**3. Results**

#### *3.1. Sociodemographic and Clinical Characteristics*

The groups showed significant differences (see Table 1) in the sociodemographic variables studied such as age (*p* = 0.009), marital status (*p* = 0.011), number of children (*p* = 0.002), family situation (*p* = 0.001), employment status (*p* = 0.001) and years of study (*p* = 0.026). The mean age of the total sample of patients was 37.72 yrs. old (SD = 7.68), observing a higher mean age in SZ+ with respect to MDD+ (*p* = 0.005). The comparison among the three groups and HC subjects did not show differences for age (F(3,153.) = 3.176; *p* = 0.167) while they did for marital status ( χ2(3) = 39.771; *p* < 0.001), economic situation (χ2(3) = 125.086; *p* < 0.001) and years of schooling (F(3,153) = 8.903; *p* < 0.001).


**Table 1.** Sociodemographic data for the three groups of patients. Means, standard deviation, percentages and statistical contrasts (ANOVA and Chi Square test).

SZ+: Substance use disorder with comorbid schizophrenia; BD+: Substance use disorder with comorbid bipolar disorder; MDD+: Substance use disorder with comorbid major depressive disorder; \* *p* < 0.05; \*\* *p* < 0.01; \*\*\* *p* < 0.001.

The analysis of the clinical variables (see Table 2) confirmed that a high percentage of patients with MDD+ were under a residential treatment in therapeutic community, in contrast with the SZ+ (χ2(1) = 19.90; *p* = 0.001) and BD+ groups (χ2(1) = 8.85; *p* = 0.003) who were receiving an outpatient follow-up. The SMI age of onset was later in the MDD+ group compared with SZ+ (*p* = 0.001) and to BD+ (*p* = 0.019). In contrast, no differences were found among the groups for medical disease comorbidities, family history and years of duration of the SMI, and global functioning (not showed in table). Regarding pharmacological treatment, the SZ+ group took a greater amount of psychotropic daily drugs than the MDD+ group (*p* = 0.026), while the BD+ group was in an intermediate position. In all groups the percentage of smoking patients was >80%, with no differences in the active smoking years (>17 years; not showed in table). The mean score of the Fagerström questionnaire for nicotine dependence was higher in the SZ+ group compared to MDD+ (*p* = 0.008). Instead, the caffeine daily intake did not exhibit differences among the groups (not showed in table). Scores on the PANSS, Hamilton and YMRS clinical scales indicated that all groups were clinically stable, although the MDD+ group (11.23 ± 5.14) had a higher HDRS score than the BD+ group (6.86 ± 5.17) (F(1,74)= 5.44; *p* = 0.024).

**Table 2.** Clinical data for the three groups of patients regarding psychiatric diagnosis and substance use disorders. Means, standard deviation, percentages and statistical contrasts (ANOVA and Chi Square test).


SZ+: Substance use disorder with comorbid schizophrenia; BD+: Substance use disorder with comorbid bipolar disorder; MDD+: Substance use disorder with comorbid major depressive disorder; SMI: Severe mental illness; N: Number; SUD: Substance use disorder; DAST-20: Drug abuse screening test. a Percentages will not equal 100 as each patient may have taken more than one substance. \* *p* < 0.05; \*\* *p* < 0.01; \*\*\* *p* < 0.001.

The results in the clinical variables related to SUD did not indicate any differences among groups for the SUD age of onset, but they did in its duration, being higher in MDD+ patients compared to SZ+ (*p* = 0.05). The SZ+ group consumed more amounts of substances compared to BD+ (*p* = 0.001) and MDD+ (*p* = 0.037), although we obtained a majority pattern of polydrug use in the entire sample (>80% in each group; not showed in table), regardless of the SMI diagnosis. The most commonly used substances in all groups were cocaine, alcohol and cannabis. The DAST-20 revealed a higher proportion of MDD+ patients with high and severe dependence compared to BD+ (χ2(3) = 7.83; *p* = 0.035). The groups did not contribute differences in the abstinence period, or in the number of relapses prior to the start of treatment. The presence of family, work and legal related problems did not exhibit differences either (not showed in table).

#### *3.2. Circadian Typology and Sleep-Wake Data*

The ANCOVA analysis (see Table 3) showed a mean score for the CSM questionnaire in the morningness range for the MDD+ group (*p* = 0.026; ηp<sup>2</sup> = 0.064), in contrast with for patients with SZ+ (*p* = 0.008) and BD+ (*p* = 0.002), who were placed in the intermediate range. The percentage of patients in the morning typology was also higher in the MDD+ group compared to the SZ+ (χ2(2) = 9.60; *p* = 0.008) and BD+ (χ2(2) = 7.81; *p* = 0.02) groups. In both SZ+ and BD+ the predominating typology was the intermediate one. Regarding sleepwake schedules, a greater total sleep duration was observed for SZ+ patients compared to MDD+ (*p* = 0.001); without differences from the BD+ group, which showed an intermediate position. Furthermore, the MDD+ group go<sup>t</sup> up earlier than SZ+ (*p* = 0.009) and BD+ (*p* = 0.015).

**Table 3.** Circadian typology and sleep-wake data for the three groups of patients. Means, percentages and differences according to the type of treatment.


SZ+: Substance use disorder with comorbid schizophrenia; BD+: Substance use disorder with comorbid bipolar disorder; MDD+: Substance use disorder with comorbid major depressive disorder; \* *p* < 0.05; \*\* *p* < 0.01; \*\*\* *p* < 0.001.

> On the other hand, the mean score on the CSM scale according to the type of treatment (outpatient vs. residential) provided a similar score for both modalities. However, the percentage of morning typology patients was higher in the residential treatment modality than in the outpatient one (*p* = 0.004). Being under an outpatient treatment program was associated to the intermediate circadian typology. The proportion of people with evening chronotype was also the minority for both treatment modalities. The influence of the type of treatment on sleep-wake schedules showed that outpatients slept for more hours (*p* = 0.001), went to bed and go<sup>t</sup> up later (*p* = 0.006 and *p* = 0.001, respectively). Furthermore, the percentage of patients who took naps and its duration was also higher in the outpatient treatment group (*p* = 0.001).

#### *3.3. Distal Skin Temperature*

Table 4 shows the results of the DST analyses for the three groups of patients and the data for the HC group. The MANCOVA carried out, both for the parametric and non-parametric indexes, showed significant differences depending on the comorbid SMI diagnoses (see Figure 1). The SZ+ group presented the highest minimum and mesor compared to the MDD+ group (*p* = 0.021), without differences from the BD+ group, which was in an intermediate position. We also found a higher M5 value for BD+ patients compared with MDD+ (*p* = 0.025).

**Table 4.** Distal skin temperature for the three groups of patients and the healthy controls group. Means, standard error and MANCOVA analyses.


SZ+: Substance use disorder with comorbid schizophrenia; BD+: Substance use disorder with comorbid bipolar disorder; MDD+: Substance use disorder with comorbid major depressive disorder; HC: healthy control group; *ηp*2: Partial square index of eta (effect size); P1: first armonic power; P12: Cumulative power of the twelfth harmonic; CI: Circadianity index; IS: Interdaily stability; IV: Intradaily variability; RA\_10: Relative amplitude multiplied by 10; M5: Mean value of the five consecutive hours of maximum temperature values; TM5: M5 time location; L10: Mean value of the 10 consecutive hours of minimum temperature values; TL10: L10 time location. a Data expressed in hours and minutes (mean and standard error). \* *p* < 0.05; \*\* *p* < 0.01; \*\*\* *p* < 0.001.

> The comparison of the DST parameters between the dual groups and the HC group showed a higher minimum value (*p* = 0.002) and mesor (*p* = 0.024) in the SZ+ group, while the Rayleigh vector (*p* = 0.036) and the accumulated potency of the first 12 harmonics (*p* = 0.039), were higher in the MDD+ group. In addition, the CI was found below the value of the HC group and the range of normality for SZ+ (*p* = 0.004) and MDD+ (*p* = 0.001). In the case of IV, the degree of fragmentation was practically null in the three dual groups and significantly different from the HC group (*p* = 0.001, in all cases). Finally, BD+ patients showed a higher M5 value than the HC group (*p* = 0.011), although the value of this parameter in the three groups indicated an adequate night's rest (see Figure 1).

> In the additional analyses carried out considering treatment modality as a fixed factor (see Table 5 and Figure 2), the MANCOVA analyses indicated that the dual outpatients presented the highest minimum, mesor and L10 values, and a later acrophase (*p* = 0.007) together with a delay in the central hour of the waking period with respect to those who received residential treatment. The last MANCOVA adding the diagnostic group factor, to determine whether the differences between the type of treatment differed according to the comorbid SMI, did not provide differences in any of the evaluated parameters.

**Figure 1.** Distal skin temperature mean waveforms for healthy controls (**A**) and dual disorders (**B**). Waveforms data are expressed as mean ± SEM in function of local time (hours:minutes). HC: Healthy Controls (dashed blue line, *n* = 40); SZ+: Substance use disorder with comorbid schizophrenia (dashed red line, *n* = 38), MDD+: Substance use disorder with comorbid major depressive disorder (dotted black line, *n* = 40), BD+: Substance use disorder with comorbid bipolar disorder (continuous green line, *n* = 36).

Finally, the results of the correlational analysis (*p* ≤ 0.01) between the DST and the clinical variables showed significant relationships with nicotine dependence. In this sense, the SZ+ group exhibited a negative relationship for the values of mesor and L10, and the Fagerström score (r = −0.469; *p* = 0.003 and r = −0.438; *p* = 0.007, respectively), that is, the higher the nicotine dependence score the lower values of both were observed. Likewise, in the MDD+ group, a negative correlation was obtained between M5 and the daily amount of cigarettes consumed (r = −0.475; *p* = 0.004); thus, in these patients, the higher the consumption of nicotine, the lower the temperature values in the five hours of maximum value.


**Table 5.** Distal skin temperature for the total sample according to treatment modality. Means, standard error and MANCOVA analyses.

P1: first armonic power; P12: Cumulative power of the twelfth harmonic; CI: Circadianity index; IS: Interdaily stability; IV: Intradaily variability; RA\_10: Relative amplitude multiplied by 10; M5: Mean value of the five consecutive hours of maximum temperature values; TM5: M5 time location; L10: Mean value of the 10 consecutive hours of minimum temperature values; TL10: L10 time location; *ηp*2: Partial square index of eta (effect size). a Data expressed in hours and minutes (mean and standard error). \* *p* < 0.05; \*\* *p* < 0.01.

**Figure 2.** Distal skin temperature mean waveforms for residential treatment (dashed black line, *n*= 50) and ambulatory treatment (continuous blue line, *n* = 60). Waveforms data are expressed as mean ± SEM in function of local time (hours:minutes).
