Cardiac dysautonomia in depression – heart rate variability biofeedback as a potential add-on therapy

Figures & data

Table 1 Testing possibilities for autonomic function

Tests of autonomic cardiovascular reflexes	Valsalva maneuver, deep breathing, isometric handgrip test, cold pressor test, mental arithmetic, orthostatic test, head-up tilt test, baroreflex sensitivity testing, heart rate variability analysis
Measurements of neurotransmitter levels	Noradrenaline spillover test
Testing of cutaneous autonomic function	Thermoregulatory sweat test, sympathetic skin response SSR, quantitative sudomotor axon reflex test, Quantitative pilomotor axon reflex test, vasomotor test
Microneurography	Muscle sympathetic nerve activity, skin sympathetic nerve activity

Notes: Table of tests of autonomic functional integrity in cardiovascular, cutaneous and metabolic systems.

Table 2 Studies in which HRV measures were calculated on a least one cohort with depression diagnoses

Study/year	Cohorts	Data	Parameters	Cardiovascular risk/treatment information	Results	Interpretation	Good practice checklist
Vasudev et al,^Citation149 2011	42 MD, 30 HC	BP and 10 mins ECG at rest	BP, LF, HF, TP, BS	Cardiovascular risk parameters included/cardio-active and psychoactive drug use included	MD is an independent predictor for systolic orthostatic hypotension, low frequency HRV and BS	Autonomic abnormalities in late-life depression is associated with development of brain white matter hyperintensities	No information on R-R interval cleaning and artefacts
Wang et al,^Citation150 2013	53 MD, 53 HC	ECG over 24 hrs	SDNN, SDANN, RMSSD,pNN50, ratio of LF/HF	Some information on cardiovascular risk/all patients were receiving SSRIs treatment	In the depression group SDNN, SDANN, RMSSD, pNN50 and HF were lower, prevalence of supraventricular arrhythmia was significantly higher than in the control group	Depression is accompanied by dysfunction of the cardiac autonomic nervous system, depression severity is linked to severity of this dysfunction.	No information on artefact identification and cleaning methods
Johansson et al,^Citation151 2010	33 MD, 20 HC	30 mins ECG at rest and BP	HR, BS and BEI	Cardiovascular risk in exclusion criteria/electroconvulsive therapy vs medical therapy	HR and BP were elevated in depressive patients before treatment compared with HC, whereas arterial BRS and BEI were reduced	The sensitivity and the number of times the arterial baroreflex is being active are reduced in MDD and this dysfunction may prevail long-term when depressive symptoms have improved	All items on checklist met
Hughes et al,^Citation152 2007	34 PTSD + MD, 28 PTSD, 16 MD, 46 HC	BP and IBI	BP, HR, BRS	No information on cardiovascular risk/psychiatric and cardiovascular medication included	Women with PTSD (with or without MDD) exhibited significantly lower resting BRS than women without PTSD. BRS decreased during the anger recall task	PTSD is associated with reduced parasympathetic nervous system functioning	No information on artefact cleaning methods
Broadley et al,^Citation153 2005	36 treated recurrent MD, 39 HC	20 mins ECG and 10 mins BP at rest	HR, BRS	Some cardiac risk factors included/treatment with antidepressants	BRS was significantly lower in patients	BRS is impaired with depression and may contribute to increased cardiac risk	R-R interval calculation briefly discussed, artefact identification not included
Moon et al,^Citation154 2013	34 MD, 27HC	5 mins ECG at rest	SDNN, RMSSD,VLF,LF, HF, TP, LF/HF	No cardiac risk factors mentioned/MD treated with SSRIs	Patients with MDD in the study had no significant main change in HRV	HRV is not sufficiently powerful to discriminate among various psychiatric illnesses	No information on artefact identification and cleaning methods
Dauphinot et al,^Citation155 2012	67 MD, 228 with history of MD	24 hrs ECG	SDNN, VLF, LF, HF, LF/HF, BRS	Some cardiac risk factors included/treatment with antidepressants in some cases	LF, VLF and LF/HF ratio were lower among subjects with depressive symptoms and history of depression, independently of antidepressant treatment	Depressive symptoms may be linked to autonomic nervous system lower performances	Artefact identification, data loss, cleaning not included
Udupa et al,^Citation90 2011	94 MD	resting ECG	SDNN, RMSSD, pNN50, TP, LF, HF, SVB	Treatment with: repetitive transcranial magnetic stimulation SSRIs and tricyclic antidepressants	Both time and frequency domain HRV measures showed increase with rTMS and decrease with TCAs; they remained virtually unchanged with SSRIs	The effects of antidepressant treatments on cardiac autonomic function abnormalities found in depression vary with the mode of treatment used	No information on extraction and cleaning of artefacts
Chang et al,^Citation156 2015	116 bipolar II depression, 591 unipolar depression, 421 HC	ECG recorded for 5 mins	VLF, LF, HF, LF/HF	Some cardiovascular risk factors included/all participants drug-naïve	Patients with BPII depression exhibited significantly lower mean R–R intervals, variance (total HRV), LF-HRV, HF-HRV but higher LF/HF ratio compared to those with UD	HRV may aid in the differential diagnosis of BPII depression and UD	No information on data analysis and cleaning, little information on demographics
Kemp et al,^Citation157 2014	98 MD	10 mins resting state ECG	R-R interval series, HRV mean square of successive squared differences and HF components	Treatment with: SSRI, SNRI, tricyclic antidepressant and other antidepressant, Cardiovascular risks: included	Tricyclic antidepressants, SNRIs and other antidepressants associated with increases in HR and decreases in its variability; depression did not display reductions in vagal activity	Mood disorders and antidepressants are increased risk for cardiovascular morbidity and mortality	All items on checklist met
Agelink et al,^Citation158 2002	25 MD	ECG and BP	HRV, RMSSDr, RMSSDd, LF, HF, LF/HF ratio	Treatment with reboxetine, no information on cardiovascular risk	Reboxetine treatment associated with decrease in absolute and relative LF power, in mean arterial pressure; significant decrease in average low- to high frequency ratio	Inhibition of brain NE reuptake by reboxetine resulted in an inhibition of central noradrenergic activity	Little information on demographics, no control group, R-R interval cleaning briefly discussed
Voss et al,^Citation159 2011	36 MD, 36 HC	30 mins ECG, BP	RMSSD, LF/HF ratio BPV, BRS	No treatment, no information on cardiovascular risk	Gender differences were detectable in HC showing predominant sympathetic modulation in males. These gender differences were abolished in patients suffering from MD, HRV was not different between patients and controls	BPV and BRS ares more sensitive to reveal depression-associated changes of autonomic function as compared to HRV	All items on checklist met
Terhardt et al,^Citation160 2013	41 MD, 28 HC	5 mins ECG and BP monitoring	LF, HF, LF/HF ratio, TP	Cardiovascular risk assessment not included, treatment with venlafaxine and mirtazapine	Depressed patients had increased heart rate and reduced HRV compared with non-depressed controls	Depression is related to reduced HRV, which might reflect sympathovagal imbalance; venlafaxine and mirtazapine led to further decline in HRV	Little information on data analysis, cleaning and demographics
Kikuchi et al,^Citation161 2009	15 MD,15 HC	ECG recorded for 5–10 mins	LF, HF and LF/HF ratio	No medication, no information on cardiovascular risk	MD group had a lower response to regular deep breathing in LF power and in LF/HF ratio	Reactivity to deep breathing revealed diminished cardiac autonomic reactivity in drug-naïve MD patients	No information on cleaning R-R intervals and artefacts
Brunoni et al,^Citation162 2013	118 MD, 118 HC	ECG for 15 mins	RMSSD, HF, HRV indices	Use of antidepressants included,risk factors for CVD assessed	Patients displayed decreased HRV relative to controls; HRV scores did not change following treatment with either a non-pharmacological or pharmacological intervention, nor did HRV increase with clinical response to treatment	Reduced HRV could be a trait-marker for MD	All items on checklist met
Hage et al,^Citation163 2017	64 MD	15 mins of ECG at rest	RSA, LF-HRV, and heart period (HP)	Maintenance on mood stabilizer and/or atypical antipsychotic throughout the study; no information on cardiovascular risk	MD subjects had significantly higher baseline RSA and LF-HRV in comparison to subjects with bipolar disorder	Reduced vagal tone and higher levels of inflammatory biomarkers may distinguish bipolar disorder from MD	All items on checklist met
Kemp et al,^Citation164 2014	72 MD, 94 HC	2 mins of ECG at rest	SDNN, RMSSD, LF, HF,PCSD1	All participants medication free, no information on cardiovascular risk	MDD patients with melancholia displayed significantly increased heart rate and lower resting-state HRV	MD patients with melancholia display robust increases in heart rate and decreases in HRV	No information on ECG used, no information on R-R interval cleaning and artefacts
Boettger et al,^Citation165 2008	18 MD, 18 HC	24 hrs ECG	SDANN, SDNN, RMSSD, AIF curve, VLF, LF, HF, TP	Cardiovascular risk not mentioned/free from medication	Power law slope was significantly reduced in patients for all intervals investigated and correlated with symptom severity	Decreased complexity of cardiac regulation in depressed patients	No information to rule out psychiatric disease in controls
Ha J et al,^Citation166 2015	30 MD, 30 HC	5-mins ECG	SDNN,RMSSD, NN50, pNN50, VLF, LF, HF, TP	Free from medication, little information on cardiovascular risks	In MD significantly lower VLF, LF, HF and TP; significantly smaller standard deviation of the NN, root mean square of the differences of the successive NN, and NN50/total number of all NNs	Low HRV may be an important predictor of both MD and CVD in elderly	No information on R-R interval cleaning and artefacts
Schulz et al,^Citation167 2010	57 MD, 57 HC	30 mins ECG and BP	SDNN, RMSSD, pNN50, Shannon entropy,BRS, LF, HF, LF/HF	Free of medication, no details on cardiovascular risk	Non-medicated depressed patients reveal a significantly changed short-term as well as long-term complexity of cardiovascular regulation	There are substantial changes in autonomic control probably due to a change of interactions between different physiological control loops in MD	Little information on recruitment and demographics
Bär et al,^Citation168 2004	18 MD, 18 HC	5 mins ECG	HRA, VLF, LF, HF, RMSSD, PLR	Examined once medicated and treatment-naive as well as after full clinical recovery/no specification on cardiovascular risk	Treatment-naive MD patients differed significantly neither in heart rate parameters nor in parameters of the PLR from HC; after antidepressant treatment, parameters of heart rate analysis and PLR changed significantly and remained different after clinical recovery	The state of depression did not influence autonomic parameters significantly; treatment influenced autonomic function far more than the disease itself	All items on checklist met

Notes: Summary of ECG recordings, HRV measures, cardiovascular risk, treatment information and results are provided, in addition to their interpretation and adherence to the GRAPH checklist on the cohort.

Abbreviations: MD, major depression; HC, healthy control; BPII, bipolar disorder; UD, unipolar depression; BP, blood pressure; HR, heart rate; BS/BRS, baroreflex sensitivity; BEI, Baroreflex effectiveness Index; IBI, interbeat interval; SVB, sympathovagal balance; RSA, respiratory sinus arrhythmia; PCSD1, deviation of the Poincaré plot perpendicular to the line of identity; CVD, cardiovascular disease; HRA, heart rate assessment; CVC, cardiac vagal control; rTMS, repetitive transcranial magnetic stimulation; TCA, tricyclic antidepressant; PLR, pupillary light reflex; SVB, sympathovagal balance; AIF, autonomic information flow; PTSD, posttraumatic stress disorder; BPV, blood pressure variability; SDNN, standard deviation of NN-normal to normal R-R intervals; SDANN, standard deviation of the average NN-intervals; RMSSD (r/d), square root of the mean of the squares of the differences between adjacent NN intervals (resting/deep breathing); NN50, consecutive NN-intervals that differ by >50 ms; pNN50, proportion of consecutive R-R intervals that differ by more >ms; TP, total power; VLF, very low frequency power; LF, low frequency power; HF, high frequency power; LF/HF, low frequency to high frequency ratio.

Table 3 Shortened protocol for heart rate variability biofeedback training

Visit 1	First, the client is introduced to the basics of HRVB mechanism and technique. Especially for patients with psychiatric disorders, it is important to deliver a psychoeducation for the intervention. It increases compliance; adherence and comfort of the patient if he is prepared for the course of action. The operator should explain well the background of the method and follow the described regimen carefully. Furthermore, it is necessary to put the results of HRVB into perspectives, namely, that the individual with affect disorders may short-and long-term improve emotion self-regulation by practicing precisely and regularly the breathing technique. When the patient is equipped with the sensors, the appearing signals on the computer screen have to be defined for the subject. During the first (or second) visit, the optimal, resonant respiratory rate is determined. The patient ought to be informed briefly on the cardiorespiratory resonance phenomenon and the role of baroreflex in it. It can be helpful, if both thoracic and abdominal breathing sensors are attached, that allow the assessment of thoracic versus abdominal components in breathing. The determination of the optimal breathing frequency starts with paced breathing around the adult average value, 0.1 Hz – 5.5–6/min respiratory rate. The clients are coached to breath evenly and not too deeply for several minutes. The clinician detects patient’s well-being and observes the coherence between respiration and HRV. Lehrer et al provided a worksheet to be filled out at each respiratory frequency (6.5–6.0–5.5–5.0–4.5) and the combination of measures and characteristics to estimate the resonant frequency. Then, the patient is informed on his optimal breathing frequency. The resonant frequency may have to be retested during the second visit. Notably, the patient’s resonance frequency will change while practicing HRVB regularly. The first visit usually appears as stressor for the patients that can influence the resonant frequency. Biofeedback can be delivered during the first visit; however, most often it is part of the second or third visit. In the end of the first visit, there is homework for the patient. With the help of a watch or a custom-made computer program/mobile application, the patient is supposed to practice breathing at resonant frequency at home for 20 mins daily. It is important gain to draw the patients attention to the beneficial effects of HRVB when applying regularly and mastering it precisely. At any stage of HRVB training, give the patient the opportunity to ask.
Visit 2	Trainees practice abdominal breathing at resonant frequency and adjacent frequencies when needed, in order to clarify the optimal breathing frequency. Patients are instructed to maintain exhalation for a longer time period that inhalation duration. Also, the subject should exhale with pursed lips, which makes exhalation less effortful. The patients are asked to practice at home the extended methodology for breathing. They should be aware of the symptoms of hyperventilation and how to avoid it. Calm the patient if at any point of the learning curve he experiences stress.
Visit 3	Abdominal breathing is further practiced if the patient was unable to learn it. The most important event of the third session is usually the introduction of HRVB to the patients. After a brief training with paced breathing, the client is asked to use their cardiotachometer line displayed in front of them. The line represents their continually changing heart rate. Ideally, the monitor displays also the respiratory activity. The patient is then instructed to breathe in phase with the heart rate while maximizing HRV. As a homework, the subject has to practice resonance frequency breathing technique with abdominal, pursued lips breathing with a clock, computer breath pacer or mobile application as mentioned earlier, then practice with a home breathing trainer when available for 20 mins, two times daily. The goal would be to achieve the maximum in smoothness of the curve and the amplitude of HRV oscillations. For the evaluation of HRVB, the conventional HRV parameters are used. LF was found especially responsive to HRVB, probably due to triggered baroreflex.
Visit 4–5	During the last sessions, the review of the breathing technique, fine tuning of the resonant frequency, supervised practice of HRVB by the client takes place. The therapist should focus on reinforcing the HRVB home practices by emphasizing its clinical gains. Any concerns, questions, doubts of the patient should be addressed.

Notes: The table provides an exemplary protocol of HRV biofeedback training which has been applied in clinical practice and some research studies. However, no consensus exists on the optimal settings and protocol.

Abbreviations: HRV, heart rate variability; HRVB, heart rate variability biofeedback.

Table 4 Details of the studies investigating HRV biofeedback intervention in major depressive disorders

Study	N(f)	Subgroups	Age1	Dx and psychological measures	Comorbidity/medications	Excluded if:	Restrictions	HRVB protocol	HRV indices	Other highlights:	Findings
Karavidas et al. ^134	MD:11(7) No control group	None	45(10.8)	DSMIV, HAM-D, BDI-II	Anxiety, dysthymic disorder, on active treatment but only 3 maintained it during the study	Primary axis I or II diagnosis for other than major depression, report of current substance abuse, cognitive impairment, non-psychiatric medications, history of psychosis, mental deficiency, CKD, CHF, heart disease, HT, chronic low BP, cardiac arrhythmias.	None reported	Lehrer 2000 with home practices	SDNN, VLF, LF, HF, pNN50	None	Increases in SDNN, pNN50, LF, HF during sessions, returned back to baseline in the end of protocol, improved depression symptoms, no correlation between the two findings
Siepmann et al. ^135	MD:14(13)HC (24(12)	HC 12: active treatment HC 12 HRVB	MD and HC together: 28(7.3)	DSMIV, BDI, STAI major depression, bipolar disease, dysthymia, recurrent depressive disorder, moderate/mild depressive episode	No information on comorbidities, on medication(antidepressant, psychotherapy, anxiolytic medication)	History of psychosis, mental deficiency, CAD,CHF, CKD,HT, hypertension, chronic low BP, cardiac arrhythmia	Hx positive for alcoholism, regular caffeine	6 sessions in 2 weeks	pNN50, VLF, LF, HF, LF/HF	Vasoconstrictory response of cutaneous blood vessels (VR)	Baseline-during HRVB-follow up after 2 weeks reduced heart rate and pNN50 at follow-up, spectral HRV variables tended to improve, unchanged VR, BDI and STAI: reduced scores during HRVB and follow up
Caldwell et al. ^137	MD:20 (20); 10 (10)	MD: 10 HRVB + psychotherapy; 10 only psychotherapy(TAU)	Reported for subgroups: HRVB 20.09(1.81); TAU: 20.20(1.47); HC 20.64(1.29)	MINI, BDI-II	None reported	Age <18 or over 25 years, use of vasoactive drugs, CVD, alcohol or drug abuse, any physiological or neurological disorders, history of electroconvulsive therapy, had injury	Exercise, caffeine, tobacco 3 hrs prior testing	Lehrer 2013, home practices	SDNN, LF, HF, LF/HF	None	Post-treatment comparisons: HRVB group showed the greater decline in depressive symptoms, SDNN, HF and LF/HF showed significant changes, relation between SDNN and depressive symptom changes
Hartogs et al. ^136	MD:7(6) No control group	None	46.4(14)	DSMIV, BDI-II, daily diary,Happiness Index, Positive Outcome List (POL)	Avoidant and dependent personality traits, current medication for 3 patients	Neuropsychiatric disorder, personality disorder, substance dependence and mental retardation	None reported	HRVB Stress Relief Program: 30	None	Heart coherence	POL recovery in 2 patients, BDI-II and POL improvement in one patient, POL in one patient deteriorated

Abbreviations: N(f), number of patients (number of female patients in brackets); Age1, age expressed as mean ± standard deviation; MD, major depression; HC, healthy controls; BDI, Beck Depression Inventory; HAM-D, Hamilton Depression Rating Scale; CKD, chronic kidney disease; CHF, chronic heart failure; HT, hypertension; BP, blood pressure; POL, positive outcome measure; SDNN, standard deviation of normal to normal R-R intervals; pNN50, proportion of consecutive R-R intervals that differ by >50 ms; VLF, very low frequency power; LF, low frequency power; HF, high frequency power; LF/HF, low frequency to high frequency ratio; HRVB, heart rate variability biofeedback; STAI, state-trait anxiety inventory; CAD, coronary artery disease; Dx, diagnosis; Hx, history; TAU, therapy as usual; MINI, Mini-International Neuropsychiatric Interview.

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