M; mean age 45.2; range 21-72) with major depression, according to the criteria of DSM-III-R, who had previously been treated with various psychotropic substances but not with lithium, were treated with either 150 mg/day amitriptyline or doxepin as monotherapy. Patients received increasing doses of either
T. Rechlin et al. /Journal
of Affective Disorders 34 (1995) 131-137
drug reaching the full dosage on the 5th day of treatment. This day was defined as day 0. None of the patients suffered from diabetes mellitus, cardiac diseases, alcoholism, neurological diseases or any diseases affecting the autonomic nervous system. 2.2. Protocol of light application Beside the treatment with either amitriptyline or doxepin, all patients underwent supportive bright-light therapy which was applied between 06:OOand 07:30 from days 1 to 14 with an intensity of > 2500 lux. From days 15 to 19, all patients underwent dim-light application ( < 200 lux) between 06:OOand 07:30. A change of medication (e.g., lithium therapy and SSRI application) was not allowed before day 20. Patients and controls were informed that bright and dim lights would be equally effective. 2.3. Control subjects 18 healthy, drug-free control persons (13 F, 5 M; mean age 43.6, range 19-74) matched for age and sex also underwent the bright- and dim-light applications.
2.4. Time HRA point HRA was performed directly before and after the 5th session of bright-and dim-light applications, respectively. On the same day, TCA plasma levels were determined by a commercially available fluorescence polarization immunoassay (FPIA; Abbott). The choice of the 5th day of light application was a compromise to allow adaptation of the patients and control persons to the method of light application and to minimize psychological stress which strongly influences the HRA parameters (e.g., Low, 1992). Additionally, it was essential to have comparable conditions with regard to medication and depression scores since HRV parameters are markedly influenced by psychotropic drugs (Rechlin et al., 1994a; Rechlin et al., 1994b; Rechlin et al., 1994~) and, possibly, by the affective disorder itself (Dalack and Roose, 1990; Bar-
133
logh et al., 1993; Rechlin, 1994b; Rechlin et al., 1994d). Therefore, it was unfortunately not practicable to compare HRV parameters in medicated patients using a before vs. after light protocol. It has been shown in SAD patients that the beneficial effects of bright-light therapy already appear after a few days of treatment (Wehr and Rosenthal, 1989). Therefore, any psychophysiological effects of bright light on autonomic functions would probably be detected on the 5th day of light application while the antidepressant TCA effects would still be lacking or at least be incomplete. 2.5. HRV measurements The patients and control subjects were not allowed to smoke or drink coffee during the last 2 h before HRA and during light application. HRA was performed in a supine position with the commercially available computer program ProSciCard (Medical Research and Diagnostic Computer Systems, Linden, Germany). The examination consisted of a 5-min HR recording while resting and a recording during deep respiration. After a resting period of at least 10 min, the CV at rest (CVr) (the SD of the distribution of R-R intervals divided by their mean> was determined from 150 artifact-free heart beats. The spectral analysis was calculated by Fast Fourier Transformation. Three frequency peaks were separated automatically (low frequency 0.01-0.05 Hz; mid frequency 0.05-0.15 Hz; high frequency 0.15-0.50 Hz). To determine the CV during deep respiration (CVdr), the subjects were instructed to breathe deeply at a frequency of 6 cycles/min (6 s inspiration, 4 s expiration) which has been shown to produce maximal HRV in healthy individuals (Mackay, 1983). This breathing rhythm was triggered by the computer using a bar graph displayed on the screen and moving up (inspiration) and down (expiration). Calculation of the CVdr was based on the registration of 100 artifact-free heart beats. It is important to know that the results of the CVr, CVdr and the spectral analysis have been shown to be independent of the HR (Ziegler et
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of Affective Disorders 34 (1995) 131-137
al., 1992). Evidence was presented indicating that vagal activity influences HRV at all frequencies up to 0.5 Hz while the sympathetic nervous system affects HRV below 0.15 Hz (Akselrod et al., 1981; Pomeranz et al., 1985). Thus, the HF power is a relatively pure parameter of parasympathetic activity. 2.4. Classification of patients and test procedures applied
The Hamilton rating scale for depression (HDRS; Hamilton, 1960) was applied on the 5th day and after 14 days of supportive bright-light therapy. The seasonal pattern assessment questionnaire (German version by S. Kasper; SPAQD) was applied on day 0 to test for SAD (SPAQ scores of > 10). A visual analogue scale (German version; VAS; Fahndrich and Linden, 1982) and the the clinical global impression (CGI) were used directly before and after the 4th session of phototherapy to rate improvement of psychic condition.
Table 1 Effects of bright-
or dim-light
(a) 90 min bright-light
Normal
% % 10-4Hz2 10-4Hz2 10-4Hz2 min.’
(b) 90 min dim-light
The statistical evaluation was carried out using Wilcoxon’s rank sum test. The HRA investigator did not know whether patients belonged to group I or II.
patients
and normal
control
subjects
(n = 18)
Group
Before
subjects
After
Before
I (n = 12) After
Group Before
II (n = 18) After
4.9 9.0 1.05 0.95 0.63 73.9
5.2 9.1 1.09 0.86 1.05 a 68.4 a
2.1 4.4 0.42 0.22 0.18 90.5
2.4 5.5 a 0.41 0.26 0.25 a 85.5 a
2.0 4.7 0.41 0.13 0.16 89.4
2.0 4.6 0.32 0.13 0.15 88.9
(n = 18)
Group
Before
After
Before
After
Before
After
3.6 9.0 0.86 0.73 0.75 73.2
3.5 8.9 0.73 0.57 0.58 67.9 =
1.6 4.8 0.30 0.13 0.23 90.1
1.8 4.9 0.35 0.18 0.27 86.0 a
2.1 4.5 0.60 0.40 0.30 93.1
2.3 4.3 0.45 0.51 0.33 87.9 a
application
Unit
CVr CVdr LF MF HF HR
on HRV in depressed
2.7. Statistical analysis
application
Unit
CVr CVdr LF MF HF HR
application
The subjects were divided into two groups. Patients showing an improvement of at least 10 mm on the VAS and at least a slight improvement of item 3.1 (therapeutic effect) on the CGI were classified as group I (n = 12; 10 F, 2 M; mean age 47.8, range 24-72) and the patients who did not fulfill these criteria as group II (n = 18; 15 F, 3 M; mean age 43.4, range 21-64). 4 patients of group I and 2 patients of group II had to be replaced for the dim-light procedure; 1 had committed suicide on day 17, 1 had been dismissed on day 15 after reaching complete remission, 4 did not agree to take part in a 2nd investigation because they were not willing to accept the nonsmoking and no caffeine condition.
% % 10-4Hz2 10-4Hz2 10-4Hz2 min.’
Normal
subjects
I (n = 12)
Group
II (n = 18)
Group 1, depressed patients with improvement of psychic condition after bright-light application; Group II, depression patients without improvement of psychic condition after bright-light application; LF, low-frequency spectral power; MF, mid-frequency spectral power; HF, high-frequency spectral power. a P < 0.025 (Wilcoxon).
T. Rechlin et al. /Journal of Affective Disorders 34 (1995) 131-137
3. Results
(a) None of the patients fulfilled the SAD criteria. The SPAQ-D scores were significantly higher in group I than in group II (4.5 vs. 1.0, P < 0.01). (b) The TCA pl asma levels on the HRA day did not show a significant difference between patients of groups I and II (198 vs. 211 ng/ml, NS). (c) The HRDS scores of groups I and II neither showed a significant difference on the HRA day (30.2 vs. 29.7, NS) nor on day 14 (12.7 vs. 19.4, NS, P = 0.08). (d) HRA revealed no significant differences between groups I and II before bright- and dimlight applications, respectively. (e) The normal control subjects had a significantly lower HR and significantly higher HRV parameters than the depressed patients (P < 0.0001) which was consistent with the effects of TCA treatment in the depressed groups (Jakobsen et al., 1984; Yeragani et al., 1992b; Rechlin et al., 1994a). (f) A significant increment of CVdr and HF power was observed in group I after bright-light application. HRV parameters were not influenced by bright or dim light in group II. The control subjects experienced a significant increment of HF power after bright light but not after dim light. As expected, HR decreased significantly after bright-light as well as after dim-light exposure due to the resting position during light application. The complete HRA results are displayed in Table 1.
4. Discussion Effects of bright-light therapy on autonomic functions (e.g., body-core temperature or heatloss response) have already been investigated in humans (Rosenthal et al., 1990; Eastman et al., 1993; Arbisi et al., 1994). To the best of our knowledge, the impact of phototherapy on HRV parameters has not been examined previously.
135
However, the results of this study should be regarded as preliminary and require cautious interpretation. We have not investigated any patients fulfilling the complete SAD criteria although patients of group I might represent subsyndromal variants (for review, see Kasper and Kamo, 1990). Furthermore, all patients were treated with either doxepin or amitriptyline, both of which have strong effects on HRV parameters (Rechlin, 1994b). Several difficulties in investigations of autonomic function (e.g., influence of stress and drug treatment) generally allow to test only within a narrow range of conditions (Low, 19921. Therefore, we decided to carry out a before and after bright/dim-light HRV protocol on the 5th day of light treatment. With these restrictions in mind, our data suggest that those depressed patients, who show an improvement of mood directly after bright-light application and who gain higher scores of seasonality, experience an increase of parasympathetic activity associated with phototherapy while the other depressed patients do not. HRV is the result of a complex reflex involving parts of midbrain, brainstem and peripheral parasympathetic nervous system. The anterior and lateral parts of the hypothalamus, which are connected to the SCN, generate parasympathetic activity (Allen and Cechetto, 1992). We suppose that this pathway might play a role in the mechanisms underlying bright-light-induced effects on the autonomic nervous system. Interestingly, it has been shown that brief light pulses can stimulate HR in anaesthesized rats. This effect is abolished by prior infusion of a competitive ligand of N-methyl-D-aspartate-(NMDA) receptors into the SCN (Amir, 1992). However, different central neurotransmitter systems, including dopamine (Chitravanshi and Calaresu, 1992; Kubo et al., 1992) and other catecholamines, serotonin and acetylcholine, are involved in the HR and HRV modulation (Shields, 1993). Thus, it is not possible to draw any conclusions with regard to specific neurotransmitters functions from our data. Nevertheless, HRV measurement seems to be a valuable tool for psychophysiological studies on treatment response (e.g., to phototherapy). Fur-
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T. Rechlin et al. /Journal
of Affective Disorders 34 (1995) 131-137
ther research will have to elucidate whether patients with SAD also experience an increment of parasympathetic parameters during bright-light therapy. Additionally, light-induced effects on autonomic functions should be examined in unmedicated depressed patients and patients treated with SSRIs as we do not know to what extent TCA treatment might have influenced our results. Examinations carried out under constant routine conditions and containing a 24-h HRV registration might help to answer the question whether bright-light therapy influences autonomic diurnal rhythms. Finally, it might be rewarding to answer the question whether light-induced alterations of parasympathetic functions possess any predictive power with regard to therapeutic efficacy of bright-light treatment.
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ELSEVIER
OF
AFFECTIVE DISORDERS
Journal of Affective Disorders 34 (1995) 131-137
Does bright-light therapy influence autonomic heart-rate parameters? Thomas Rechlin by*, Maria Weis b, Kurt Schneider a, Ulrich Zimmermann Wolfgang P. Kaschka b
b,
a Department of Psychiatry, University of Erlangen-Nuremberg, Erlangen, Germany b Department of Genetics, University of Erlangen-Nuremberg,
Erlangen, Germany
Received 24 March 1994; revised 16 January 1995; accepted 16 January 1995
Abstract 30 inpatients suffering from major depression (DSM-III-R), who did not fulfill the criteria of seasonal affective disorder &4D), were treated with either doxepin or amitriptyline as monotherapy and supportively with bright light for 14 days. From days 15 to 19, bright light was replaced by dim light. 18 drug-free control subjects underwent an analogous sequence of bright- and dim-light applications. Phototherapy was applied between 06:OO and 07:30. Heart-rate (HR) analysis was performed in the patients and control subjects before and after the 5th session of bright and dim lights, respectively. 12 patients (40%) experienced improvement of mood during bright-light therapy (group I) while 18 (60%) did not (group II). Patients of group I, who reached significantly higher scores in the seasonal pattern assesssment questionnaire than patients of group II, showed an increase of the coefficient of HR variation (HRV) during deep breathing as well as an increment of the high-frequency (HF) peak of spectral analysis exclusively after the bright-light sessions. Patients of group II did not show a significant alteration of these parameters, neither under the conditions of bright-light treatment nor under dim light. The control subjects experienced an increment of the HF power exclusively after bright light. The results suggest that a distinct subgroup of patients with non-SAD major depression shows a more pronounced light-associated increment of parasympathetitally controlled cardiac functions than the other depressed patients and the controls. HRV measurements seem to be a valuable tool for further psychophysiological studies on treatment response (e.g., to phototherapy). Keywords:
Bright-light
therapy;
Parasympathetic
function;
1. Introduction Seasonal affective disorders elicited theoretical and practical
(SAD) have interests as
* Corresponding author. Address: Psychiatrische Universitltsklinik, Schwabachanlage 6, 91054 Erlangen, Germany. Fax: (49) (9131) 854436. 0165-0327/95/$09.50
Heart-rate
Heart-rate
variation
bright-light therapy (> 2500 lux) proved to be an effective treatment of this special form of depression (Rosenthal et al., 1984; Terman et al., 1989; Sack et al., 1990; Kasper, 1994; Lam, 1994). It has been suggested that patients suffering from subsyndromal SAD (S-SAD) also benefit from phototherapy (Kasper et al., 1989; Delito et al., 1991; Kripke et al., 1992). However, others
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denied any therapeutic response in patients with non-SAD (Mackert et al., 1991). In normal subjects, who are rather unaffected by seasonal changes, bright-light application is not beneficial (Rosenthal et al., 1987; Genhart et al., 1993). It is generally supposed that the biological effects of bright light are mediated by the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. Several hypotheses concerning the therapeutic mechanisms of bright-light treatment have been discussed, including the melatonin hypothesis, the circadian phase-shift theory, the circadian amplitude reduction hypothesis, the photoperiod theory, but also placebo effects (for review, see Rosenthal and Wehr, 1992). It has also been suggested that the neurotransmitters serotonin (e.g., Rao et al., 1992) and dopamine (e.g., Depue et al., 1990) play an essential role in the SAD pathophysiology. However, the underlying pathogenetic SAD mechanisms have not been sufficiently clarified. The methodology of computerized heart-rate (HR) analysis (HRA) has been applied to investigate the autonomic state in psychiatric disorders and the impact of psychopharmacological therapies on autonomic cardiac regulation (Rechlin et al., 1994a; Rechlin et al., 1994b; Rechlin et al., 1994~; Rechlin et al., 1994d). Balogh et al. (1993) have employed measurements of HR variability (HRV) to investigate the treatment responses to different classes of antidepressants. Peripheral HRV control, which depends on the ability of the autonomic nervous system to vary the intervals between consecutive heart beats according to physiological requirements, is mainly exerted by the parasympathetic vagus nerve. The central mechanisms of cardiovascular and respiratory regulation have not yet been clarified in every detail, however, important influences are carried out by various brainstem areas, the limbic system and the hypothalamus (Spyer, 1988). It is still an unsettled question whether or not affective disorders are by themselves associated with an altered parasympathetic activity represented by decreased HRV parameters (Dalack and Roose, 1990; Yeragani et al., 1992a; Friedman et al., 1993; Yeragani et al., 1993; Rechlin et al., 1994d; Stein and Asmundson, 1994). How-
ever, investigations in patients treated with tricyclic antidepressants (TCA; Jakobsen et al., 1984; Yeragani et al., 1992b; Rechlin, 1994a; Rechlin, 1994b; Rechlin et al., 1994a) or clozapine (Zahn and Pickar, 1993; Rechlin et al., 1994b) revealed decreased R-R variation which is probably, at least in part, due to the anticholinergic effects of these drugs. On the other hand, treatment with 20 mg paroxetine, a selective inhibitor of serotonin reuptake (SSRI), did not influence HRV (Rechlin et al., 1994~). The HRA method might also be a valuable tool in chronobiologically oriented research on affective disorders since HRV parameters show diurnal variation (Cornelissen et al., 1990; Kleiger et al., 1991; Noritake et al., 1992). In a previous study, we noted higher evening values of HRV parameters in TCA-treated depressed patients with typical diurnal variation of mood (improvement in the evening) whereas patients without diurnal mood variations did not show extensive differences between morning and evening values (Rechlin et al., 1995). Since it has been shown that the central circadian regulation of HR parameters is triggered by light and destruction of the SCN suspends circadian HR regulation (Saleh and Winget, 1977), studies on HRV parameters in depressed patients treated with bright light are of great theoretical and practical interests. The present study was designed to compare HRV parameters in severely depressed inpatients (major depression, DSM-III-R) and in normal control persons matched for age and sex before and after standardized treatment with bright as well as dim light. 2. Methods 2.1. Patients and therapy 30 inpatients (25 F, 5 M; mean age 45.2; range 21-72) with major depression, according to the criteria of DSM-III-R, who had previously been treated with various psychotropic substances but not with lithium, were treated with either 150 mg/day amitriptyline or doxepin as monotherapy. Patients received increasing doses of either
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drug reaching the full dosage on the 5th day of treatment. This day was defined as day 0. None of the patients suffered from diabetes mellitus, cardiac diseases, alcoholism, neurological diseases or any diseases affecting the autonomic nervous system. 2.2. Protocol of light application Beside the treatment with either amitriptyline or doxepin, all patients underwent supportive bright-light therapy which was applied between 06:OOand 07:30 from days 1 to 14 with an intensity of > 2500 lux. From days 15 to 19, all patients underwent dim-light application ( < 200 lux) between 06:OOand 07:30. A change of medication (e.g., lithium therapy and SSRI application) was not allowed before day 20. Patients and controls were informed that bright and dim lights would be equally effective. 2.3. Control subjects 18 healthy, drug-free control persons (13 F, 5 M; mean age 43.6, range 19-74) matched for age and sex also underwent the bright- and dim-light applications.
2.4. Time HRA point HRA was performed directly before and after the 5th session of bright-and dim-light applications, respectively. On the same day, TCA plasma levels were determined by a commercially available fluorescence polarization immunoassay (FPIA; Abbott). The choice of the 5th day of light application was a compromise to allow adaptation of the patients and control persons to the method of light application and to minimize psychological stress which strongly influences the HRA parameters (e.g., Low, 1992). Additionally, it was essential to have comparable conditions with regard to medication and depression scores since HRV parameters are markedly influenced by psychotropic drugs (Rechlin et al., 1994a; Rechlin et al., 1994b; Rechlin et al., 1994~) and, possibly, by the affective disorder itself (Dalack and Roose, 1990; Bar-
133
logh et al., 1993; Rechlin, 1994b; Rechlin et al., 1994d). Therefore, it was unfortunately not practicable to compare HRV parameters in medicated patients using a before vs. after light protocol. It has been shown in SAD patients that the beneficial effects of bright-light therapy already appear after a few days of treatment (Wehr and Rosenthal, 1989). Therefore, any psychophysiological effects of bright light on autonomic functions would probably be detected on the 5th day of light application while the antidepressant TCA effects would still be lacking or at least be incomplete. 2.5. HRV measurements The patients and control subjects were not allowed to smoke or drink coffee during the last 2 h before HRA and during light application. HRA was performed in a supine position with the commercially available computer program ProSciCard (Medical Research and Diagnostic Computer Systems, Linden, Germany). The examination consisted of a 5-min HR recording while resting and a recording during deep respiration. After a resting period of at least 10 min, the CV at rest (CVr) (the SD of the distribution of R-R intervals divided by their mean> was determined from 150 artifact-free heart beats. The spectral analysis was calculated by Fast Fourier Transformation. Three frequency peaks were separated automatically (low frequency 0.01-0.05 Hz; mid frequency 0.05-0.15 Hz; high frequency 0.15-0.50 Hz). To determine the CV during deep respiration (CVdr), the subjects were instructed to breathe deeply at a frequency of 6 cycles/min (6 s inspiration, 4 s expiration) which has been shown to produce maximal HRV in healthy individuals (Mackay, 1983). This breathing rhythm was triggered by the computer using a bar graph displayed on the screen and moving up (inspiration) and down (expiration). Calculation of the CVdr was based on the registration of 100 artifact-free heart beats. It is important to know that the results of the CVr, CVdr and the spectral analysis have been shown to be independent of the HR (Ziegler et
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of Affective Disorders 34 (1995) 131-137
al., 1992). Evidence was presented indicating that vagal activity influences HRV at all frequencies up to 0.5 Hz while the sympathetic nervous system affects HRV below 0.15 Hz (Akselrod et al., 1981; Pomeranz et al., 1985). Thus, the HF power is a relatively pure parameter of parasympathetic activity. 2.4. Classification of patients and test procedures applied
The Hamilton rating scale for depression (HDRS; Hamilton, 1960) was applied on the 5th day and after 14 days of supportive bright-light therapy. The seasonal pattern assessment questionnaire (German version by S. Kasper; SPAQD) was applied on day 0 to test for SAD (SPAQ scores of > 10). A visual analogue scale (German version; VAS; Fahndrich and Linden, 1982) and the the clinical global impression (CGI) were used directly before and after the 4th session of phototherapy to rate improvement of psychic condition.
Table 1 Effects of bright-
or dim-light
(a) 90 min bright-light
Normal
% % 10-4Hz2 10-4Hz2 10-4Hz2 min.’
(b) 90 min dim-light
The statistical evaluation was carried out using Wilcoxon’s rank sum test. The HRA investigator did not know whether patients belonged to group I or II.
patients
and normal
control
subjects
(n = 18)
Group
Before
subjects
After
Before
I (n = 12) After
Group Before
II (n = 18) After
4.9 9.0 1.05 0.95 0.63 73.9
5.2 9.1 1.09 0.86 1.05 a 68.4 a
2.1 4.4 0.42 0.22 0.18 90.5
2.4 5.5 a 0.41 0.26 0.25 a 85.5 a
2.0 4.7 0.41 0.13 0.16 89.4
2.0 4.6 0.32 0.13 0.15 88.9
(n = 18)
Group
Before
After
Before
After
Before
After
3.6 9.0 0.86 0.73 0.75 73.2
3.5 8.9 0.73 0.57 0.58 67.9 =
1.6 4.8 0.30 0.13 0.23 90.1
1.8 4.9 0.35 0.18 0.27 86.0 a
2.1 4.5 0.60 0.40 0.30 93.1
2.3 4.3 0.45 0.51 0.33 87.9 a
application
Unit
CVr CVdr LF MF HF HR
on HRV in depressed
2.7. Statistical analysis
application
Unit
CVr CVdr LF MF HF HR
application
The subjects were divided into two groups. Patients showing an improvement of at least 10 mm on the VAS and at least a slight improvement of item 3.1 (therapeutic effect) on the CGI were classified as group I (n = 12; 10 F, 2 M; mean age 47.8, range 24-72) and the patients who did not fulfill these criteria as group II (n = 18; 15 F, 3 M; mean age 43.4, range 21-64). 4 patients of group I and 2 patients of group II had to be replaced for the dim-light procedure; 1 had committed suicide on day 17, 1 had been dismissed on day 15 after reaching complete remission, 4 did not agree to take part in a 2nd investigation because they were not willing to accept the nonsmoking and no caffeine condition.
% % 10-4Hz2 10-4Hz2 10-4Hz2 min.’
Normal
subjects
I (n = 12)
Group
II (n = 18)
Group 1, depressed patients with improvement of psychic condition after bright-light application; Group II, depression patients without improvement of psychic condition after bright-light application; LF, low-frequency spectral power; MF, mid-frequency spectral power; HF, high-frequency spectral power. a P < 0.025 (Wilcoxon).
T. Rechlin et al. /Journal of Affective Disorders 34 (1995) 131-137
3. Results
(a) None of the patients fulfilled the SAD criteria. The SPAQ-D scores were significantly higher in group I than in group II (4.5 vs. 1.0, P < 0.01). (b) The TCA pl asma levels on the HRA day did not show a significant difference between patients of groups I and II (198 vs. 211 ng/ml, NS). (c) The HRDS scores of groups I and II neither showed a significant difference on the HRA day (30.2 vs. 29.7, NS) nor on day 14 (12.7 vs. 19.4, NS, P = 0.08). (d) HRA revealed no significant differences between groups I and II before bright- and dimlight applications, respectively. (e) The normal control subjects had a significantly lower HR and significantly higher HRV parameters than the depressed patients (P < 0.0001) which was consistent with the effects of TCA treatment in the depressed groups (Jakobsen et al., 1984; Yeragani et al., 1992b; Rechlin et al., 1994a). (f) A significant increment of CVdr and HF power was observed in group I after bright-light application. HRV parameters were not influenced by bright or dim light in group II. The control subjects experienced a significant increment of HF power after bright light but not after dim light. As expected, HR decreased significantly after bright-light as well as after dim-light exposure due to the resting position during light application. The complete HRA results are displayed in Table 1.
4. Discussion Effects of bright-light therapy on autonomic functions (e.g., body-core temperature or heatloss response) have already been investigated in humans (Rosenthal et al., 1990; Eastman et al., 1993; Arbisi et al., 1994). To the best of our knowledge, the impact of phototherapy on HRV parameters has not been examined previously.
135
However, the results of this study should be regarded as preliminary and require cautious interpretation. We have not investigated any patients fulfilling the complete SAD criteria although patients of group I might represent subsyndromal variants (for review, see Kasper and Kamo, 1990). Furthermore, all patients were treated with either doxepin or amitriptyline, both of which have strong effects on HRV parameters (Rechlin, 1994b). Several difficulties in investigations of autonomic function (e.g., influence of stress and drug treatment) generally allow to test only within a narrow range of conditions (Low, 19921. Therefore, we decided to carry out a before and after bright/dim-light HRV protocol on the 5th day of light treatment. With these restrictions in mind, our data suggest that those depressed patients, who show an improvement of mood directly after bright-light application and who gain higher scores of seasonality, experience an increase of parasympathetic activity associated with phototherapy while the other depressed patients do not. HRV is the result of a complex reflex involving parts of midbrain, brainstem and peripheral parasympathetic nervous system. The anterior and lateral parts of the hypothalamus, which are connected to the SCN, generate parasympathetic activity (Allen and Cechetto, 1992). We suppose that this pathway might play a role in the mechanisms underlying bright-light-induced effects on the autonomic nervous system. Interestingly, it has been shown that brief light pulses can stimulate HR in anaesthesized rats. This effect is abolished by prior infusion of a competitive ligand of N-methyl-D-aspartate-(NMDA) receptors into the SCN (Amir, 1992). However, different central neurotransmitter systems, including dopamine (Chitravanshi and Calaresu, 1992; Kubo et al., 1992) and other catecholamines, serotonin and acetylcholine, are involved in the HR and HRV modulation (Shields, 1993). Thus, it is not possible to draw any conclusions with regard to specific neurotransmitters functions from our data. Nevertheless, HRV measurement seems to be a valuable tool for psychophysiological studies on treatment response (e.g., to phototherapy). Fur-
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T. Rechlin et al. /Journal
of Affective Disorders 34 (1995) 131-137
ther research will have to elucidate whether patients with SAD also experience an increment of parasympathetic parameters during bright-light therapy. Additionally, light-induced effects on autonomic functions should be examined in unmedicated depressed patients and patients treated with SSRIs as we do not know to what extent TCA treatment might have influenced our results. Examinations carried out under constant routine conditions and containing a 24-h HRV registration might help to answer the question whether bright-light therapy influences autonomic diurnal rhythms. Finally, it might be rewarding to answer the question whether light-induced alterations of parasympathetic functions possess any predictive power with regard to therapeutic efficacy of bright-light treatment.
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